Trends in the Diagnosis and Treatment of Syphilis

Trends in the Diagnosis and Treatment of Syphilis lVIEYER H. SLATKIN, lVLD., F.A.C.P.*

The remarkable effectiveness, the simplicity, speed and low cost of treatment of syphilis following the advent of penicillin has revolutionized the clinical management of the disease. Formerly, the syphilitic patient sought help at clinics or in a hospital; now the private physician shoulders most of the responsibility for diagnosing and treating syphilis. However, the diagnosis of syphilis in some cases may prove to be difficult. Great progress has been made in the serodiagnosis of syphilis following the introduction of the Treponema Pallidum Immobilization (TPI) Test and other tests using T. pallidum as the antigen. DIAGNOSIS

All persons suspected of having syphilis should have a thorough medical history, and careful and complete clinical examinations. Special diagnostic procedures including lumbar puncture, x-ray and fluoroscopy of the heart and great vessels, and specific tests for syphilis, such as the TPI, may be indicated. Blind treatment with penicillin is unfair to the patient. At the same time, every effort should be made in order to avoid misdiagnosing syphilis. Positive standard serologic tests for syphilis (STS) are diagnostic, if there is a clear-cut history of previous infection. On the other hand, the history relating to syphilis may be misleading by intention or otherwise, and in many instances there remains only the positive STS on which to base the diagnosis. It is very important to evaluate carefully a positive serologic test. When a history of syphilitic infection is not available, it is necessary to differentiate true from false positive serologic reactions. In these instances a TPI test should be done. The results may establish From the Department of Dermatology, College of Physicians and Surgeons, Columbia University, and the Dermatology Service, Presbyterian HospitaJ, New York, N.Y. * Assistant Clinical Professor of Dermatology, College of Physicians and Surgeons, Columbia University; Attending Dermatologist, Presbyterian Hospital

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the diagnosis of a biologically false positive serologic reaction and save the patient and physician a great deal of anxiety. Early Syphilis

Early syphilis includes primary and secondary syphilis. Early syphilis can be diagnosed by darkfield examination of the accessible skin or mucous membrane lesions and by examination of material taken by gland puncture. STS is negative during the incubation period and for the first weeks of primary syphilis (seronegative stage of primary syphilis). In this stage of syphilis, darkfield examination is the only method available for laboratory confirmation of syphilis. In primary and secondary syphilis, positive darkfield tests are conclusive and immediately establish the diagnosis. In the seropositive stage of primary syphilis and secondary syphilis, darkfield technique is an additional aid in the diagnosis. All genital, perianal and other suspicious skin lesions should be examined, and syphilis may be ruled out only after the appropriate serologic tests and repeated darkfield examinations of the serum from the lesion or associated glands have been done. Should the darkfield examinations be negative and the lesions still be suspicious, the patient should be questioned about having received local or systemic treponemicidal drugs. Any questionable case should be followed for approximately four months to rule out infection. The TPI and STS may be positive or negative in the primary stage, depending on the length of time the infection has been present. The STS usually becomes positive before the TPI test. The clinical manifestations of secondary syphilis are varied. The diagnosis is usually made on the basis of the appearance of the skin and mucous membrane lesions, darkfield examination and the results of the STS. The STS is positive at high titer in almost all patients whereas the TPI becomes positive more slowly and may be negative in approximately 10 to 15 per cent of cases. Latent and Late Syphilis

In latent syphilis the diagnosis is made only by means of positive STS and a past history of syphilis. There are no visible lesions, and the physical examination is normal. Complete laboratory examinations, including radiographs and spinal fluid tests, show no abnormalities. A positive serologic test may be the only evidence of infection. This is diagnostic when there is a clear-cut history of previous infection. In order to establish the final diagnosis of latent syphilis, and rule out the possibility of nonspecific reactions in those patients who cannot give an exact medical history of syphilis or who deny previous syphilitic infection, the TPI test should be done. The patient should also have a spinal fluid examination, including a complement fixation test for syphilis. If the spinal fluid is positive, the diagnosis is not late latent syphilis but asymptomatic neuro-

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syphilis. Approximately 25 per cent of untreated latent cases progress and give clinical manifestations later in life. Syphilis in its late symptomatic stages may involve the skin, mucous membranes, bones and viscera. At times the diagnosis may be difficult, and often a biopsy and x-ray examinations are needed in addition to the STS. The STS in cases of cardiovascular syphilis is helpful when positive. In 20 to 25 per cent of these cases, however, the STS is negative and in such instances the TPI test has proved to be very useful. The patients with neurosyphilis may be asymptomatic and the only evidence of the disease may be found in the cerebrospinal fluid. Increases in the cell count and in total protein measure the activity of the infection, and positive TPI and/or complement fixation tests in the cerebrospinal fluid confirm the diagnosis. Examination of the spinal fluid should be done at least once in every patient with a diagnosis of syphilis. A spinal fluid examination should be done 12 to 18 months after the diagnosis and treatment of early syphilis. Waiting this length of time will permit the temporary changes often seen in the spinal fluid in early syphilis to subside. In suspected latent, late symptomatic and neurosyphilis, spinal fluid examination should be done at once to determine the degree of involvement of the nervous system. In patients with symptomatic or asymptomatic syphilitic involvement of the central nervous system, repeated spinal fluid examinations are needed to follow the results of therapy. If the cerebrospinal fluid shows no evidence of syphilitic involvement two years after completion of adequate treatment for early syphilis, there is little likelihood that neurosyphilis will develop from that particular infection. Congenital Syphilis

An infant with early congenital syphilis may be very ill with signs of a severe generalized infection. The diagnosis is established in the same manner as for secondary syphilis. The diagnosis of congenital syphilis cannot be made solely on the basis of positive STS and/or TPI tests because passive transfer of antibodies from the mother to her noninfectious fetus may result in positive serologic tests in the infant for several months. Temporary positive serologic tests from the infant's or the cord blood do not by themselves indicate infection or that treatment is needed. Passive transfer of reagin may also occur if the mother is a biologically false positive reactor. In passive transfer, serial quantitative testing of the infant's serum will show gradual lowering of titers without treatment and the serum will become negative within the third month. Rising titers of the baby's STS and positive STS after three months are highly suspicious and usually indicate syphilitic infection. On the other hand, the congenitally infected infant may show no physical signs of syphilis. Serologic tests may remain negative or weakly

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reactive for several weeks to several months and then become strongly positive. Such a child must be regarded as an early latent syphilitic. LABORATORY TESTS FOR SYPHILIS Since the discovery of the T. pallidum by Schaudinn and Hoffman in 1905 and the introduction of the Wassermann test in the following year, laboratory examinations have been used to corroborate the clinical diagnosis of syphilis.

Reagin Tests In spite of technical improvements in recent years in the various routine tests such as Wassermann, Kahn, Kline, VDRL, etc., they still yield a certain proportion of results that are negative (noureactive) in the presence of syphilis (false negative), and others that are positive (reactive) in the absence of this disease (false positive). However, reliance is still placed largely on these routine serologic procedures and the proper interpretation of their results, although many new procedures such as the TPI, FTA and RPCF have been instituted. The information obtained with the standard serologic tests for syphilis (STS) in clinical syphilis is all that is usually necessary. It is true that they are not entirely specific for syphilitic antibodies, but they are highly accurate and have the advantage of being practical and widely available. All reagin tests are based on a reaction between a nonspecific antigen consisting of a lipoidal beef-heart extract, and an antibody in the syphilitic serum called reagin. Reagin is part of the gamma globulin fraction of serum. It is not a specific antibody and can appear in the blood of patients with diseases other than syphilis. Following the invasion of Treponema pallidum in the human host, multiple antibodies are formed to this organism, specific treponemal antibodies and reagin. The tests employing nontreponemal antigens are basically of two types, fiocculation and complement fixation. The commonly used flocculation tests are the Venereal Disease Research Laboratories (VDRL) slide test, the Mazzini cardiolipin test, the Kline cardiolipin test and the Kahn Standard test. The VDRL cardiolipin flocculation test has now become the standard test in most laboratories. It is reliable and usually suffices, if repeatedly reactive, to confirm the clinical diagnosis of syphilis. The most commonly used complement fixation tests is the Kolmer, which employs a cardiolipin lecithin antigen. SPl!]CIAL REAGIN Tl!]s'fs. In recent years, several reagin tests have been developed for special circumstances, as when economic rapid screening of a large number of persons is desired. 1. Rapid Plasma Reagin Test (RPR), 1957. The antigen suspension used in this test is derived from the basic VDRL antigen containing cardiolipin, lecithin and cholesterol.1 8 This test eliminates the necessity for inactivating the serum by

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heating. It is a rapid, on-the-spot serologic test for syphilis completed in minutes, and can be used under field conditions with a mobile laboratory. It is reported to have a high sensitivity and a specificity equivalent of the conventional serologic tests. 2. Plasmacrit Test, 1962. Plasma which is usually discarded after microhematocrit determination is used for serologic testing.1 The test is an extension of the principles of the RPR and a similar method is used. 3. Unheated Serum Reagin Test (USR), 1961. Unheated serum is used for testing. It eliminates the water bath and saves time normally used to inactivate the serum required in the VDRL test. 16 4. RPR Card Test, 1962. This test uses the Brewer Plasma Collection Card and a modified RPR antigen.J7 In testing, three drops of blood from a finger prick are used. The test requires no test tubes, microscope or centrifuge. Comparison of this test with standard reagin test has shown excellent correlation. It was developed to provide a test which could be carried out in the field or at the bedside, without the need for any specialized laboratory equipment. It permits the use of unheated serum or plasma and offers a reproducible and rapidly performed qualitative test procedure.

INTERPRETATION OF TEST RESULTS. The STS in use at the present time enables the physician to detect syphilitic infection with a relatively high degree of accuracy. These tests measure the presence of Wassermann antibody or reagin developed in the blood, and sometimes in the spinal fluid, during the course of infection. Reagin is not a specific antibody. All standard serologic tests for syphilis, regardless of type, are therefore nonspecific. The more experience one has with the management of syphilis, the more wary one becomes of the validity of the diagnosis when it is based only on the results of the STS. Difficulties in interpretation of the tests are due to their inherent nonspecificity, as well as to quantitative and qualitative variability. The results of the STS should be evaluated in combination with the general examination for syphilis. The problem of positive serologic tests for syphilis in a patient without history or clinical evidence of the disease has been aggravated by the fact that many people are treated with antibiotics which have antisyphilitic effects even though not given for this purpose. This is true of penicillin, the tetracyclines, erythromycin and chloramphenicol. The intake of the antibiotics may mask the classic signs of the disease, and the syphilitic patient who has received subtherapeutic doses of antibiotics may be misdiagnosed as a biologic false positive reactor. A negative STS may occur in association with positive darkfield lesions and with stigmata of congenital infection including active interstitial keratitis, neurosyphilis and cardiovascular syphilis. All negative STS should be repeated if clinical suspicion warrants it and the TPI test should be used if there is any question about the diagnosis. A positive STS is often of high diagnostic value. If a person has had a single unconfirmed positive STS, the test should be repeated and a careful clinical evaluation should be made. In absence of clinical signs of syphilis, a positive test may be the only means for discovering latent,

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congenital, visceral, early cardiovascular and other forms of syphilis. The STS is strongly positive in asymptomatic neurosyphilis, osseous syphilis and visceral syphilis. Usually the STS is strongly positive for about a period of six months, beginning approximately three weeks after the appearance of the chancre. Maximum reactivity is reached during the second stage of the disease, when the test is 100 per cent positive. From then on the incidence of positive results in the blood gradually declines. Some of the gravest forms of syphilis, e.g., advanced cardiovascular syphilis, may show negative STS. Formerly in most serologic laboratories it was the practice to supplement flocculation tests with complement fixation reactions. The results of these tests did not always agree. Some variations in the results of STS are also common when the serum is tested in two different laboratories by identical methods. This is particularly true of weakly reactive specimens. This variability of weakly positive serologic reactions is largely technical in nature and should be understood by all physicians. There is no single STS or battery of such tests that will completely exclude syphilitic infection. In fact, using the TPI reaction, we have been unable to find evidence that anyone of the various STS presently in use is more valuable than others for the diagnosis of syphilis. The treatment of syphilis has the general effect of changing the STS results from positive to negative. The degree to which it does depends on several factors, including the amount and kind of treatment, the character of the infection, and the duration of the disease prior to treatment. The reversal of positive serologic reactions to negative occurs most frequently when treatment is instituted in the early stages of infection; it becomes increasingly difficult when the disease is of longer duration. Serologic test results that do not become negative after adequate treatment are spoken of as "fixed" or "irreversible." If the serologic reactions remain positive in high titer after adequate antisyphilitic treatment, it is important to ascertain whether there are underlying cardiovascular or neurosyphilitic complications that may not have been recognized. Quantitative tests are very helpful because they establish a standard of reactivity from which changes can be measured. They should be performed when the patient is first seen so that a serologic baseline is established. Response to treatment may result in a fall in the titer. Reactivation of the disease is shown by a rising titer. A one- or two-tube variation in quantitative titer is not significant. Treponemal Tests

The limitations of the reagin tests have provided an impetus for the development of serologic tests specific for syphilis. During the past 15 years numerous tests have been developed with antigens derived from the etiologic agent of the disease, T. pallidum. The aim is specific serologic

TRENDS IN THE DIAGNOSIS AND TREA'l'MENT OF SYPHILIS

829 testing for syphilis. Some of these tests are of proven clinical value and are of indispensable help to the physician. Others are of academic and research interest only. Treponemal testing such as the Treponemal Immobilization (TPI) test has its greatest value when the routine STS cannot give the solution. They help to distinguish between biologic false positive and true positive reagin tests for syphilis. They help to establish a correct diagnosis in patients who have clinical evidence of syphilis, particularly late syphilis, but who give nonreactive blood and spinal fluid reagin tests. They assist in the diagnosis in patients who epidemiologically should have the disease, but who have negative clinical and serologic evidence. The treponemal tests are mainly used as verification tests in problem cases and supplement but do not replace the STS. The treponemal tests are indispensable tools in the diagnosis of syphilis. Of all the new tests, the Treponemal Immobilization test, which was first described in 1949, is still the standard test. It has great specificity. It is, however, difficult to perform. The laboratory performing the test must maintain a rabbit colony for the ready source of living treponemes. Highly trained and skilled technicians are necessary to assure proper reproducibility of the test. Because of the difficulty of the technical procedure and cost involved, few laboratories have adopted this test. THE TREPONEMAL IMMOBILIZATION TEST (TPI), 1949. In 1949 Nelson and Mayer developed the TPI test for the specific diagnosis of syphilis using live virulent treponemes. 15 This test is based on the demonstration of the presence of a specific antibody in the sera of syphilitic persons. The antibody is distinct from the Wassermann type antibody and has the specific ability to immobilize in vitro virulent T. pallidum. This immobilizing antibody is present in human sera shortly after the onset of syphilitic infection. It is associated with the globulin fraction of the serum, requires complement for its action, is relatively heat stable, and is apparently treponemicidal. In syphilitic patients, the TPI antibody develops slowly during the early stages of the disease; thereafter, the percentage of positive immobilization result increases during the infection. The TPI antibody does not appear in the sera of healthy individuals, or in persons with other diseases except yaws, pinta and bejel. In essence, the TPI test is based upon the fact that, in the presence of active complement, the motile treponemes obtained from rabbits' testicular syphilomas are immobilized if demonstrable amounts of the antibody are present in a patient's blood or spinal fluid. The treponemes immobilized as compared to controls are counted under darkfield illumination, with the percentage results based on this count. The differentiation of positive and negative tests is usually quite clear-cut. Nonspecific immobilization may occur if penicillin or other treponemicidal agents are present in the serum, or if the specimen has been collected in tubes that are not chemically clean. The TPI reaction, at the present time is the best available test of syphilis. The specificity of the test is high, approaching 98 to 99 per

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centY· 12 There are, however, certain limitations which must be kept in mind in order to interpret properly the results. Treponemal immobilizing antibody appears in the serum during the primary and secondary stages of syphilitic infection but later than reagin. Although the STS results are positive for 100 per cent of patients with secondary syphilis, Magnuson and Thompson 9 encountered negative results of TPI tests in 13.8 per cent of their patients with secondary syphilis. Therefore, in regard to primary and secondary syphilis, the TPI test offers no advantage over the existing diagnostic methods and may even have less to offer than routine procedures. If prompt and adequate treatment is not given in the early stages of the disease, the TPI antibody, once it appears, apparently persists indefinitely in the patient's serum. This is contrary to the spontaneous decline, over years, in the Wassermann type reagin, seen in a large number of untreated syphilitic persons. If adequate penicillin treatment is given for early syphilis the TPI test may never become positive, or if it does the level of immobilizing antibody will decline significantly over a period of months, and may become negative with the passage of time. In a patient with latent or late syphilis in whom the TPI antibody has had an opportunity to develop sufficiently, no significant decline in immobilizing antibody can be expected, no matter how much antisyphilitic treatment is given. On the basis of current evidence it appears likely that the immobilizing antibody will continue to be present during the remainder of such a patient's life. Thus, as valuable as it is as a diagnostic procedure, the TPI test cannot be used as a guide to the adequacy of treatment. The TPI test with spinal fluid is also of value as a diagnostic test for neurosyphilis, although Miller l3 found negative reactions in 14 of 100 undoubted cases of neurosyphilis. A negative TPI test in spinal fluid, therefore, does not exclude the diagnosis of neurosyphilis. Positive results in spinal fluid, however, have not been found except in the presence of other convincing evidence of neurosyphilis. Thus a TPI test with spinal fluid, when it is positive, is diagnostic of past or present neurosyphilis, even in patients in whom the spinal fluid complement fixation test has become normal as a result of effective treatment or the passage of time. The TPI antibody, like reagin, also passes the placental barrier, but in contrast to reagin, it persists in the blood of an infant up to seven months of age or even longer. In such cases the TPI reaction apparently does not become negative until the Wassermann-type reagin has disappeared. Congenitally syphilitic children, adequately treated shortly after birth, regularly show negative TPI reactions when tested many years later. However, if no treatment is given until the late manifestations of congenital syphilis become apparent, then the TPI test remains positive as it does in acquired and latent syphilis. The introduction of the TPI test has forced us to change our entire concept of the significance of even the weakly positive STS in the absence of signs of syphilis. We have known numerous patients who gave weakly

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positive reactions to Mazzini tests and negative reactions to all other routine serologic tests, who on further study showed a positive reaction to the TPI test and then admitted to having had syphilis. Conversely, other patients with positive Kolmer reactions proved to have negative TPI reactions and no evidence of past or present syphilis. Moreover, the titer of STS apparently does not necessarily have the significance formerly attributed to it, since some of our patients now considered to be biologic false positive (BFP) reactors had high STS titers. Evidence accumulated during the past 15 years at the Columbia Presbyterian Medical Center has reaffirmed the usefulness of the TPI reaction in establishing the diagnosis of either syphilis or BFP reaction. Our serologic laboratory under the direction of Dr. J. Lowry Miller has performed many TPI tests. On the basis of a large amount of evidence which shows a very close correlation between the results of the TPI test and clinical diagnosis, we believe that this reaction is the most accurate laboratory procedure available at this time for diagnosis of syphilis. The greater our experience with the TPI test, the more we have learned to depend on it for help in diagnosing lues, particularly in the more complicated and difficult cases, and often after all other diagnostic procedures have been exhausted. The TPI test has been particularly helpful in our management of pregnant women with reactive STS and with no signs or symptoms of syphilis. At the present time we have come to regard patients who show repeated positive TPI tests, done in our laboratory, as having had syphilis. The TPI test has proved to be of greatest value in helping to distinguish between biologic false positive and true positive reagin tests (STS) for syphilis. It helps to establish a correct diagnosis in patients who have clinical evidence of syphilis, particularly late syphilis, who have negative STS in the blood and spinal fluid. It assists in the diagnosis in patients with negative STS such as a marital partner or a mother who is seronegative and has given birth to a congenital syphilitic child. It also helps to establish a correct diagnosis in patients who have clinical evidence of syphilis, particularly late syphilis, when there is a negative STS in the blood and in the spinal fluid as may occur in cardiovascular or central nervous system syphilis. OTHER TREPONEMAL TESTS. In contrast to living virulent T. pallidum which is necessary for the TPI test, several new tests have been developed which utilize killed pathogenic T. pallidum, or extracts of these. An antigen prepared from the cultured avirulent Reiter strain is also being used. Because these procedures do not require living T. pallidum as antigen, the latter may be prepared in relatively large quantities and stored economically for use as needed. These tests are not as time-consuming as the TPI procedure and the presence of penicillin or other treponemicidal agents in the specimen to be tested does not interfere with the reaction. The more promising tests which have had extensive evaluation and application after

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the TPI are the Fluorescent Treponemal Antibody (FT A) test and the Reiter Protein Complement Fixation (RPCF) test. The treponemal antigen tests are listed below in accordance with Garson's classification based on certain characteristics of the antigen used in the test procedures: 8 1. Tests using whole-body virulent Treponema pallidum (Nichols' strain) as antigen.

A. Tests using viable organisms: 1. Treponema Pallidum Immobilization (1949) 2. Treponema Pallidum Methylene Blue (1956) B. Tests using, or usually using, nonviable organisms: 1. Treponema Pallidum Agglutination (1953) 2. Treponema Pallidum Immune Adherence (1953) 3. Whole-body Treponema Pallidum Complement Fixation Test (1956) 4. Fluorescent Treponemal Antibody Test (1957) n. Tests using a chemical fraction derived from whole-body virulent Treponema pallidum (Nichols' strain) as antigen: A. Treponema Pallidum Complement Fixation (1955) B. Treponemal Wassermann Reaction (1957) C. Treponema Pallidum Cryolysis Protein (1958) Ill. Tests using a chemical fraction derived from whole body Reiter treponeme as antigen: A. Reiter Protein Complement Fixation (1957) B. Kolmer Test with Reiter Protein Antigen (1958)

REITER PROTEIN COMPLEMENT FIXATION TEST (RPCF). This test utilizes as antigen a protein fraction derived from the avirulent Reiter strain of treponemes. 8 The Reiter strain of nonpathogenic treponemes has been cultivated on artificial media since 1922. In contrast, no one has as yet succeeded in maintaining the growth of virulent T. pallidum in this way. The Reiter treponemes, however, share a common group antigen with T. pallid urn. D' Allesandro and Dardanoni have shown that protein extracts from nonpathogenic Reiter organisms are antigenic and capable of reacting with syphilitic sera. 7 This is the basis of the RPCF test. The antigen is in the form of a dry stable powder that can be easily, quickly and inexpensively reconstructed by a skilled technician when needed. The test is in essence a complement fixation test based on the Kolmer complement fixation procedure. The RPCF procedure apparently depends on an antibody which differs from that involved in the TPI test and other treponemal reactions described above. The antibody prepared against Reiter protein does not immobilize T. pallidum in the presence of complement. The RPCF test has demonstrated higher sensitivity and specificity than the standard Wassermann complement fixation tests in the diagnosis of syphilis. It is realized, however, that the test does not serve as a satisfactory substitute for the TPI test. The RPCF is less sensitive than the TPI test, especially when it is used in interpretive results in syphilis of long duration. When doubt exists in the VDRL results, most local public health laboratories are equipped to do treponemal tests such as the RPCF or the TPCF. Carpenter, Miller and Boak suggest the use of a triple test plan for those cases that cannot be diagnosed by the routine STS.4 The VDRL

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slide fiocculation test is carried out on all serum samples as a screening procedure. If the results of the test on the serum of a patient with no history or clinical manifestation of syphilis is nonreactive, it indicates absence of syphilis. If the serum tested is positive or weakly positive then the serum is tested with the RPCF test. A corroborative reactive or weakly reactive RPCF is considered evidence of past or present infection of syphilis. If however, the RPCF is nonreactive and does not corroborate the positive or weakly positive VDRL, then the Treponemal Immobilization test is required. A positive TPI test indicates present or past syphilitic infection. A negative TPI test indicates a biologic false positive reaction. The TPI test is used as the confirmatory procedure on serum nonreactive in the RPCF test. TREATMENT Penicillin

Penicillin is now the drug of choice in the treatment of syphilis in all its stages. There is no indication for the use of heavy metals, nor is there any advantage in combining penicillin with heavy metals regardless of the stage of infection. Penicillin has never lost its efficacy against T. pallidum. The therapeutic effect of penicillin in repeated courses is as great as that observed in the initial course. It is effective, relatively free from important side effects, it is inexpensive and permits patients to complete their treatment schedules conveniently. T. pallidum is one of the most sensitive of all micro-organisms to penicillin, but its destruction requires longer exposure to the antibiotic than is true of other organisms. In the treatment of syphilis it is important not only to be sure that the total dosage is adequate, but also that the duration of treatment is sufficiently prolonged for that stage of infection. Time is an important factor in the treatment of syphilis. Since 1943, when penicillin was first introduced by Mahoneylo for the treatment of syphilis, greatly improved preparations have become available. Main reliance is still placed on the use of long-acting repository preparations. These are slowly absorbed and permit adequate treatment on an ambulatory basis. Three different types of penicillin preparations are being used. Procaine penicillin G in aqueous suspension is used only on occasion. This preparation is given intramuscularly 600,000 units daily or 900,000 units every other day. The recommended dosage in early syphilis is ten daily intramuscular injections of 600,000 units each. In an effort to reduce further the already small number of injections required and further simplify treatment of syphilis, a new repository penicillin has been developed. This is benzyl amine penicillin salt or benzathine penicillt·n G. Single intramuscular injections of 2.4 million units

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of this preparation are said to give effective blood levels which last for as long as two weeks with good therapeutic results. 19 Benzathine penicillin G is injected intramuscularly once a week, with a total dose of each injection of 2,400,000 units distributed in two sites, usually 1.2 million units into each buttock. This preparation is used mainly when the patient can return for treatment only once weekly or is not likely to return. Some recommend one injection or two injections at an interval of one week in early syphilis, two injections at an interval of one week in late syphilis. In neurosyphilis dosage is increased to 6 to 9 million units. Procaine penicillin G in oil containing 2 per cent aluminum monostearate (P AM) has thus far proved to be the most suitable preparation for the treatment of syphilis in all its forms. We have used this slowly absorbed penicillin exclusively in the Presbyterian Hospital during the past 15 years. P AM gives effective and prolonged concentrations of penicillin in the blood serum with infrequent injections. One injection of 900,000 units of P AM maintains an effective blood level in most patients for about four days. Our schedules provide for injections of 900,000 units (3 ml.) of P AM intramuscularly twice weekly until the desired total dosage has been reached. It is well known that, in order to destroy T. pallidum, high concentrations of penicillin are not necessary. Therefore PAM, which maintains a low penicillin concentration over a long period of time, is very useful. This has added advantage since the longer it takes to administer a given total dosage of penicillin in the treatment of syphilis, the more effective is the therapy. Penicillin by mouth is generally regarded as unsatisfactory in the treatment of syphilis, because it is impossible to be certain that outpatients will take the medication regularly or that its absorption from the gastrointestinal tract will be sufficient to maintain adequate blood levels. In the treatment of this disease we are primarily concerned with obtaining a cure and not with measuring the minimal effective amounts of penicillin required in each case. Therefore, we aim to administer more than the absolute minimum amounts of penicillin needed. We are inclined to overtreat rather than risk undertreating a serious chronic disease such as syphilis which has the ability to lie dormant in the body for long periods of time. This attitude is reflected in our schedules. Table 1 gives the schedule in use for the treatment of syphilitic patients at the Columbia-Presbyterian Medical Center. PAM is used in a dosage of 900,000 units (3 m!.) intramuscularly twice weekly on an ambulatory basis. The total amount of penicillin to be given depends on the stage of infection. In early syphilis serologic and clinical cures are rapidly achieved. The easiest form of syphilis to cure is primary syphilis before the STS has become positive (seronegative chancre stage). In seropositive primary and in secondary syphilis larger amounts of penicillin and longer treatment are required. For all practical purposes, however, 7.2 million units of PAM given over a period of four weeks will suffice for all patients

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Table 1.

Schedule for the Treatment of Syphilitic Patients in Use at the Columbia-Presbyterian Medical Center

TYPE OF SYPHILIS

NUMBER OF INJECTIONS

Primary and secondary. . . . . . . . .. Early latent ................... , Late latent. " ................. , Cardiovascular ................ , Asymptomatic neurosyphilis. . . .. Syphilitic meningitis ........... , Tabes dorsalis ................. ' Meningovascular .............. ' Paresis ....................... , Primary optic atrophy .......... , Interstitial keratitis ............ , Congenital: 2 months to 2 years .......... ,

DUHATION OF TRI<]ATMENT

(weeks)

4 5 8 9

8 10 16 18 18 18 20 24 28 28 28

9 10 12 14 14 14

10

5

2 to 5 years .................. 10

5

9

TOTAL DOSAGE (PIWCAINE PENICILLIN G CONTAINING 2 PER CENT ALUMINUM MONOSTEARATE)

(millions of units)

7.2

9.0 14.4 16.2 16.2 16.2 18.0 21.6 25.2 25.2 25.2

15,000 units per lb. body weight twice weekly 6 million (600,000 units twice weekly)

with early syphilis. The treatment we give for latent syphilis is more prolonged and requires a larger dosage of penicillin than that for early syphilis. Nine to 14.4 million units of PAM administered in the course of five to eight weeks is our usual schedule. It may appear that the dosage indicated in our schedule is "more than adequate." This may be true. But our experience during the past 15 years using this same schedule in treating a large number of patients with syphilis including neurosyphilis and syphilis in pregnancy has been excellent. We have therefore been reluctant to change our schedules and to reduce the treatment to minimum dosage. Re-treatment even in patients with neurosyphilis has been unnecessary in almost all cases. Large doses over prolonged periods of time are especially recommended for the treatment of neurosyphilis. We have also made it a rule not to discharge any treated syphilitic patients but to follow their progress as long as possible. Table 2 gives the schedule for the treatment of syphilitic patients as recommended by the United States Public Health Service in Public Health Service Publication No. 743-1960. SOME RECENT CONCLUSIONS. Collart and his colleagues reported finding treponemes resembling T. pallidum of little or no virulence in the lymph nodes of both man and animals with longstanding syphilis years after treatment with large doses of penicillin and penicillin with arsenicals.6 • 6 These reports have raised much interest. 20 Conventional serum tests for syphilis (STS) were negative, but the TPI tests were positive.

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Treatment Dj Patients with Syphilis

(Recommended by the United States Public Health Service)

TYPE OF SYPHILIS

Primary and secondary

PAM

BENZATHINE PENICILLIN G

4.8 million units total, usually 2.4 million units total, 1.2 million units in given 2.4 million units at first session and 1.2 million each buttock, by inunits at each of two subsetramuscular injecquent injections 3 days tion apart

Latent syphilis: If spinal fluid examination is nonreactive

4.8 million units total, usually 2.4 million units total, 1.2 million units in given 2.4 million units at first session and 1.2 million each buttock, by inunits at each of two subtramuscular injecquent injections 3 days tion apart If no spinal fluid examina4.8 million units total, tion is done, treatment given 2.4 million must encompass the posunits, 1.2 in each buttock each session, sibility of asymptomatic at 7-day intervals neurosyphilis Asymptomatic neurosyphilis ) 6.0 to 9.0 million units total, 6.0 to 9.0 million units total, given 3.0 milgiven 1.2 million units at Symptomatic neurosyphilis 3-day intervals lion units at 7-day Cardiovascular Late benign syphilis intervals Congenital: Early congenital (under 2 Total dosage of 100,000 units 50,000 units per kg. of body weight. Total per kg. of body weight. May years' duration) dose administered as be given in divided doses at 2- or 3-day intervals a single intramuscular injection Late congenital (over 2 If spinal fluid is nonreactive, years' duration) treat as latent syphilis. If spinal fluid is reactive, treat as neurosyphilis

Their overall results have led Collart and his co-workers to the following conclusions: The organism is T. pallidum and these treponemes appear to preserve their vitality. In the majority of cases, they appeared to have lost all or part of their virulence and existed in the tissue as commensal organisms. They also concluded that penicillin treatment if given late in the disease is unable to eradicate all the treponemes which have been present in the organism for a long period of time, and that the persistence of treponemes in the tissue provided an explanation of the continued presence of immobilizing antibodies after treatment. Also, they concluded that cortisone can sometimes reactivate latent syphilis in rabbits. These are unexpected conclusions in view of the excellent practical results of penicillin in the treatment of the treponematoses. Confirmation of Collart's discovery would have a profound effect on our ideas of diagnosis, course and treatment of syphilis.

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Treatment Results and Post-treatment Observation After completion of treatment the patient should have adequate physical examinations and quantitative STS at regular intervals. Patients treated for early syphilis should be examined every two weeks for the first three months and then at monthly intervals for the remainder of the first post-treatment year. The serologic titer usually falls to low levels within the first six months after treatment and the STS is expected to become negative in approximately six to twelve months. Low titers persisting longer than expected, however, are not indications for re-treatment. In some patients the STS remains weakly positive for two to three years before becoming negative. If, however, there is a sustained rise in titer from previous levels (serorelapse) or if infectious lesions appear, re-treatment should be given immediately. The serologic relapse usually appears before the clinical relapse. Children with congenital syphilis must be observed for several years after the completion of antisyphilitic therapy. Titered STS is made at monthly intervals for the first year, and then every three months for three years. The STS, in cases of congenital syphilis adequately treated before six months of age, will usually become negative within one year. The probability of persistently positive STS increases as the time before treatment is prolonged. If congenital syphilis is not treated until after the second year, the syphilitic child usually will develop seroresistance. In early latent syphilis, the titer of the STS falls progressively after adequate treatment and it becomes negative in approximately one year. Sometimes the STS remains weakly positive, but this should cause no concern unless there is evidence of relapse. In the late latent and late symptomatic forms of syphilis the STS is routinely made at intervals of at least once a month during the first year following treatment and then at less frequent intervals, i.e., every three to six months. Patients with late syphilis who are treated with penicillin continue to have positive STS for years after adequate therapy. The primary aims of treatment of persons with late syphilis are the cure of the infection and the prevention of further progression of the disease, not seronegativity. Reagin continues to be found in the blood stream and sometimes in the cerebrospinal fluid long after the infection is arrested. Many patients show some fluctuations in the STS titers during the years following treatment for late syphilis. The re-treatment of previously adequately treated late latent or late symptomatic syphilitic persons solely for a persistently positive or fluctuating low titer STS is unnecessary and not recommended. Attempts to produce a seronegativity in these patients by further treatment are usually futule. In other words, the physician should treat the patient, not the blood test. If, however, a sudden and sustained rise in the STS titer occurs after adequate therapy and a previous satisfactory serologic response, it may signify a serologic relapse and be the precursor of a clinical relapse. It may also indicate reinfection. In either case, immediate re-treatment is

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instituted. To be significant, the rise in serologic titer must be progressive and sustained, and it must be greater than a fourfold (two serial dilution) increase from previous baseline levels. Alternate Antibiotics In the event the patient cannot receive penicillin because of an allergic background or when there is a history or evidence of penicillin sensitivity, the broadspectrum antibiotics can be substituted. They have been found to be effective in the treatment of syphilis, particularly in the early stages of infection. Among the broad-spectrum antibiotics available and with known potency in respect to syphilis are oxytetracycline hydrochloride (Terramycin), chlortetracycline hydrochloride (Aureomycin), chloramphenicol (Chloromycetin) and erythromycin stearate (Erythrocin). There has also been limited experience in early syphilis with novobiocin calcium (Cathomycin) and Synnematin B. Erythromycin and the tetracyclines are considered the best of these drugs. The recommended dosage is a total of 20 to 30 gm. of erythromycin or 30 to 40 gm. of tetracycline administered orally in four divided daily doses for a period of ten to fifteen days. The dosage schedules for the broad-spectrum antibiotics have not been established to the extent that penicillin schedules have. When prescribing alternate antibiotics, the patient should be closely supervised during the course of treatment and followed carefully at regular intervals after treatment. At the present time, the broad-spectrum antibiotics cannot be regarded as equal substitutes for penicillin in the management of syphilis.

Syphilis in Pregnancy

Syphilis in pregnancy presents all the problems of diagnosis of syphilis, in addition to the problems of pregnancy. Often pregnancy occurs during the latent stages of syphilis and no skin lesions are present. In many instances the history of syphilitic infection is difficult to obtain or is unreliable. It is very important to evaluate carefully a positive STS. Congenital syphilis in this era is preventable in almost every instance. Routine premarital and prenatal blood testing is most important. Prenatal blood tests should be made not only at the beginning but at regular intervals during pregnancy. The earlier in pregnancy the diagnosis of syphilis is established and penicillin started, the better the prognosis for the pregnant woman and the fetus. The evidence is that syphilitic infection of the fetus does not take place before the fifth month of intrauterine life. The aim is to cure the infected mother before the fifth month of pregnancy in order to avoid intrauterine infection of the fetus. Abortion during the early months of pregnancy is usually not due to syphilis and other causes should be sought. Sometimes pregnancy may produce special problems in the management of syphilis. The treatment of syphilis in pregnancy is the same as for any syphilitic person. It is never too late to start treatment and good results may be obtained even when treatment is given as late as the last weeks or days before delivery. However, when the diagnosis is made close to term, daily injections of 600,000 units of crystalline procaine penicillin G in aqueous suspension is given for a total dose of 9,000,000 units in 15 days. If the

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839

patient delivers before the treatment is completed, the injections are continued postpartum and the infant and mother are carefully followed clinically and serologically for evidence of syphilitic infection. Penicillin given early in pregnancy will prevent infection of the fetus. It will also cure syphilis if the infection has been contracted by the fetus in utero. Infants born with congenital syphilis respond to penicillin as do adults with secondary syphilis. Penicillin is well tolerated by infants and the cure rate is high when adequate treatment is given. Dosage may be based on body weight and 15,000 units of PAM per pound, given twice weekly for five weeks, will be sufficient. The accumulated evidence shows that it is not necessary to give penicillin treatment during each pregnancy, if the patient has had at least one adequate course of treatment. To establish the adequacy of previous antiluetic therapy, data regarding the kind of treatment, amount given, length of time in days under active treatment, duration of follow-up observation, and the serologic results, must be obtained. Pregnant women previously treated for syphilis should have regular clinical examination and quantitative STS at monthly intervals throughout pregnancy. If there is any question at all about the adequacy of the previous treatment or the possibility of an active syphilitic infection, re-treatment should be started at once. FALSE POSITIVE BIOLOGIC REACTION

Positive standard tests for syphilis such as VDRL and Kolmer generally indicate present or past syphilitic infection. In many instances, however, a positive STS is the expression of a nonspecific biologic phenomenon that can be induced by a variety of diseases. These reactions are known as biologically false positive (BFP) serologic reactions. The decline in the number of persons with syphilis following the use of penicillin has been associated with an increase in the proportion of BFP reactions. Routine serologic testing for syphilis has now assumed added importance, if only because it detects a number of individuals with BFP reactions who may have other serious and hitherto unrecognized systemic disease. In series of probable BFP reactions studied, approximately 50 per cent of the patients ultimately proved to have syphilis, and about 50 per cent of patients with suspected latent syphilis are found to have biologic false positive reactions when tested by the TPI test. The TPI test finds its greatest value in this group. The BFP reactions may be classified as temporary (acute) or persistent (chronic). The acute BFP reaction may occur in a variety of bacterial, viral, plasmodial, protozoal and rickettsial diseases. It may be associated with mild upper respiratory infections, infectious mononucleosis, recent vaccination for smallpox, etc. In fact, any recent febrile illness or

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immunization procedure is a potential cause of false positive STS. The BFP is most frequently encountered between the ages of 21 to 30 years and is twice as common among females as among males. In these infections it clears spontaneously and the STS of these patients gradually becomes normal within two to six months. This form of BFP reaction may be studied and recognized by means of a series of titered STS. The diagnosis of syphilis can therefore be ruled out by waiting until the STS titer falls to negative. In pregnancy, since speed in diagnosis is essential, a TPI test should be made immediately in order to rule out an acute BFP reaction. Persistent (chronic) biologically false positive STS may occur in lupus erythematosus, leprosy, malaria and other diseases. More often, however, the precipitating cause of the reaction cannot be found. A false positive reaction to STS may persist for years and even for life. Patients in this group present by far the most difficult problem in diagnosis. Moore and Mohr indicate that the BFP reaction is often not innocuous in its implications and may represent an early sign of a serious underlying disease such as systemic lupus erythematosus, periarteritis nodosa, rheumatoid arthritis and rheumatic fever. 14 The BFP reaction is most frequently seen in systemic lupus erythematosus. Most of the patients with lupus erythematosus who have been discovered in this way have been young women and many have had false positive STS for years before clinical signs of their disease became manifest. Patients with repeatedly positive serological tests for syphilis who have no clinical evidence or history of syphilis or other treponematoses should be carefully investigated. A TPI test is indicated and examination of the spinal fluid should be considered. Repeated negative TPI tests performed in a reliable laboratory constitute evidence that the reaction is not due to syphilis and establishes the diagnosis of BFP reaction. Once the diagnosis of BFP reaction is made, a special investigation should be undertaken to determine the possible causes. It is questionable whether pregnancy, in itself, may cause temporary biologically false positive STS. Biologically false positive reactions have occurred in women during pregnancy, just as in other persons. Boak's study points to the possibility that pregnancy may be the sole cause of a false positive STS but this is still controversial and more data will be needed before its general acceptance. 2 SUMMARY

Despite certain limitations, the physician has at the present time the tools needed for proper diagnosis and management of the overwhelming majority of patients with syphilis. The laboratory diagnosis of syphilis has been greatly simplified so that batteries of tests and sending samples of the same blood to various laboratories are seldom required. The extensive research in the serology of syphilis during the last decade has resulted in

TRENDS IN THE DIAGNOSIS AND TREATMENT OF SYPHILIS

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the development of a multiplicity of tests, many of which have had limited practical use. It is essential that only adequately tested procedures that yield dependable results are used. The discovery and development of the Treponema Pallidum Immobilization (TPI) test has made available to the physician the most effective procedure for differentiating persons with biologic false-positive reactions from patients infected with T. pallidum. The complexities involved in the technical performance of the TPI test have resulted in a search for simpler, more economic procedures that have comparable sensitivity and specmcity and could be adapted for routine use in clinical and public health laboratories. The Fluorescent Treponemal Antibody (FTA) test possesses a high degree of specmcity and has shown excellent correlation with the TPI results. This procedure gives promise that it might serve as a possible substitute for the TPI in the future. The Reiter Protein Complement Fixation (RPCF) test currently available to the physician is significant only when reactive. It cannot be used as an exclusion test. The TPI reaction is still the best established treponemal test for syphilis. The availability of these tests does not reduce the physician's responsibility from obtaining an adequate history and performing the necessary physical examination and making a diagnosis of syphilis before treatment is instituted. Present treatment is rapid and usually safe. The recommended preparations are procaine penicillin G with 2 per cent aluminum monostearate in oil (PAM) and benzathine penicillin. When penicillin is contraindicated because of an allergic background or when there is a history or evidence of penicillin sensitivity, the broad-spectrum antibiotics can be substituted. They cannot, however, be regarded as equal to penicillin in the treatment of syphilis. It is of the utmost importance to fully establish the allergic status of the patient prior to institution of therapy with penicillin. Collart and his colleagues' study points to the renewal of interest in treponematoses research and the need for long-time studies on the survival and infectivity of treponemes in the body. It warns us to be continuously alert and cautious when appraising long-term results in syphilis. Because of the infrequency of clinical syphilis, the diagnosis should not be omitted from consideration in the differential diagnosis of patients with obscure signs and symptoms. Despite recent advances in the diagnosis and treatment of syphilis, control is still a major problem, there is still a large reservoir of infection in this country and the world which defies eradication, and there are still difficult problem cases.

REFERENCES 1. Andujar, J. J. and Mazurek, E. E.: The plasmacrit test on capillary blood. Am. J. Clin. Path. 31: 197-204, 1959.

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2. Boak, R. A., Carpenter, C. M., Miller, J. N., Drusch, H. E., Chapman, J. M. and Heidbreder, G. A.: Biologic false positive reactions for syphilis in pregnancy as determined by the Treponema pallidum immobilization test. Surg. Gynec. & Obst. 101: 75] -752, 1955. 3 Cannefax, G. R. and Garson, W.: Reiter protein complement fixation test for syphilis. Pub. Health Rep. 72: 335-340, 1957. 4. Carpenter, C. M., Miller, J. N. and Boak, R. A.: A "triple-test plan" for the serologic diagnosis of syphilis-a modern-day approach. New England J. Med. 263: LOI6-10]8, 1960. 5. Collart, P., Borel, L ..J. and Durel, P.: Significance of spiral organisms found after treatment in late human and experimental syphilis. Brit. J. Vener. Dis. 40: 81-89, 1964. 6. Collart, P., Borel, L. J. and Durel, P.: Ann. Inst. Pasteur. 102: 596, 1962; 102: 693, 1962; 103: 958, 1962; Ann. Derm. Syph. (Paris) 89: 488, 1962. 7 D' Allesandro, G. and Dardanoni, L.: Isolation and purification of the protein antigen of the Reiter treponeme. Am. J. Syph. 37: 137-150, 1953. 8. Garson, W: Recent developments in the laboratory diagnosis of syphilis. Ann. Int. Med. 51: 748-758,1959. 9. Magnuson, H. J. and Thompson, F. A.: Treponemal immobilization test of normal and syphilitic serums. J. Yen. Dis. Inform. 30: 309-320, 1949. 10 Mahoney, J. F., Arnold, R. C. and Harris, A.: Penicillin treatment of early syphilis: A preliminary report. J. Vener. Dis. Inform. 24: 355-357, 1943. 11. Miller, J. L., Slatkin, M. H., Brodey, M., Wechsler, H. L. and Hill, J. H.: Studies with the treponemal immobilization test. J.A.M.A. 154: 1241-1247, 1954. 12. Miller, J. L., Slatkin, M. H., Feiner, R. R., Portnoy, J. and Cannon, A. B.: Treponemal immobilization test: Reliability of results for the diagnosis of syphilis. J.A.M.A. 149: 987-991, 19.52. 13. Miller, J. L., Slatkin, M. H. and Hill, J. H.: Significance of the Treponema pallidum immobilization test on spinal fluid. J.A.M.A. 160: 1394-1397, 1956. 14. Moore, J. E. and Mohr, C. F.: Biologically false positive serologic tests for syphilis: Type, incidence and cause. J.A.M.A. 150: 467-473, 1952. 15. Nelson, R. A., Jr. and Mayer, M. M.: Immobilization of Treponema pallidum in vitro by antibody produced in syphilitic infection. J. Exper. Med. 89: 369-393, 1949. 16. Portnoy, J., Bossak, H. N., Falcone, V. and Harris, A.: Rapid plasma reagin test wit.h unheated serum and new improved antigen suspension. Pub. Health Rep. 76: 933-935, 1961. 17. Portnoy, J., Brewer, J. H. and Harris, A.: Rapid plasma reagin card test for syphilis and other treponematoses. Pub. Health Rep. 77: 645-652, 1962. IS. Portnoy, J., Garson, W. and Smith, C. A.: Rapid plasma reagin test for syphilis. Pub. Health Rep. 72: 761-766, 1957. 1!l. Smith, C. A., Kamp, M., Olansky, S. and Price, E. V.: Benzathine penicillin G in the treatment of syphilis. Bull. World Health Org. 15: 1087-1096, 1!l56. 20. Willcox, R. R.: Implications of the reported finding of treponemes of little or no virulence after the treatment of syphilis with penicillin. Brit. J. Vener. Dis. 40: 90-9.5, 1964. 873 Ocean Avenue Brooklyn 26, N Y.