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RELATIONSHIPS BETWEEN MYCOPLASMA AND THE ETIOLOGY OF NONGONOCOCCAL URETHRITIS AND REITERS SYNDROME+ Denys K. Ford Department of Medicine, Canadian Arthritis and Rheumatism Society Research Unit, University of British Columbia. Vancouver, B.C., Canada Mycoplasma have been isolated from the human genital tract for 30 years, and yet their role in the production of disease is still not clarified. Initially, the isolates had a typical “fried-egg” morphology and were classified as M. horninis or M. ferrnentans strains.’ A recent study2 in Vancouver, B. C., Canada, confirmed that M. horninis 1 was the most common organism having classical morphology, with 94 of 100 strains from women and all of 17 strains from men being serologically typed by the disc inhibition method of Clyde3 as M. horninis 1. The remaining six strains from women fermented glucose, and were thought to be related to M. ferrnentans although they were not inhibited by M. ferrnentans antiserum. No M. horninis 2 organisms were found. In 1956, Shephard4 described the T- strains, which have subsequently proved to be not only morphologically and cul- turally different but also biochemically and serologically distinct from M. horninis 1 and M. ferrnentans. In evaluating the relationships between mycoplasma and the etiology of non- gonococcal urethritis and Reiter’s syndrome, the triad of urethritis, arthritis, and conjunctivitis, each of the three strains of genital mycoplasma has to be con- sidered. In the author’s laboratory, work has, however, centered largely on the T-strain mycoplasma because studies e l s e ~ h e r e ~ . ~ have suggested that the “large- colony” strains are more likely to be saprophytic than pathogenic. The methods of culture have been described previously7 with the exception that, in the past year, urea in concentrations up to 1% has been added to broth medium because it was noted to be an essential metabolite.8 TABLE 1 summarizes the incidence of isolation of mycoplasma from the genital tracts of men and women in Vancouver. It is evident that both T-strain and large- colony (subsequently typed as M. horninis 1 in about 95% of cases) mycoplasma can be found in the genital tracts of asymptomatic men and women. It is also evident that the incidence of T-strains in patients with nongonococcal urethritis (79%) is higher than in “control” males (21% and 47%), but the incidence of large-colony mycoplasma is somewhat lower (27% ) in patients with nongonoc- occal urethritis than in jail inmates (37% ) who are assumed to be promiscuous. This suggests a greater probability that T-strain mycoplasma rather than M. horninis strains are etiologically related to nongonococcal urethritis and the response of nongonococcal urethritis and T-strains to erythromycine may be used as supportive circumstantial evidence for this hypothesis. It has been POS- sible by means of the metabolic-inhibition test of Purcelllo to make a preliminary study of the antibody response of patients with nongonococcal urethritis against their own T-strain isolates. However, nine of 11 patients showed no rise of titer between acute and convalescent serum samples, while only two patients showed antibody rises from 0 to titers of 1 in 4 and 1 in 16. Thus, at the present time, it is not possible to state with certainty that T-strain mycoplasma are a primary cause of nongonococcal urethritis. Federal Health Grant 609-7-40. These studies have been supported by the Canadian Arthritis and Rheumatism Society and 501

RELATIONSHIPS BETWEEN MYCOPLASMA AND THE ETIOLOGY OF NONGONOCOCCAL URETHRITIS AND REITER'S SYNDROME

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Page 1: RELATIONSHIPS BETWEEN MYCOPLASMA AND THE ETIOLOGY OF NONGONOCOCCAL URETHRITIS AND REITER'S SYNDROME

RELATIONSHIPS BETWEEN MYCOPLASMA AND THE ETIOLOGY OF NONGONOCOCCAL URETHRITIS AND REITERS SYNDROME+

Denys K. Ford Department of Medicine, Canadian Arthritis and Rheumatism Society Research Unit,

University of British Columbia. Vancouver, B.C., Canada

Mycoplasma have been isolated from the human genital tract for 30 years, and yet their role in the production of disease is still not clarified. Initially, the isolates had a typical “fried-egg” morphology and were classified as M. horninis or M. ferrnentans strains.’ A recent study2 in Vancouver, B. C., Canada, confirmed that M. horninis 1 was the most common organism having classical morphology, with 94 of 100 strains from women and all of 17 strains from men being serologically typed by the disc inhibition method of Clyde3 as M. horninis 1. The remaining six strains from women fermented glucose, and were thought to be related to M. ferrnentans although they were not inhibited by M. ferrnentans antiserum. No M. horninis 2 organisms were found. In 1956, Shephard4 described the T- strains, which have subsequently proved to be not only morphologically and cul- turally different but also biochemically and serologically distinct from M. horninis 1 and M. ferrnentans.

In evaluating the relationships between mycoplasma and the etiology of non- gonococcal urethritis and Reiter’s syndrome, the triad of urethritis, arthritis, and conjunctivitis, each of the three strains of genital mycoplasma has to be con- sidered. In the author’s laboratory, work has, however, centered largely on the T-strain mycoplasma because studies e l s e ~ h e r e ~ . ~ have suggested that the “large- colony” strains are more likely to be saprophytic than pathogenic. The methods of culture have been described previously7 with the exception that, in the past year, urea in concentrations up to 1% has been added to broth medium because it was noted to be an essential metabolite.8

TABLE 1 summarizes the incidence of isolation of mycoplasma from the genital tracts of men and women in Vancouver. It is evident that both T-strain and large- colony (subsequently typed as M. horninis 1 in about 95% of cases) mycoplasma can be found in the genital tracts of asymptomatic men and women. It is also evident that the incidence of T-strains in patients with nongonococcal urethritis ( 7 9 % ) is higher than in “control” males (21% and 47%) , but the incidence of large-colony mycoplasma is somewhat lower (27% ) in patients with nongonoc- occal urethritis than in jail inmates (37% ) who are assumed to be promiscuous. This suggests a greater probability that T-strain mycoplasma rather than M. horninis strains are etiologically related to nongonococcal urethritis and the response of nongonococcal urethritis and T-strains to erythromycine may be used as supportive circumstantial evidence for this hypothesis. It has been POS- sible by means of the metabolic-inhibition test of Purcelllo to make a preliminary study of the antibody response of patients with nongonococcal urethritis against their own T-strain isolates. However, nine of 11 patients showed no rise of titer between acute and convalescent serum samples, while only two patients showed antibody rises from 0 to titers of 1 in 4 and 1 in 16. Thus, at the present time, it is not possible to state with certainty that T-strain mycoplasma are a primary cause of nongonococcal urethritis.

Federal Health Grant 609-7-40. These studies have been supported by the Canadian Arthritis and Rheumatism Society and

501

Page 2: RELATIONSHIPS BETWEEN MYCOPLASMA AND THE ETIOLOGY OF NONGONOCOCCAL URETHRITIS AND REITER'S SYNDROME

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Page 3: RELATIONSHIPS BETWEEN MYCOPLASMA AND THE ETIOLOGY OF NONGONOCOCCAL URETHRITIS AND REITER'S SYNDROME

Ford: Mycoplasma and Urethritis 503 Previous claims 1 1 ~ 1 2 ~ 1 3 ~ 1 4 ~ 1 5 that mycoplasma were isolated from the synovial

or conjunctival exudate of patients with Reiter’s syndrome have not yet been con- firmed. In the author’s laboratory, 15 synovial and five conjunctival specimens from 17 cases, untreated by broad-spectrum antibiotics, have been cultured by methods considered optimal at the time of study for T-strain mycoplasma, but no strains have been recovered. The incidence of T-strains in the genital tract of patients with Reiter’s syndrome is not significantly different from the incidence in patients with uncomplicated nongonococcal urethritis. No adequate serological data is yet available on the serum antibody levels against T-strains in patients with Reiter’s syndrome. However, there is no current data to support the hypothesis that T-strains are etiologically related to Reiter’s syndrome.

The application of Purcell’s metabolic-inhibition test to the study of T-strains has revealed that a number of distinct serotypes exist. The data is not complete, but the results of serotyping 32 genital isolates, each of which was cloned three times, with six rabbit antisera are shown in TABLE 2. The antisera were prepared

TABLE 2 SEROLWIClu. INHIBlTION OF GENITAL ISOLATES OF T-STRAIN MYCOPLASMA

23 27 co 354 7 Pi

23 (4’) 4096t 0 0 0 0 8

AntiscNm

Orsanism

27 (3) 0 8192 128 32 128 8

c o (2) 64 8 8192 0 4 4

354 (5) 16384 16 512 8192 32 16

7 (2) 64 0 0 0 16384 512

Pi (1) 64 128 64 32 256 16384

Number of organisms with similar reactions. t Reciprocal of titer.

One isolate w a not significantly inhibited by any antiserum. 13 isolates were inhibited by one or more antisera but were not readily classifiable by the above antisera on account of low titers or multiple inhibition.

by intravenous injections of deposits from 100 ml-16 hour broth cultures on days 1, 3, 5 , 8, 10, 12 and 19. It would appear that there are at least six different sero- types, that there is variable antigenic overlap between some types, that not all isolates can be typed with the present antisera and that isolates from patients with Reiter’s syndrome are not all of one serotype.

Mycoplasma resembling T-strains culturally, morphologically and biochem- ically can be isolated from throat swabs of approximately 5% of healthy individ- uals. TABLE 3 shows the results of serotyping of five such isolates with the rabbit antisera prepared against genital isolates. It would appear that the oral strains are not serologically distinct from the genital strains .

More information needs to be obtained before final assessments of the patho- genicity of genital mycoplasma can be made .

Page 4: RELATIONSHIPS BETWEEN MYCOPLASMA AND THE ETIOLOGY OF NONGONOCOCCAL URETHRITIS AND REITER'S SYNDROME

504 Annals New York Academy of Sciences TABLE 3

~ E U O L ~ I C A L INHlBlTION OF ORAL ISOLATES OF T-STRAIN MYCOPLASMA BY ANT~SERA AGAINST GENITAL ISOLATES

Antiserum 23

Organlsm 27 co 354 7 Pi

*o -1 2048. 256 128 1024 16 64

0 -2 4096 16 <4 2048 64 8

0-3 <4 4096 128 <4 256 16

0-4 256 4 16 4 16 32

0-5 256 8 128 4 128 64

Reciprocal of titer.

References 1. EDWARD, D. G. FF. & E. A. FFWNDT. 1956. Classification and nomenclature of organ-

isms of the pleuropneumonia group. J. Gen. Microbiol. 14: 197. 2. FORD, D. K. & M. DUVERNET. 1966. Antigenic types of “large-colony’’ human genital

mycoplasmas. J. Bacteriol. 91 : 899. 3. CLYDE, W. A. 1964. Mycoplasma species identification based upon growth-inhibition

by specific antisera. J. Immunology 92: 958. 4. SHBPARD, M. C. 1956. T-form colonies of pleuropneumonia-like organisms. J. Bacteriol.

711 362. 5. NICOL, C. S. & D. G. FF. EDWARD. 1953. Role of organisms of the pleuropneumonia

moup in human genital infections. Brit. J. Vener. Dis. 29: 141. 6. FREIJNDT, E. A. 1956. Occurrence and ecology of Mycoplasma species (pleuro-

pneumonia-like organisms) in the male urethra. Brit. J. Vener. Dis. 32: 188. 7. FORD, D. K. 1962. Culture of human genital “T-strain” pleuropneumonia-like organ-

isms. J. Bacteriol. 84: 1028. 8. SHEPARD, M. C., R. M. CHANOCK & R. H. F’URCELL. Personal communications. 9. SHEPARD, M. C., C. D. LUNCEPORD & R. C. BAKER. 1966. T-strain mycoplasma: Selec-

tive inhibition of erythromycin in-vitro. Brit. J. Vener. Dis. 42: 21. 10. PURCELL, R. H., D. TAYLOR-ROBINSON, D. WONO & R M. CHANOCK. 1966. A color test

for the measurement of antibody to T-strain mycoplasmas. J. Bacteriol. 92: 6. 11. D m s , L., M. W. ROPES, W. E S M ~ , S. MADOFF & W. BAUEU. 1948. Role of pleuro-

pneumonia-like organisms in genito-urinary and joint diseases. New Engl. J. Med. 238s 509 and 563.

12. Kuzgu, W. C. 8t E. A. MANKLE. 1950. Cortisone acetate and Terramycin in poly- arthritis of rats. Proc. Soc. Exp. Biol. Med. 74: 677.

13. BUTAS, C. A. 1957. Isolation of pleuropneumonia-like organisms from two cases of polyarthrith. Canad. J. Microbiol. 3: 419.

14. JONSSON, J. 1961. Mycoplasma organisms in synovial fluid from rheumatic joints. Acta Rheum. Scand. 7: 287.

15. BARTHOLOMEW, L. E. & J. HXMES. 1965. Isolation and characterization of mycoplasmas (PPLO) from patients with rheumatoid arthritis, systemic lupus erythematosus and Reiter’s syndrome. Arth. and Rheum. 8: 376.