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Reiter’s Syndrome Treated Successfully with Dihydrostreptomycin
THE JOURNAL OF~UROLOGY
Vol. 64, No. 2, August 1950 Printed in U.S.A.
REITER'S SYNDROME TREATED SUCCESSFULLY WITH DIHYDROSTREPTOMYCIN ROBERT H. HEPBURN
There have now been several reports of patients with Reiter's syndromearthritis, urethritis, conjunctivitis-apparently successfully treated with streptomycin.1 · 2 • 3 • 4 • 5 Preceding methods have not had anything like these cleancut results. Fever, typhoid vaccine, neoarsphenamine, iodides, salicylates, sulfonamides, penicillin, gold salts, urotropin, and local antiseptics have had only equivocal effect. The reported cases have usually lasted several months, many with remissions and relapses for years, before finally achieving spontaneous cure. The etiological agent ofReiter's syndrome is unproven. The clinical triad is, however, so characteristic that it has maintained its designation as a "syndrome" and may eventually become a respectable "disease". The reported cases, since Reiter 6 first drew attention to the picture, have for the most part had negative or nonspecific smears, sterile or nonspecific cultures of urethral discharge, joint fluid, conjunctiva! sacs, penile, or mucous membrane lesions. Pleuropneumonialike organisms, called L organisms from their appearance on culture, were retrieved from several cases by Dienes.1 These organisms bid fair to be proven the etiological agent. For a fascinating introduction to the L organism the studies of Dienes should be consulted. The following observations are largely in summary of or drawn from his writings: The name pleuropneumonia comes from bovine pleuropneumonia. L organisms were first cultured in 1898 from cattle with pleuropneumonia. Since 1935 they have been found in dogs, rats, mice, man, and as saprophytes in sewage and soil. Variant forms of other bacteria may give rise to organisms with similar properties; at least this is one explanation of the finding of L type organisms in cultures of other bacteria, particularly those cultures to which penicillin has been added. L organisms are filtrable, invisible in highly infectious tissues or body fluids, but, as distinguished from viruses, grow in dead media. Most satisfactory culture results for human strains have been achieved anaerobically -with media containing human serum. Agar squares, with developed 2 to 3-day old colonies on them can then be stained and set up for microscopy. L organisms are not sufficiently characteristic on darkfield examination. The fact that, being delicate, they are destroyed by the smear technique, and that special methods and training are required for their identification is reason enough for failure to find them by the average hospital laboratory at present. L organisms recovered from man have not been pathogenic for laboratory animals; consequently recognition by animal inoculation is not feasible. Dienes, L., et al.: New Eng. J. Med., 238: 509 and 563, 1948. Warthin, T. A.: Am. J. Med., 4: 827-835, 1948. Azzolini, U. and Pasucci, F.: Gior. ital. oftal., 1: 14-22, 1948. 4 Comroe, B. I.: Arthritis and Allied Conditions (edited by J. L. Hollander). Philadelphia: Lea and Febiger, 1949, revised edition. 6 Ravina, A. and Pecher, V., et al.: Bull. Soc. med. h6p. Paris, 65: 539-41, 1949. 6 Reiter, H.: Deutsche med. Wchnschr., 42: 1535, 1916. 413 1 2
3
414
ROBERT H. HEPBURN
W allerstein et al.7 reported 2 cases with Reiter's syndrome in which the patients had a high antibody titer against antigen prepared from a pleuropneumonialike organism isolated from a patient with endocarditis apparently due to this organism. 8 It is evident that animal and human strains of L organisms are serologically different. Further studies are needed to elucidate this problem. The high percentage occurrence of L organisms as a normal part of the cervical flora (26 per cent of 214 cases in Dienes' series) and vaginal flora (14 per cent in Klieneberger-Nobel's group of 50 pregnant women 9), but more especially the apparent much more frequent occurrence in inflammations of the genito-urinary tract, suggest that transmission to the male may occur by sexual contact, thus constituting in fact a new venereal disease,-though this remains to be proven. The L organism is not common in the male genito-urinary tract as versus the female. Dienes found its presence in secretions from the respiratory tract, conjunctiva, spinal, pleural, or synovial fluid, and stools nil except in patients receiving penicillin and in the synovial fluid of 2 patients with Reiter's syndrome. In addition to Reiter's syndrome, the organisms have been found as the sole retrievable miscreant in cases of nonspecific urethritis,1 of cystitis, and may even prove to be the cause of ureteritis and pyelonephritis. 10 The relation of Reiter's syndrome to abacterial pyuria has been pointed out, but the failure of Reiter's syndrome to respond to arsenicals suggests a different etiological agent. The sensitivity of pleuropneumonia-like organisms to streptomycin has been demonstrated in rats. 11 Human strains have been inhibited by 20 micrograms per cubic centimeter. Dienes, from observing his patients treated with streptomycin, states: "The results of streptomycin therapy were not conclusive but indicate that the drug is probably effective in most cases of uncomplicated genito-urinary tract disease due to pleuro-pneumonia-like organisms. In Reiter's syndrome the results were sufficiently suggestive to warrant further trial of this therapy." Comroe 4 says: "Three of our cases of Reiter's syndrome at the Hospital of the University of Pennsylvania were treated with streptomycin in doses of 2 gm. daily for 1 week. There was marked improvement of all the symptoms in 1 case with recurrence 3 weeks after discontinuation of treatment. One case subsided completely within 2 weeks without recurrence, and the third case seemed to subside under treatment but prostatic massage promptly produced an exaccerbation even though the patient Wti,S still receiving streptomycin. Further studies with this form of treatment are necessary before it can be evaluated critically, but streptomycin therapy is certainly worthy of trial in infectious uro-arthritis." It would appear that for the practicing physician in general, and the urologist in particular, it is well worth emphasizing that the L organism may be associated Wallerstein, R., Vallee, B. L. and Turner, L.: J. Infect. Dis., 79: 134-140, 1946. Herschberger, C., Dantes, D. A. and Schwartzman, G.: J. Mt. Sinai Hosp., 12: 295308, 1945. 9 Klineberger-N obel, E.: Lancet, 2: 46, 1945. 1 ° Colby, F. H.: J. Urol., 52: 415-419, 1944. 11 Powell, H. M., Jamieson, W. A. and Rice, R. M.: Proc. Soc. Exper. Biol. and Med., 62: 8, 1946. 7 8
REITER'S SYNDROME TREATED WITH DIHYDROSTREPTOMYCIN
415
with acute or chronic inflammations of the urethra, prostate, bladder, possibly tho upper urinary tract, with or without simultaneous involvement of joints, conjunctivae, mucous membranes, even skin; the present "urine culture sterile" report may hide the presence of these organisms; streptomycin is effective in removing L organisms from the genito-urinary tract of man; and streptomycin is the first reported really effective treatment of Reiter's syndrome. To the streptomycin-treated cases of Reiter's syndrome I should like to add a case apparently responding to dihydrostreptomycin. P. T. (Hartford Hospital Nos. 617-592 and 618-078), a 16 year old American boy of Italian extraction, noted the sudden onset, 2 weeks before a 26 day hospital admission, of severe burning dysuria with a few drops of pus at the end of each urination. Occasionally the urine contained streaks of bloody material. These symptoms continued though gradually somewhat diminished by time of admission. There was no history of exposure to venereal disease. The patient was slender, fatigued-looking, rather highly excited. The blood pressure was 170/110. A drop of creamy white pus could be milked from the urethra. The white blood cell count was 8,800, hematocrit 47.5. Blood smear: polymorphonuclears 62, eosinophiles 2, lymphocytes 30, monocytes 6, platelets normal. Fasting blood sugar 108. Blood sedimentation rate 16 m.m. in 1 hour. Blood Hinton and Mazzini negative. Urinalysis normal except for alkaline reaction. Urine culture sterile. Urethral smear: pus 4 plus, mixed flora 1 plus, no gonococci. Culture of urethral pus under CO2: B. coli 2 plus, diphtheroid bacilli 2 plus, no gonococci. Because the patient was essentially asymptomatic and was thought to be a case of nonspecific urethroprostatitis, he was discharged to the care of his family physician. Just prior to discharge a slight bilateral conjunctivitis was noted and the possibility of Reiter's syndrome entertained. Three days later the patient was re-admitted with his conjunctivae fiery red and edematous. Both knees had been considerably swollen for 2 days, were fluctuant and somewhat reddened though only slightly tender. The urethral discharge had ceased. Rectal temperature 102.SF, blood pressure 160/90. White blood cell count 13,000. Blood smear: polymorphonuclears 74, eosinophiles 4, lymphocytes 20, monocytes 1. Red cells showed hyperchromia 2 plus, anisocytosis 1 plus. Blood sedimentation rate 74 m.m. in 1 hour. An excretory urogram on the sixth day and an electrocardiogram on the twelfth day after admission were normal. Films of the knees on the sixth day showed intracapsular and soft parts thickening. Aureomycin was begun as follows: Capsules 1 (250 mg.) every 4 hrs. or 1.5 gm. 1st day Capsules 2 (500 mg.) every 6 hrs. or 2.0 gm. 2nd day Capsules 2 (500 mg.) every 4 hrs. thereafter, i.e. 3.0 gm. daily Temperature fell to 100.2F rectally by the evening of the third day, then rose to about 100 every evening till the seventh day when aureomycin was discontinued. The conjunctivitis had diminished but the knees remained swollen. Mapharsen 0.04 gm. was then given intravenously every other day for a total
416
ROBERT H. HEPBURN
of 3 injections or 0.12 gm. During Mapharsen therapy the temperature rose more each evening till it reached 103F on the fifth day of Mapharsen therapy. This drug was then discontinued and dihydrostreptomycin 0.7 gm. was given intramuscularly twice daily for 9 days. Temperature fell to normal on the fourth day of this regimen. It remained normal thereafter. The voided urine, which had shown 2 plus albumin and 2 to 4 plus white cells, cleared after the second day of dihydrostreptomycin and became normal. It had been usually alkaline before dihydrostreptomycin and became usually acid after it was begun. The knees likewise improved steadily and were only slightly puffy after the ninth day of dihydrostreptomycin at which time the drug was discontinued. Three days later the patient was discharged asymptomatic. It is possible but unlikely that the remission was spontaneous; it occurred long before that of the vast majority of reported cases. The marked rapidity of improvement on dihydrostreptomycin points strongly to that improvement being a result of therapy. It is likewise possible that more prolonged aureomycin administration might have resulted in improvement in the knees, but at the time the lack of change in them dampened our enthusiasm for continuing the expensive drug. The patient has now been free of any symptoms for over 12 months. A few weeks after going home he resumed athletics. This winter he is on his school basketball team playing an active schedule. SUMMARY
A case of Reiter's syndrome apparently responding to one course of dihydrostreptomycin is presented in support of several similar reported cases. More than a year has passed without recurrence. The facts concerning pleuropneumonialike or L organisms are summarized since these organisms are a most likely candidate for the position of etiological agent in Reiter's syndrome and are also sensitive to streptomycin. It is suggested by implication that there is enough evidence of L organism pathogenicity to warrant deliberate search for them as a part of bacteriologic diagnosis in many cases of obscure urinary tract inflammation.
85 Jefferson St., Hartford 6, Conn
Vol. 64, No. 2, August 1950 Printed in U.S.A.
REITER'S SYNDROME TREATED SUCCESSFULLY WITH DIHYDROSTREPTOMYCIN ROBERT H. HEPBURN
There have now been several reports of patients with Reiter's syndromearthritis, urethritis, conjunctivitis-apparently successfully treated with streptomycin.1 · 2 • 3 • 4 • 5 Preceding methods have not had anything like these cleancut results. Fever, typhoid vaccine, neoarsphenamine, iodides, salicylates, sulfonamides, penicillin, gold salts, urotropin, and local antiseptics have had only equivocal effect. The reported cases have usually lasted several months, many with remissions and relapses for years, before finally achieving spontaneous cure. The etiological agent ofReiter's syndrome is unproven. The clinical triad is, however, so characteristic that it has maintained its designation as a "syndrome" and may eventually become a respectable "disease". The reported cases, since Reiter 6 first drew attention to the picture, have for the most part had negative or nonspecific smears, sterile or nonspecific cultures of urethral discharge, joint fluid, conjunctiva! sacs, penile, or mucous membrane lesions. Pleuropneumonialike organisms, called L organisms from their appearance on culture, were retrieved from several cases by Dienes.1 These organisms bid fair to be proven the etiological agent. For a fascinating introduction to the L organism the studies of Dienes should be consulted. The following observations are largely in summary of or drawn from his writings: The name pleuropneumonia comes from bovine pleuropneumonia. L organisms were first cultured in 1898 from cattle with pleuropneumonia. Since 1935 they have been found in dogs, rats, mice, man, and as saprophytes in sewage and soil. Variant forms of other bacteria may give rise to organisms with similar properties; at least this is one explanation of the finding of L type organisms in cultures of other bacteria, particularly those cultures to which penicillin has been added. L organisms are filtrable, invisible in highly infectious tissues or body fluids, but, as distinguished from viruses, grow in dead media. Most satisfactory culture results for human strains have been achieved anaerobically -with media containing human serum. Agar squares, with developed 2 to 3-day old colonies on them can then be stained and set up for microscopy. L organisms are not sufficiently characteristic on darkfield examination. The fact that, being delicate, they are destroyed by the smear technique, and that special methods and training are required for their identification is reason enough for failure to find them by the average hospital laboratory at present. L organisms recovered from man have not been pathogenic for laboratory animals; consequently recognition by animal inoculation is not feasible. Dienes, L., et al.: New Eng. J. Med., 238: 509 and 563, 1948. Warthin, T. A.: Am. J. Med., 4: 827-835, 1948. Azzolini, U. and Pasucci, F.: Gior. ital. oftal., 1: 14-22, 1948. 4 Comroe, B. I.: Arthritis and Allied Conditions (edited by J. L. Hollander). Philadelphia: Lea and Febiger, 1949, revised edition. 6 Ravina, A. and Pecher, V., et al.: Bull. Soc. med. h6p. Paris, 65: 539-41, 1949. 6 Reiter, H.: Deutsche med. Wchnschr., 42: 1535, 1916. 413 1 2
3
414
ROBERT H. HEPBURN
W allerstein et al.7 reported 2 cases with Reiter's syndrome in which the patients had a high antibody titer against antigen prepared from a pleuropneumonialike organism isolated from a patient with endocarditis apparently due to this organism. 8 It is evident that animal and human strains of L organisms are serologically different. Further studies are needed to elucidate this problem. The high percentage occurrence of L organisms as a normal part of the cervical flora (26 per cent of 214 cases in Dienes' series) and vaginal flora (14 per cent in Klieneberger-Nobel's group of 50 pregnant women 9), but more especially the apparent much more frequent occurrence in inflammations of the genito-urinary tract, suggest that transmission to the male may occur by sexual contact, thus constituting in fact a new venereal disease,-though this remains to be proven. The L organism is not common in the male genito-urinary tract as versus the female. Dienes found its presence in secretions from the respiratory tract, conjunctiva, spinal, pleural, or synovial fluid, and stools nil except in patients receiving penicillin and in the synovial fluid of 2 patients with Reiter's syndrome. In addition to Reiter's syndrome, the organisms have been found as the sole retrievable miscreant in cases of nonspecific urethritis,1 of cystitis, and may even prove to be the cause of ureteritis and pyelonephritis. 10 The relation of Reiter's syndrome to abacterial pyuria has been pointed out, but the failure of Reiter's syndrome to respond to arsenicals suggests a different etiological agent. The sensitivity of pleuropneumonia-like organisms to streptomycin has been demonstrated in rats. 11 Human strains have been inhibited by 20 micrograms per cubic centimeter. Dienes, from observing his patients treated with streptomycin, states: "The results of streptomycin therapy were not conclusive but indicate that the drug is probably effective in most cases of uncomplicated genito-urinary tract disease due to pleuro-pneumonia-like organisms. In Reiter's syndrome the results were sufficiently suggestive to warrant further trial of this therapy." Comroe 4 says: "Three of our cases of Reiter's syndrome at the Hospital of the University of Pennsylvania were treated with streptomycin in doses of 2 gm. daily for 1 week. There was marked improvement of all the symptoms in 1 case with recurrence 3 weeks after discontinuation of treatment. One case subsided completely within 2 weeks without recurrence, and the third case seemed to subside under treatment but prostatic massage promptly produced an exaccerbation even though the patient Wti,S still receiving streptomycin. Further studies with this form of treatment are necessary before it can be evaluated critically, but streptomycin therapy is certainly worthy of trial in infectious uro-arthritis." It would appear that for the practicing physician in general, and the urologist in particular, it is well worth emphasizing that the L organism may be associated Wallerstein, R., Vallee, B. L. and Turner, L.: J. Infect. Dis., 79: 134-140, 1946. Herschberger, C., Dantes, D. A. and Schwartzman, G.: J. Mt. Sinai Hosp., 12: 295308, 1945. 9 Klineberger-N obel, E.: Lancet, 2: 46, 1945. 1 ° Colby, F. H.: J. Urol., 52: 415-419, 1944. 11 Powell, H. M., Jamieson, W. A. and Rice, R. M.: Proc. Soc. Exper. Biol. and Med., 62: 8, 1946. 7 8
REITER'S SYNDROME TREATED WITH DIHYDROSTREPTOMYCIN
415
with acute or chronic inflammations of the urethra, prostate, bladder, possibly tho upper urinary tract, with or without simultaneous involvement of joints, conjunctivae, mucous membranes, even skin; the present "urine culture sterile" report may hide the presence of these organisms; streptomycin is effective in removing L organisms from the genito-urinary tract of man; and streptomycin is the first reported really effective treatment of Reiter's syndrome. To the streptomycin-treated cases of Reiter's syndrome I should like to add a case apparently responding to dihydrostreptomycin. P. T. (Hartford Hospital Nos. 617-592 and 618-078), a 16 year old American boy of Italian extraction, noted the sudden onset, 2 weeks before a 26 day hospital admission, of severe burning dysuria with a few drops of pus at the end of each urination. Occasionally the urine contained streaks of bloody material. These symptoms continued though gradually somewhat diminished by time of admission. There was no history of exposure to venereal disease. The patient was slender, fatigued-looking, rather highly excited. The blood pressure was 170/110. A drop of creamy white pus could be milked from the urethra. The white blood cell count was 8,800, hematocrit 47.5. Blood smear: polymorphonuclears 62, eosinophiles 2, lymphocytes 30, monocytes 6, platelets normal. Fasting blood sugar 108. Blood sedimentation rate 16 m.m. in 1 hour. Blood Hinton and Mazzini negative. Urinalysis normal except for alkaline reaction. Urine culture sterile. Urethral smear: pus 4 plus, mixed flora 1 plus, no gonococci. Culture of urethral pus under CO2: B. coli 2 plus, diphtheroid bacilli 2 plus, no gonococci. Because the patient was essentially asymptomatic and was thought to be a case of nonspecific urethroprostatitis, he was discharged to the care of his family physician. Just prior to discharge a slight bilateral conjunctivitis was noted and the possibility of Reiter's syndrome entertained. Three days later the patient was re-admitted with his conjunctivae fiery red and edematous. Both knees had been considerably swollen for 2 days, were fluctuant and somewhat reddened though only slightly tender. The urethral discharge had ceased. Rectal temperature 102.SF, blood pressure 160/90. White blood cell count 13,000. Blood smear: polymorphonuclears 74, eosinophiles 4, lymphocytes 20, monocytes 1. Red cells showed hyperchromia 2 plus, anisocytosis 1 plus. Blood sedimentation rate 74 m.m. in 1 hour. An excretory urogram on the sixth day and an electrocardiogram on the twelfth day after admission were normal. Films of the knees on the sixth day showed intracapsular and soft parts thickening. Aureomycin was begun as follows: Capsules 1 (250 mg.) every 4 hrs. or 1.5 gm. 1st day Capsules 2 (500 mg.) every 6 hrs. or 2.0 gm. 2nd day Capsules 2 (500 mg.) every 4 hrs. thereafter, i.e. 3.0 gm. daily Temperature fell to 100.2F rectally by the evening of the third day, then rose to about 100 every evening till the seventh day when aureomycin was discontinued. The conjunctivitis had diminished but the knees remained swollen. Mapharsen 0.04 gm. was then given intravenously every other day for a total
416
ROBERT H. HEPBURN
of 3 injections or 0.12 gm. During Mapharsen therapy the temperature rose more each evening till it reached 103F on the fifth day of Mapharsen therapy. This drug was then discontinued and dihydrostreptomycin 0.7 gm. was given intramuscularly twice daily for 9 days. Temperature fell to normal on the fourth day of this regimen. It remained normal thereafter. The voided urine, which had shown 2 plus albumin and 2 to 4 plus white cells, cleared after the second day of dihydrostreptomycin and became normal. It had been usually alkaline before dihydrostreptomycin and became usually acid after it was begun. The knees likewise improved steadily and were only slightly puffy after the ninth day of dihydrostreptomycin at which time the drug was discontinued. Three days later the patient was discharged asymptomatic. It is possible but unlikely that the remission was spontaneous; it occurred long before that of the vast majority of reported cases. The marked rapidity of improvement on dihydrostreptomycin points strongly to that improvement being a result of therapy. It is likewise possible that more prolonged aureomycin administration might have resulted in improvement in the knees, but at the time the lack of change in them dampened our enthusiasm for continuing the expensive drug. The patient has now been free of any symptoms for over 12 months. A few weeks after going home he resumed athletics. This winter he is on his school basketball team playing an active schedule. SUMMARY
A case of Reiter's syndrome apparently responding to one course of dihydrostreptomycin is presented in support of several similar reported cases. More than a year has passed without recurrence. The facts concerning pleuropneumonialike or L organisms are summarized since these organisms are a most likely candidate for the position of etiological agent in Reiter's syndrome and are also sensitive to streptomycin. It is suggested by implication that there is enough evidence of L organism pathogenicity to warrant deliberate search for them as a part of bacteriologic diagnosis in many cases of obscure urinary tract inflammation.
85 Jefferson St., Hartford 6, Conn