Scandinavian Journal of Infectious Diseases
ISSN: 0036-5548 (Print) 1651-1980 (Online) Journal homepage: http://www.tandfonline.com/loi/infd19
Benign Gonococcemia with Skin Lesions and Arthritis Maj Svanbom, Elias Bengtsson, Tore Strandell & Gösta Tunevall To cite this article: Maj Svanbom, Elias Bengtsson, Tore Strandell & Gösta Tunevall (1970) Benign Gonococcemia with Skin Lesions and Arthritis, Scandinavian Journal of Infectious Diseases, 2:3, 191-200 To link to this article: http://dx.doi.org/10.3109/inf.1970.2.issue-3.07
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Date: 06 November 2015, At: 11:59
Scand J Infect Dis 2: 191-200, 1970
BENIGN GONOCOCCEMIA WITH SKIN LESIONS AND ARTHRITIS Maj Svanbom, Elias Bengtsson, Tore Strandell and Gosta Tunevall
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From the Hospital for Infectious Diseases, Roslagstull Hospital, Stockholm, Sweden
ABSTRACT. An account is given of 16 cases of benign gonococcemia during the period Dec. 1, 1967 to Oct. 31, 1969. 15 patients were women, 1 man, and the average age was 29 years. The typical clinical picture consisted of fever, joint affection combined with a vesiculopapular, frequently hemorrhagic exanthema and genital gonococcal infection with usually slight or no symptoms and a good general condition throughnut, Neisseria gonerrhoeae was Isolated from the blood in 1 case. Positive cultures were more frequently obtained from the genital and anal mucous membranes. With the fluorescent antibody technique gonococci were demonstrated from an efftorescence of 1 patient. Serological response was demonstrated in 8 patients. All cases had an unequivocal clinical picture. Penicillin resistance did not occur, but a reduction in sensitivity was noted in 1 case. Treatment had prompt effect, but spontaneous healing was also seen. No complications or relapses were noted.
Generalized gonococcal infections can be manifested as a serious septicemia but also as a benign variant with recurring fever, mild arthritis and characteristic skin lesions. The latter form which may have been observed as early as in 1781 (34) was observed again about the turn of the century (5, 18) and has been reported rather frequently during the 1930's (20, 27, 32). The disease has received renewed interest in recent years 0, 2-4, 6, 9-10, 12-13, 19, 21, 23, 28-29, 41) after being largely disregarded in the intervening period. This report describes 16 patients with similar clinical pictures, which we observed during the years 1967-1969. The usual absence of venereal history and the difficulty to demonstrate the presence of the causative gonococci are stressed. METHODS From all patients suspected of sepsis a series of 3 blood cultivations was done, and this was repeated until growth was obtained or we considered that therapy had to be started. After termination of treatment new blood cultivations were performed if possible after 1 week, after 1 and 13* - 701954
6 months and after 1 year. The samples for blood cultures were taken with aid of the closed system of Wallmark (40), a vacuum flask containing a small amount of anticoagulant "Liquoid" solution. Besides in the usual media the blood was inoculated on hematin agar plates which were incubated in a CO 2-rich atmosphere for 2 days. Blood was incorporated also in 2 agar plates; one was incubated aerobically, the other anaerobically. Flasks, tubes and plates were examined every other day for at least 10 days. Gonococcal diagnosis was based upon colony appearance, oxidase test and direct microscopy of methylene blue-and gram-stained smears, fermentation tests and verification with the fluorescent antibody (FA) technique. Material from the genital and anal mucous membranes was taken with a charcoal-treated swab and placed in Stuart's transport medium. The tubes were kept at room temperature if they could not be cultured immediately. The material was inoculated on 2 hematin agar plates; to one was added polymyxin and ristocetin according to Thayer and Martin (38). The same procedure was applied to material from joints and skin efflorescences. With this material it was also attempted to show the presence of gonococci with the FA technique. Samples from skin lesions were taken with a syringe and needle by injection of sterile saline into a vesicle and reaspiration. In later cases we made scrapings of vesicle bottoms after the integument or crust had been removed. This technique of sampling is now in current use. Aspirates or scrapings were cultivated in the same manner as described above. In addition, smears were prepared for examination with the FA technique. Serum, taken upon admission and, as a rule, after 2 weeks, was tested for complement fixation (CF) with gonococcal antigen and subjected to a flocculation test, the so-called Gono-Ballung. Wasserman's reaction (WR) was also carried out." Determination of the sensitivity to benzylpenicillin, streptomycin, tetracycline and chloramphenicol was performed routinely on all the strains. In later cases the strains were also tested against sulphonamides. The determinations were performed with the paper disc method according to Ericsson (11). The FA examination of case 16 and CF tests in 6 cases were done by Dr Dan Danielson, the Regional Hospital, orebro, Sweden.
1
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Determination of the antibiotic concentration in serum was often performed during treatment. In cases receiving treatment with more than one substance, the antibacterial activity (ABA) of serum was studied with the patient's own strain as test organism. During the hospital stay the patients were regularly examined physically once a week by one and the same investigator. Routine blood and urine analysis, X-ray of the heart and lungs and ECG were done on the same occasions. Phonocardiograms (FCG) were recorded as soon as possible after admission and, in all but a few cases, before discharge from the hospital. Other X-ray and laboratory analyses were performed when required. Out of 16 patients 13 were investigated about 1 month after discharge with clinical examination, ECG and Xray of the heart and lungs as well as blood and urine analysis. Again, all patients were examined by one and the same physician (M. S.).
MATERIAL In a series of patients admitted with septicemia 19681969, 16 had the triad fever, arthritis and cutaneous lesions. As criterion for the diagnosis gonococcemia when this triad was displayed we demanded demonstration of gonococci in the urogenital region, in blood or in skin lesions, or serological indication. In 1 case, however, the typical clinical picture was considered sufficient for diagnosis. Of the 16 patients, IS were women. The average age was 29.0 years (17-55); 2 were teenagers, 9 between 20-30 years, 1 between 30-40 and 4 over 40 years. Six patients were students, the remainder had various occupations and belonged to different social groups. 13 were unmarried or divorced. Previous venereal infection was denied by 14 women, while the only male patient admitted gonorrhea 1 year before the current sickness and one woman 23 years before. A promiscuous way of life or the use of narcotics could not be shown in these patients. Only 8 of the 15 women used contraceptives; 7 took gestagenic substances and 1 had a spiral. In 1 case information was lacking. In order to illustrate the clinical manifestations and the course of the illness, 3 cases will be described.
CASE REPORTS Case I
A 54-year-old divorced woman. Symptoms of cystins developed I month after the last coitus, and after an additional 2 weeks subfebrile temperature increasing, reddened and sore infiltrations on the lower legs as well as arthralgia in the right knee and gradually in the right hand. Upon admission the general condition was unaffected, the temperature was 37.6°, and 2 types of cutaneous efflorescences were seen: 1) on the lower legs pink, sore infiltrations with increased temperature, varying in size, and 2) on the right thumb grip, the abdomen and lower legs, lesions with hemorrhagic contents and a central crust, less in size and with a surrounding pink halo. Scand J Infect Dis 2
No symptoms from any joints were present. During the first week in the hospital new cutaneous efflorescences appeared on the fingers and lower legs, 5-10 mm in diameter with a central dark red area and a surrounding erythematous zone. Simultaneously swelling and increased heat of the left ankle occurred. Gonococci were cultivated from the blood but not from the skin lesions. CF against gonococcal antigen was positive. WBC 10550/mm3, ESR 85 mmj l h. Tests for antinuclear factors in the serum were positive in 1/125 dilution against nuclear antigen and in 1/25 dilution against smooth muscle tissue. At a later examination both tests were negative. The following laboratory examinations were negative or within normal limits: liver and renal function tests, antistreptolysin (AS) and antistaphylolysin (ASta) tests, Widal reaction and WR as well as tests for rheumatoid factor and LE cells. ECG, FCG and X-ray of the lungs and heart were normal. No treatment was given until 2 months after the first symptoms appeared (3 months after infection). The patient was without fever and symptoms, when treatment, benzylpenicillin 6 million IV/day for 2 weeks, was given. She was followed up for 2 years and has had no symptoms. Repeated blood cultures have been negative. Case 7
A 17-year-old female student who 1 year earlier had 2 attacks of cystitis, which were treated with suiphonamides. She had a slight discharge after these attacks but was in general healthy. She denied having had venereal diseases. The last coitus was followed by increased vaginal discharge. She became ill 1 month later with high fever, chills, general myalgia and a small number of cutaneous efflorescences of hemorrhagic character on the thigh and trunk. The fever subsided after several days but subsequently the same symptoms returned every week. Upon admission 2 months after falling ill she was relatively unaffected. The temperature was 37.6°. The left wrist was swollen and tender, and painful upon movement. Some skin eruptions with hemorrhagic pea-sized pustules were located on the right middle finger and isolated erythematous maculopapules on the elbow and back of the hand as well as remnants of earlier efflorescences on the thigh. Gonococci were demonstrated in cultures from the urethra and rectum but not by direct microscopy. Repeated blood cultures were negative. FA test and cultures from the skin efflorescences as well as CF with gonococcal antigen were negative. WBC 10900, ESR 70 mm, Tests for C-reactive protein (CRP) were positive and there was a slight elevation of the alfa-2 fraction on electrophoresis of serum. Other examinations were negative or within normal limits: blood platelets, bleeding and coagulation times, liver and renal function tests, AS, ASta, WR, rheumatoid factor, ECG, FCG and X-ray of lungs. She was treated with 1 million IV benzylpenicillin + 1.2 million IV procaine penicillin G twice daily for 5 days. Fever and symptoms subsided already after one day's treatment. Follow-up examinations according to the rules of the V.S. National Health Service have been negative.
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Benign gonococcemia Case 16 A 47-year-old divorced woman, who had gonorrhea in 1945-1946 with salpingitis, and pregnancy toxicosis in 1961. The last coitus was in the beginning of September. Two weeks afterwards she fell ill during menstruation with general malaise and fainting and a rash on the middle finger of the left hand. Chills and fever 38.3-39.5° continued for 2 days. After a few days of low-grade fever the temperature rose again to 39.5° with myalgia in the left upper arm, rash on the right gluteal region, on the left elbow and the inner side of the right knee. No vaginal discharge appeared, and no signs of cystitis. Upon admission her general condition was unaffected. The temperature was 38.7°, the blood pressure 200/110 mmHg. On the bend of the first phalanx of the left middle finger an efflorescence with a dark crust was seen, 2-3 mm in size; in the right gluteal region 2 hemorrhagic pustules were found and on the inner side of the right knee joint an efflorescence, 2-3 mm in diameter, with a central pustule. No objective joint symptoms were noticed. Two days after admission and before treatment was initiated 3-4 typical eruptions arose on the right lower leg, 1 on the second toe of the right foot and 1 in the nape of the neck and also arthralgia in the right shoulder and right knee. Intense erythema and swelling appeared as well as restriction of movement of the left elbow. Examinations with FA technique of material from the base of vesiculo-papules on the elbow and gluteal region gave positive results and CF with gonococcal antigen was positive in dilution 1: 10 (Dr Dan Danielson, orebro). Cultures for gonococci from blood, cervix, urethra and rectum were negative. WBC 16400, ESR 35 mm, serum iron 54 fAg/IOO ml. Other examinations were negative or gave values within normal limits: AS, ASta, liver and renal function tests and X-ray of lungs. ECG showed slight ST depressions in connexion with tachycardia. The patient was treated with the routine penicillin combination twice daily for 7 days. The fever subsided on the third day of treatment. Follow-up examinations have been normal.
RESULTS Incubation period All women denied knowledge or suspicion of venereal infection; the one male patient stated, however, a suspicion of such. The incubation time could be determined in only a single case in which the occasion of exposure was reported to be 18 days before the onset of illness. The rest of the cases demonstrate the difficulties in this respect. Eight patients reported several possibilities of exposure between 2 and 10 weeks before falling ill. Seven patients either did not know or did not wish to give information on the time of exposure.
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Fever The fever on admission and at start of treatment is illustrated by the following figures: < 37.4° 37.4-37.9° 38-38.9° 39-40°
On admission At start of treatment
2 8
3 3
6 3
5 1
(l patient was not treated with antibiotics)
Four of the patients had fever bouts prior to admission; in 1 case no less than 4 relapses occurred, in another case 2 relapses besides the current fever. The periods of fever occurred between 1 month and 4-5 months before the onset of the current illness. The duration of fever before admission was on the average 4.5 (1-10) days. The fever before admission had been high and remittent in 11 cases. In 3 cases no or merely a slight fever occurred but chills suggested fever of a high remittent type. In 1 case the fever was low and remittent, in another a continuous, moderate increase of temperature had existed. Urogenital symptoms Five patients had signs of cystitis, 3 of these also discharge. Purulent vaginal discharge was found in 6 patients without symptoms of cystitis. Four women and the male patient had neither symptoms of cystitis nor discharge. Salpingitis was found in 1 only out of 12 women gynecologically examined. Nene of the patients was pregnant, but delivery had taken place in 2 cases, 3 and 11 months, respectively, before the onset of the illness. The onset of illness in connection with the menstruation period could be established in 4 cases. Two women were in the menopause and 1 woman had still amenorrhea after delivery. In no case any pelvic operation or gynecologic intervention had taken place. Skin eruptions In all cases skin efflorescenses appeared simultaneously or in close association with the other symptoms of the triad. In 3 cases new eruptions in connection with fever were observed after admission. The efflorescenses were isolated and irregularly distributed with a clear predilection for juxtaarticular regions, In Table I it is shown that in all 16 cases the distal parts of the upper exScand J Infect Dis 2
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Table I. Localization of cutaneous manifestations
Case no.
Face
Body
+
1
2
Upper extremities
Lower extremities
Prox. part
Prox. part
Dist. part
+ + + + + + + + + + + + + + + +
+ +
+
16
11
12
+
3
4
+
+
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5
+
6
7
+
+
+
+
+ +
+
+ +
+
8
9 10 11 12 13
+
14 15 16
Total
+ + 4
9
5
Dist. part
+ + + + + + + + +
+ + + + + + + + + + +
tremities were engaged, in 12 cases the distal parts of the lower extremities. Thereafter followed the proximal parts of the lower extremities and the trunk, while the proximal parts of the upper extremities and the face were affected less often. The number of efflorescenses varied from a few up to about 15. Different stages of development of the rash were observed simultaneously in 13 cases.
Initially discrete erythematous maculae less than 5 mm in diameter occurred in 6 cases; from 5 mm to 2 em in 5; and more than 2 cm in 2 cases. In 2 cases the sizes were not recorded. These maculae developed into papules and vesiculo-pustules, generally (13 cases) with hemorrhagic contents. In one case only pustules appeared and in another only crusts. The completely developed efflorescence constituted a sore vesiculo-pustule with dirty grey necrotic tissue in the center and surrounded by a thin reddish violet edge which in tum was surrounded by a reddish halo. In one case a bullous development could be noticed. Finally, there remained only the central crust which left a brownish discoloration behind. In 1 case erythema nodosum-like efflorescenses appeared and in another case a general erythema. In 2 cases histologic examinations were carried out on excised efflorescenses. In one of these there was a fibrinoid degeneration in the walls and occluding fibrin thrombosis in the lumen of some small arterioles in the corium connective tissue. Some inflammatory cell infiltration in the surrounding area was noted, partly with leucocytes. Also some veins appeared changed, principally with inflammatory cell infiltration. The corium connective tissue was edematous. Also, the subcutis presented signs of inflammation along the vessels. In the second case a dense perivascular inflammatory infiltration containing lymphocytes as well
Table II. Distribution of joint engagements The figures indicate the number of joints with notable changes in the respective region. The figures in parentheses indicate subjective disturbances Case no.
Shoulder
Elbow
Hand
(I)
6
(I)
7
(2)
8 9 10
(I)
(I) (I) 1 1
Knee
Foot
(I) (I)
3 1
(I) (I)
2 1
(I) 2 2
1 I (3)
I 1+(1)
(I)
1
(I)
2+(5)
7+(1)
Scand J Infect Dis 2
(2) (3) (2) (3) (2)
4 (I)
I (3)
5 1 I
(I) 7+(3)
1 1 4 I 1 I 5
I (I)
1 2
2+(3)
No. of joints
3
2
11
Total
Hip
(I)
1
2 3 4 5
12 13 14 15 16
Finger
(I)
8+(4)
5+(3)
(I) 1 (2) 31 +(20)
Benign gonococcemia
Table III. Joint engagement in 16 cases of gonococcemia with cutaneous manifestations No. of affected joints 2
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No. of patients
5
3
4
5
6
7
4
2
2
o
2
as leucocytes was found in the corium connective tissue. In a few places the inflammation was of a granulomatous type with a tendency towards giant cell formation. Several small vessels with similar perivascular infiltrations showed occlusions with fibrin thrombi. No fibrinoid degeneration of the walls could be demonstrated. The perivascular skin changes continued as far down as to the subcutaneous layer. Whether the changes were of the "bacterial embolus" type could neither be ascertained nor excluded.' Changes of the joints
The knee joints were affected most often, thereafter in the following order: finger, elbow, foot, shoulder, hand, and hip joints (Table II). Most of The biopsies were examined by Dr Hans Nordenstam, The Serafimer Hospital, Stockholm.
1
Table IV. Bacteriological and serological findings NO~not
done Serology
Cultivation Case no. I 2 3
Cervix
Urethra
Rectum
ND
NO
+ +
+ +
NO NO
+
+ + +
CF test
+
+
+ +
4 5 6 7
+ + +
8
9 10
+
+
11
+ + +
+ +
12 13 14a 15 16
a The only male individual.
GonoBaIIung
+ +
+ + +
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the cases had polyarticular engagements, while in 5 cases only monoarticular attacks had occurred (Table III), usually in large joints. In 11 cases an exudate occurred in at least one joint. With some exceptions the exudate was scarce and could be used for bacteriological diagnosis in one case only. In only 5 cases there were definite signs of a tenosynovitic engagement. X-ray of affected joints was made in 5 cases. No effusion, swelling of the soft tissue, or skeletal changes could be demonstrated. Other clinical findings In 4 patients the spleen was slightly enlarged and in 5 cases the liver, without changes in liver function tests, however. No signs of meningitis or conjunctivitis were seen. Laboratory findings ESR was raised in all patients but one, and the CRP test was positive, when performed. Half of the patients had leucocytosis (> 10 000 cells/ mm"). No anemia was found but about half of the cases had a low serum iron concentration. In 1 case a slight increase of serum glutamic oxaloacetic transaminases (SGOT) together with positive flocculation reactions and liver enlargement was noticed. These findings were rechecked and found to persist. Further, in 1 case there was an isolated serum glutamic pyruvic transaminase (SGPT) increase which rapidly returned to a normal value. No enlargement of the liver could be found in these patients by palpation or X-ray examination. In 1 case a slight hematuria was present on admission with 3-4 red blood cells per high power field without simultaneous increase of serum creatinine. The serum creatinine value was normal also in the other patients. Hemolytic anemia with icterus or thrombocytopenia did not occur in any case. Bacteriology and serology As is shown in Table IV, 9 out of 15 cases from which cultivations were performed had growth of gonococci from the cervix and / or urethra. In 3 of 14 investigations performed, growth was demonstrated also from the rectum. In spite of the fact that 3-14 blood cultivations were performed on all the patients before the start of treatment, positive blood cultures were Scand J Infect Dis 2
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Table V. Minimum inhibiting concentrations as calculated from the paper disc test according to H. Ericsson (11) Case no. 2 3 5 6 7
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II \2 13
Penicillin (IU/mt) 0.05 0.02 0.2 0.1 0.1 0.01 0.\ >0.1
Streptomycin (mcg/rnl) 0.1 4 6a 4 6a 1
25 b
0.5
Tetracycline (mcg/rnl)
Chloramphenicol (mcg/rnl)
0.1 0.1 0.2 0.1 0.5 0.2 I 0.1
0.5 0.1 0.1 0.2 0.5 0.1 2 0.05
Sulphonamides (mcg/rnl)
0.5
4a 0.2 6a >0.2
a Classified as moderately sensitive. b
Classified as slightly sensitive.
obtained in I case only, namely the case that initiated our investigation. From vesicle contents, direct microscopy was performed in 5, cultivations in 14, and FA tests in 12 cases. These investigations turned out negative for all patients except one, where gonococci were demonstrated with the FA method. In 6 cases cultivation from all sites were negative. In 5 of them the diagnosis was supported through positive serological reactions. The demonstration of gonococci from skin lesions with the FA method in one of the seropositive patients, and a positive cultivation from the sexual partner of another seropositive patient constituted further support for the diagnosis in these cases. Of the 8 cases with positive serology, the GonoBallung was positive in 3 and CF in 5, all the latter belonging to the 6 cases investigated by Dr Dan Danielsson. Of the 8 cases with negative serological findings 5 were followed up with repeated tests but remained negative. The WR reaction was negative in all cases. Joint puncture was made in 2 patients. Exudate was obtained from one of these. Gonococci could not be demonstrated in the exudate. The results of determinations of the sensitivity to antibiotics are reported in Table V. All tested strains were sensitive to between 0.02 and 0.2 IV penicillin/rnl, Three strains showed lowered sensitivity to streptomycin, and so did 2 of 5 strains tested against sulphonamides. In cases in which both sensitivity test and concentration determinations were performed serum concentrations were recorded which exceeded the minimum inhibiting concentration for the particular strain by much more than 10-fold. These Scand J Infect Dis 2
observations corresponded to a rapid effect on the disease in all cases. Electrocardiographic and phonocardiographic examinations In 10 of the 16 patients all ECG and FCG examinations were normal. In no patient were there any definite proofs of myocarditis, endocarditis or pericarditis, although the findings in one patient may raise the suspicion of pericarditis. Auscultation in this case revealed no abnormal findings; only a systolic murmur over the pulmonary artery. FCG on the day after admission (heart rate 100/min) showed a midsystolic murmur over the second left intercostal space of rather low intensity and medium frequency. There was also a faint and short middiastolic murmur and a faint atriosystolic murmur at the same location. One week later, at a heart rate of 85/min, only a very faint short middiastolic murmur could be recorded. The initial ECG showed tachycardia and slight ST-T depressions which were completely absent 1 week later when an ectopic atrial rhythm was present in a part of the recording. The ECG:s thus did not indicate pericarditis. In two other subjects an ectopic atrial rhythm was recorded once during the hospital stay; in one of them this rhythm had also been recorded at a hospital stay 2 years previously. Still another patient showed ectopic atrial rhythm at the control I month after the hospital stay. Premature beats were rare; in one patient only was a premature atrial beat recorded. No ventricular premature beats were observed, neither ST or T changes indicative of myocarditis.
Benign gonococcemia
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Treatment 13 patients were treated with penicillin. 11 of them received a combined preparation for intramuscular injection consisting of 1 million IU benzylpenicillin and 1.2 million IU procaine penicillin. This combination was recommended by the Royal Medical Board Circular of April 30, 1963. However, the daily dose and the period of treatment were increased as recommended for gonorrhea with complications by the Venereal Disease Branch of the US Public Health Service, and accepted also by the Swedish authorities. One patient was treated with benzylpenicillin, one was given penicillin V orally. Penicillin allergy was presumed in 2 patients; one was treated with tetracycline and the other with erythromycin. The patient with negative cultivations but with typical clinical picture was discharged without treatment. The period of treatment was on the average 7.8 days with limit values of 0 and 17 days. Rise of temperature during treatment occurred in one case, probably due to a respiratory infection and/ or mastitis. All patients receiving treatment responded with promt improvement of objective and subjective symptoms. The time of hospitalization was on the average 20.9 days with limit values of 6 and 44 days.
Follow-up examinations All patients had completed the treatment. Subsequent controls with cultures from genital locations were performed in 12 cases, 9 at ambulatory venereologic clinics and 3 at Roslagstull Hospital. Unfortunately, no follow-up cultures were done in 4 cases. Among these were 2 cases which were initially bacteriologically negative. One patient could not be found again. The customary somatic control has been done in 13 cases at 1-7 visits. The longest observation time was 2 years. All control investigations turned out negative.
DISCUSSION Variations in host resistance may be a reason for the difference between the serious and the benign forms of gonococcemia. Also, it could be a question of differences in bacterial virulence (22). On the other hand, the bacteria even in the benign
197
form may be of high virulence, namely in the rare case where gonococcemia has been shown in both partners in a sexual relationship (4, 6). Blood cultivation is generally positive in cases of the serious form but as a rule it is negative in the benign type. Probably bacteria reach the blood stream in small numbers and only sporadically. The patients of this series presented symptoms, courses of events and a sexual distribution which were similar to those of previous materials (1-4, 6, 9-10, 12-13, 19, 21, 23, 28-29, 41). Asymptomatic carriers occur more frequently among women than among men. An infection, undiagnosed and consequently not treated for a long time, therefore could cause a gonococcemia more often in women than among men. A support for this hypothesis can be that the syndrome has been more often seen in men during recent years (1, 3, 6, 23,41), at the same time as asymptomatic gonorrhea in males has got more frequent (3, 16, 24-25, 30). It has been assumed that the use of hormonal contraceptive substances might create a greater risk for gonococcemia. Menstruation, pregnancy and delivery have been looked upon as provoking acute exacerbations and generalization of gonococcal infection (4, 6, 21, 28, 35). In some cases in our investigation there was indication that these factors were important. The mean age was rather high, 29 years, in this as well as in some previous materials (20, 32, 41), considering that the maximum frequency of gonorrhea lies in the age group 15-19 years among women in Sweden. Men have their maximum rate above the age of 25 and dominate in frequency over women from this age onwards. The high share of students contrasts to the corresponding figures for narcotic addicts with septicemia in Sweden (36). Narcotic misuse is not believed to exist in our present material. It was through a positive blood culture that our attention was drawn to the triad of symptoms associated with gonococcemia. It is surprising that there is no more case with a positive blood culture in the whole group of patients. The difficulty to isolate gonococci from blood has been stressed in several earlier surveys (1, 12, 23). Besides the intermittent appearance of bacteremia this difficulty may be connected with previous antibiotic treatment. That the syndrome is due to gonococcemia has been confirmed by a large number of investigations where positive blood cultures Scand J Infect Dis 2
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have been obtained (2-4, 6, 18-20,41). The gonococci were demonstrated in our material in most cases from the genital and anal mucous membranes. When the cultivations from these were negative, this implied that the primary localization was already eliminated (1, 4, 13). Like several other investigators (1, 6, 23, 41) we have been unsuccessful in cultivating gonococci from skin lesions. Probably the bacteria succumb very rapidly due to their sensitivity to physical and chemical influences as well as to cellular and humoral defense mechanisms (10). However, gonococci have been sufficiently often demonstrated in cultures from skin efflorescences to ascertain that these are really septic infarctions (1213, 20, 27, 32). Some authors state that it is easier to demonstrate gram-negative diplococci in skin lesions with microscopy of smears than by culture (1, 4). This could not be confirmed by our investigations. Successful results with the FA method have been reported in the last few years (10, 19). This method is not dependent upon viability of the microorganisms which is, of course, the necessary condition for cultivation. Our failures with the FA test in all cases but the last one can be partly explained by a less suitable method for sampling, which has now been abandoned. Since the cultivation frequently fails, the possibility for serological diagnosis becomes important. In this material the microbiological diagnosis was based solely on positive serological reactions in 3 cases. In women gonorrhea is completely free of symptoms in as many as 55 % (16) and sometimes the disturbances are so slight that often a long time elapses before a doctor's help is sought (25). In our study group 4 women were completely without subjective disturbances from the urogenital region. Most, however, had symptoms which ought to motivate a venereological investigation. None of the patients connected their urogenital disturbances with their febrile illness involving rash and arthritis. Our investigation, with only 1 case of gynecologically verified salpingitis, showed that normal gynecologic status is obviously no guarantee that gonorrhea does not exist (20). The only man in the material had no signs of urethritis. Evidently asymptomatic gonorrhea is a factor to reckon with also in men. The number of men with slight symptoms of urethritis is conScand J Infect Dis 2
tinually rising and amounted to 18 % in Sweden in 1966 (16). Fever, one of the components included in the triad, occurred in all patients. The temperature did not describe any typical curve, but fever periods of short duration, often recurring together with simultaneous appearance of cutaneous eruptions, occurred as a rule. Spontaneous abatement of fever was not an unusual phenomenon either, and even definitive healing of the infection without antibacterial therapy was noticed. The skin efflorescences are sufficiently characteristic to lead the observer to the right diagnosis of this disease, which otherwise could appear quite confusing. Besides the demonstration of gonococci in such efflorescences their macroscopic appearance with a central necrosis surrounded innermost by a violet zone caused by extravascular bleeding and by an outer hyperemic halo agrees well with the presumption of a septic infarction. The histopathological findings observed in biopsies of skin efflorescences in 2 of our cases are consistent with an angitis, and similar pictures have also been described in other surveys (4, 12). Further, predominant peripheral localization of the efflorescences is another indication of their embolic origin. Unlike other complications of genital gonorrhea arthritis showed an obvious decline in frequency after the introduction of antibiotic therapy (15, 17). The arthritis has also assumed ;1 tendency more often to be of a polyarticular type (15, 31). It has a predilection for the female sex (15, 21, 31), up to 83 % (15), and it is frequently reversible (15, 31). Joint involvement is an obligatory phenomenon in the benign gonococcemia syndrome. A polyarticular attack, at least initially, is most common (1, 6, 21, 28). This is seldom appreciated and is in contrast to the monoarticular pattern generally observed previously in bacterial infections in general (8) and gonorrheal ones in particular. The initially often mild polyarthritis is characterized by an asymmetrical involvement with slight migrating arthritis or arthralgia. In some cases a gradual intensifying and localizing to one single joint occurs subsequently. Tenosynovitis, which according to certain authors was so common in gonorrheal infection that they used it as a criterion for diagnosis (15, 21, 28), occurred in 5 cases only in our investiga-
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Benign gonococcemia tion. Arthritis and periarticular inflammation were more common in our patients and similar observations have been described in another survey (1). The quantity of exudate, however, was often insufficient for aspiration (21). The fact that cultivation of gonococci from joint exudates is frequently unsuccessful does not contradict the gonorrheal etiology (21, 31). According to Goobar and Clark (15) the agent was isolated from only 25 % of their cases. Keiser et al. (21) have also pointed out that even when the arthritis is associated with clinical, and may be bacteriological, evidence of gonococcal sepsis, isolation of gonococci from the synovial exudate seldom succeeds. Increase in serum transaminases and liver and spleen enlargement, regarded as signs of generalized organ manifestations, were observed in a few of our cases. However, in one of them these findings can be ascribed to alcoholic misuse and in none of the others were there any clinical or anamnestic indications of their being provoked by the gonococcal infection. In the past, the serious variant of gonococcemia was a common cause of acute and subacute endocarditis (37). In a recent material of 95 patients with endocarditis, however, Friedberg et al. (14) did not find anyone with gonococcal infection. The affinity of the gonococci to serous membranes can also cause pericarditis as a metastatic infection. Among 414 patients with purulent pericarditis Boyle et al. (7) observed 2 cases associated with gonococci, and Vietzke (39) reported 2 cases of pericarditis in patients with gonococcal arthritis. Myocarditis does not seem to be a common complication. Keiser et al. (21) did not find myocarditis in any of 24 patients with gonococcal septicemia. The present study does not reveal any definite cardiac complications. In one patient the FCG showed murmurs of too low intensity to be heard on auscultation, timed in midsystole, middiastole and in presystole and recordable only over the second left intercostal space. This is not a quite normal finding and should in this case be suggestive rather of an extracardiac friction rub than of a relative or absolute tricuspid stenosis. As the ECG showed no signs of pericarditis and the patient had no clinical symptoms the diagnosis is not clear. Ectopic atrial rhythm as a transient finding in 4 out of the 16 patients seems to be a
199
high frequency. However, it is an unspecific finding highly influenced by vegetative factors and does not suffice for the diagnosis of acute myocarditis. In one of the patients this rhythm was present also before this study. The general and local symptoms were less impressive than is usually the case in generalized infections. The milder course of events in benign gonococcemia has also been pointed out by other authors (26). An unaffected general condition without progress of the symptoms and the absence of complications during the time of observation emphasize the benign character of the disease. Many cases during the last few years which, according to their clinical pictures, have been interpreted as cases of low grade staphylococcal sepsis may very well have been cases of the benign gonococcal syndrome. Differential diagnosis must distinguish also between other forms of sepsis, among others meningococcemia, where similar skin manifestations and similar clinical pictures have been described (33). Among other differential diagnoses can be named typhoid fever, tuberculosis, Henoch-Schonlein's purpura, systemic lupus erythematodes, periarteritis nodosa, drug allergies and some viral diseases. In 14 cases described by Abu-Nassar et al. the most common misdiagnoses were rheumatic fever and nongonorrheal endocarditis with bacteremia (1). Over half of our cases were referred under the suspicion of septicemia but only one case as suspected gonorrhea. The others arrived with the diagnosis of cystopyelitis or rheumatic infection, erythema nodosum, rheumatic fever or lues, "exanthema and arthritis" and, in 3 cases, "fever of unknown origin". Penicillin is the drug of choice and the few patients who have been found to harbour strains with lowered sensitivity to penicillin or who showed allergy to penicillin could be successfully treated with other antibiotics. The relatively short time of treatment necessary deviates considerably from that called for in other forms of septicemia (1).
REFERENCES 1. Abu-Nassar, H., Hill, N., Fred, H. L. & Yow, E. M.: Cutaneous manifestations of gonococcemia: a review of 14 cases. Arch Intern Med (Chicago) 112: 731, 1963. 2. Ackerman, A. B.: Hemorrhagic bullae in gonococcemia. New Eng J Med 282: 793, 1970.
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3. Ackerman, A. R & Calabria, C.: Asymptomatic gonorrhea, the gonococcal carrier state, and gonococcemia in men. JAMA 196: 101, 1966. 4. Ackerman, A. R, Miller, R. C. & Shapiro, L.: Gonococcemia and its cutaneous manifestations. Arch Derm (Chicago) 91: 227, 1965. 5. Audry, c.: Gonococcie metastatique de la peau (angiodermite suppuree a gonocoques). Ann Derm Syph (Paris) 6: 544, 1905. 6. Bjornberg, A. & Gisslen, H.: Benign gonococcal sepsis with skin lesions. Brit J Vener Dis 42: 100, 1966. 7. Boyle, J. D., Pearce, J. D. & Guze, L. R: Purulent pericarditis. Medicine (Bait) 40: 119, 1961. 8. Chartier, Y., Martin, W. J. & Kelly, P. J.: Bacterial arthritis: Experiences in the treatment of 77 patients. Ann Intern Med 50: 1462, 1959. 9. Cowan, L.: Gonococcal ulceration of the tongue in the gonococcal dermatitis syndrome. Brit J Vener Dis 45: 228, 1969. 10. Danielsson, D. & Michaelsson, G.: The gonococcal dermatitis syndrome. Acta Dermatovener (Stockholm) 46: 257, 1966. 11. Ericsson, H.: Rational use of antibiotics in hospitals. Scand J Clin Lab Invest, Suppl. 50, 1960. 12. Fred, H. L., Eiband, J. M., Martincheck, L. A & Yow, E. M.: More on gonococcal dermatitis. Arch Intern Med (Chicago) 115: 191, 1965. 13. Frichot, R C. & Everett, M. A: Gonorrhea: arthritis, septicemia and cutaneous manifestations. A case report. J Okla Med Ass 60: 597, 1967. 14. Friedberg, C. K, Goldman, H. M. & Field, L. E.: Study of bacterial endocarditis. Arch Intern Med (Chicago) 107: 74, 1961. 15. Goobar, J. E. & Clark, G. M.: Rheumatological manifestations of gonorrhea. Arch Interam Rheum 7: 1, 1964. 16. Hansson, S.: Transactions of the Annual Meeting of the Swedish Medical Society, Stockholm 1968. 17. Hench, P. S. & Boland, E. W.: The management of chronic arthritis and other rheumatic diseases among soldiers of the United States Army. Ann Intern Med 24: 808, 1946. 18. Hewes, H. T.: Two cases of gonorrheal rheumatism with specific bacterial organisms in the blood. Boston Med Surg J 131: 515, 1894. 19. Kahn, G. & Danielsson, D.: Septic gonococcal dermatitis. Demonstration of gonococci and gonococcal antigens in skin lesions by immunofluorescense. Arch Derm (Chicago) 99: 421, 1969. 20. Keil, H.: A type of gonococcal bacteriaemia with characteristic haemorrhagic vesiculopustular and bullous skin lesions. Quart J Med 7: 1, 1938. 21. Keiser, H., Ruben, F. L., Wolinsky, E. & Kushner, I.: Clinical forms of gonococcal arthritis. New Eng J Med 279: 234, 1968. 22. Kellog, D. S., Jr, Peacock, W. L., Jr, Deacon, N. E., Brown, L. & Pirkle, C. I.: Neisseria gonorrhoeae: virulence genetically linked to clonal variation. J Bact 85: 1274, 1963. 23. Kvoming, S. A.: Acute skin eruptions in generalized gonorrhoea. Danish Med Bull 10: 188, 1963.
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24. Landsman, G. S. & Gelmi, 0.: Asymptomatic gonorrhea in the male. Southern Med J 52: 750, 1959. 25. Liden, S.: Gonorrefallen fortsatter at! oka - betydelsen av medicinska faktorer. Lakartidn 66: 907, 1969. 26. Lomholt, S.: Generalized gonococcal infection. In: Venereal Diseases in General Practice, p. 163. H. K. Lewis & Co. Ltd., London 1946. 27. Margolin, E. S.: Gonorrheal dermatitis as part of systemic gonorrhea. Urol Cutan Rev 47: 512, 1943. 28. Montgomery, M. M. & Poske, R. M.: Dermal disorders and rheumatic diseases. Med Clin N Amer 49: 85, 1965. 29. O'Sullivan, E. P.: Gonorrhoea in skin. Brit Med J 1: 1508, 1964. 30. Pariser, H., Farmer, A. D. & Marino, A: Asymptomatic gonorrhea in the male. Southern Med J 57: 688, 1964. 31. Partain, J. 0., Catchart, E. S. & Cohen, A. S.: Arthritis associated with gonorrhoea. Ann Rheum Dis 27: 156, 1968. 32. Reitzel, R. J. & Kohl, C.: Identification of gonococci in complications of gonorrhea. JAMA 110: 1095, 1938. 33. Robinson, S. S.: Septicemic eruptions: With special reference to the differentiation of septic and drug eruptions. Urol Cutan Rev 41: 490, 1937. 34. Selle: Medicina clinica 1781. Quoted from Buschke, A: Hautkrankheiten bei Gonorrhoe, In: Handbuch der Geschlechtskrankheiten, p. 276 (eds. E. Finger, J. Jadassohn, S. Ehrman & I. Gross). A HOlder, Wien and Leipzig 1912. 35. Spink, W. W. & Keefer, C. S.: Latent gonorrhea as cause of acute polyarticular arthritis. JAMA 109: 325, 1937. 36. Svanbom, M., Bengtsson, E., Strandell, T. & Tunevall, G.: Septicemia in narcotic addicts. To be published. 37. Thayer, W. S.: Gonococcal endocarditis. Edinburgh Med J 38: 314, 1931. 38. Thayer, J. D. & Martin, J. E., Jr.: A selective medium for the cultivation of N. gonorrhoea and N. meningitidis. Public Health Rep 79: 49, 1964. 39. Vietzke, W. M.: Gonococcal arthritis with pericarditis. Arch Intern Med (Chicago) 117: 270, 1966. 40. Wallmark, G.: Personal communication. 41. Wolff, C. B., Goodman, H. V. & Vahrman, J.: Gonorrhoea with skin and joint manifestations. Brit Med J 2: 271, 1970.
M. Svanbom, M.D., Roslagstulls sjukhus, Box 5901, S-11489 Stockholm, Sweden
ISSN: 0036-5548 (Print) 1651-1980 (Online) Journal homepage: http://www.tandfonline.com/loi/infd19
Benign Gonococcemia with Skin Lesions and Arthritis Maj Svanbom, Elias Bengtsson, Tore Strandell & Gösta Tunevall To cite this article: Maj Svanbom, Elias Bengtsson, Tore Strandell & Gösta Tunevall (1970) Benign Gonococcemia with Skin Lesions and Arthritis, Scandinavian Journal of Infectious Diseases, 2:3, 191-200 To link to this article: http://dx.doi.org/10.3109/inf.1970.2.issue-3.07
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Date: 06 November 2015, At: 11:59
Scand J Infect Dis 2: 191-200, 1970
BENIGN GONOCOCCEMIA WITH SKIN LESIONS AND ARTHRITIS Maj Svanbom, Elias Bengtsson, Tore Strandell and Gosta Tunevall
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From the Hospital for Infectious Diseases, Roslagstull Hospital, Stockholm, Sweden
ABSTRACT. An account is given of 16 cases of benign gonococcemia during the period Dec. 1, 1967 to Oct. 31, 1969. 15 patients were women, 1 man, and the average age was 29 years. The typical clinical picture consisted of fever, joint affection combined with a vesiculopapular, frequently hemorrhagic exanthema and genital gonococcal infection with usually slight or no symptoms and a good general condition throughnut, Neisseria gonerrhoeae was Isolated from the blood in 1 case. Positive cultures were more frequently obtained from the genital and anal mucous membranes. With the fluorescent antibody technique gonococci were demonstrated from an efftorescence of 1 patient. Serological response was demonstrated in 8 patients. All cases had an unequivocal clinical picture. Penicillin resistance did not occur, but a reduction in sensitivity was noted in 1 case. Treatment had prompt effect, but spontaneous healing was also seen. No complications or relapses were noted.
Generalized gonococcal infections can be manifested as a serious septicemia but also as a benign variant with recurring fever, mild arthritis and characteristic skin lesions. The latter form which may have been observed as early as in 1781 (34) was observed again about the turn of the century (5, 18) and has been reported rather frequently during the 1930's (20, 27, 32). The disease has received renewed interest in recent years 0, 2-4, 6, 9-10, 12-13, 19, 21, 23, 28-29, 41) after being largely disregarded in the intervening period. This report describes 16 patients with similar clinical pictures, which we observed during the years 1967-1969. The usual absence of venereal history and the difficulty to demonstrate the presence of the causative gonococci are stressed. METHODS From all patients suspected of sepsis a series of 3 blood cultivations was done, and this was repeated until growth was obtained or we considered that therapy had to be started. After termination of treatment new blood cultivations were performed if possible after 1 week, after 1 and 13* - 701954
6 months and after 1 year. The samples for blood cultures were taken with aid of the closed system of Wallmark (40), a vacuum flask containing a small amount of anticoagulant "Liquoid" solution. Besides in the usual media the blood was inoculated on hematin agar plates which were incubated in a CO 2-rich atmosphere for 2 days. Blood was incorporated also in 2 agar plates; one was incubated aerobically, the other anaerobically. Flasks, tubes and plates were examined every other day for at least 10 days. Gonococcal diagnosis was based upon colony appearance, oxidase test and direct microscopy of methylene blue-and gram-stained smears, fermentation tests and verification with the fluorescent antibody (FA) technique. Material from the genital and anal mucous membranes was taken with a charcoal-treated swab and placed in Stuart's transport medium. The tubes were kept at room temperature if they could not be cultured immediately. The material was inoculated on 2 hematin agar plates; to one was added polymyxin and ristocetin according to Thayer and Martin (38). The same procedure was applied to material from joints and skin efflorescences. With this material it was also attempted to show the presence of gonococci with the FA technique. Samples from skin lesions were taken with a syringe and needle by injection of sterile saline into a vesicle and reaspiration. In later cases we made scrapings of vesicle bottoms after the integument or crust had been removed. This technique of sampling is now in current use. Aspirates or scrapings were cultivated in the same manner as described above. In addition, smears were prepared for examination with the FA technique. Serum, taken upon admission and, as a rule, after 2 weeks, was tested for complement fixation (CF) with gonococcal antigen and subjected to a flocculation test, the so-called Gono-Ballung. Wasserman's reaction (WR) was also carried out." Determination of the sensitivity to benzylpenicillin, streptomycin, tetracycline and chloramphenicol was performed routinely on all the strains. In later cases the strains were also tested against sulphonamides. The determinations were performed with the paper disc method according to Ericsson (11). The FA examination of case 16 and CF tests in 6 cases were done by Dr Dan Danielson, the Regional Hospital, orebro, Sweden.
1
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Determination of the antibiotic concentration in serum was often performed during treatment. In cases receiving treatment with more than one substance, the antibacterial activity (ABA) of serum was studied with the patient's own strain as test organism. During the hospital stay the patients were regularly examined physically once a week by one and the same investigator. Routine blood and urine analysis, X-ray of the heart and lungs and ECG were done on the same occasions. Phonocardiograms (FCG) were recorded as soon as possible after admission and, in all but a few cases, before discharge from the hospital. Other X-ray and laboratory analyses were performed when required. Out of 16 patients 13 were investigated about 1 month after discharge with clinical examination, ECG and Xray of the heart and lungs as well as blood and urine analysis. Again, all patients were examined by one and the same physician (M. S.).
MATERIAL In a series of patients admitted with septicemia 19681969, 16 had the triad fever, arthritis and cutaneous lesions. As criterion for the diagnosis gonococcemia when this triad was displayed we demanded demonstration of gonococci in the urogenital region, in blood or in skin lesions, or serological indication. In 1 case, however, the typical clinical picture was considered sufficient for diagnosis. Of the 16 patients, IS were women. The average age was 29.0 years (17-55); 2 were teenagers, 9 between 20-30 years, 1 between 30-40 and 4 over 40 years. Six patients were students, the remainder had various occupations and belonged to different social groups. 13 were unmarried or divorced. Previous venereal infection was denied by 14 women, while the only male patient admitted gonorrhea 1 year before the current sickness and one woman 23 years before. A promiscuous way of life or the use of narcotics could not be shown in these patients. Only 8 of the 15 women used contraceptives; 7 took gestagenic substances and 1 had a spiral. In 1 case information was lacking. In order to illustrate the clinical manifestations and the course of the illness, 3 cases will be described.
CASE REPORTS Case I
A 54-year-old divorced woman. Symptoms of cystins developed I month after the last coitus, and after an additional 2 weeks subfebrile temperature increasing, reddened and sore infiltrations on the lower legs as well as arthralgia in the right knee and gradually in the right hand. Upon admission the general condition was unaffected, the temperature was 37.6°, and 2 types of cutaneous efflorescences were seen: 1) on the lower legs pink, sore infiltrations with increased temperature, varying in size, and 2) on the right thumb grip, the abdomen and lower legs, lesions with hemorrhagic contents and a central crust, less in size and with a surrounding pink halo. Scand J Infect Dis 2
No symptoms from any joints were present. During the first week in the hospital new cutaneous efflorescences appeared on the fingers and lower legs, 5-10 mm in diameter with a central dark red area and a surrounding erythematous zone. Simultaneously swelling and increased heat of the left ankle occurred. Gonococci were cultivated from the blood but not from the skin lesions. CF against gonococcal antigen was positive. WBC 10550/mm3, ESR 85 mmj l h. Tests for antinuclear factors in the serum were positive in 1/125 dilution against nuclear antigen and in 1/25 dilution against smooth muscle tissue. At a later examination both tests were negative. The following laboratory examinations were negative or within normal limits: liver and renal function tests, antistreptolysin (AS) and antistaphylolysin (ASta) tests, Widal reaction and WR as well as tests for rheumatoid factor and LE cells. ECG, FCG and X-ray of the lungs and heart were normal. No treatment was given until 2 months after the first symptoms appeared (3 months after infection). The patient was without fever and symptoms, when treatment, benzylpenicillin 6 million IV/day for 2 weeks, was given. She was followed up for 2 years and has had no symptoms. Repeated blood cultures have been negative. Case 7
A 17-year-old female student who 1 year earlier had 2 attacks of cystitis, which were treated with suiphonamides. She had a slight discharge after these attacks but was in general healthy. She denied having had venereal diseases. The last coitus was followed by increased vaginal discharge. She became ill 1 month later with high fever, chills, general myalgia and a small number of cutaneous efflorescences of hemorrhagic character on the thigh and trunk. The fever subsided after several days but subsequently the same symptoms returned every week. Upon admission 2 months after falling ill she was relatively unaffected. The temperature was 37.6°. The left wrist was swollen and tender, and painful upon movement. Some skin eruptions with hemorrhagic pea-sized pustules were located on the right middle finger and isolated erythematous maculopapules on the elbow and back of the hand as well as remnants of earlier efflorescences on the thigh. Gonococci were demonstrated in cultures from the urethra and rectum but not by direct microscopy. Repeated blood cultures were negative. FA test and cultures from the skin efflorescences as well as CF with gonococcal antigen were negative. WBC 10900, ESR 70 mm, Tests for C-reactive protein (CRP) were positive and there was a slight elevation of the alfa-2 fraction on electrophoresis of serum. Other examinations were negative or within normal limits: blood platelets, bleeding and coagulation times, liver and renal function tests, AS, ASta, WR, rheumatoid factor, ECG, FCG and X-ray of lungs. She was treated with 1 million IV benzylpenicillin + 1.2 million IV procaine penicillin G twice daily for 5 days. Fever and symptoms subsided already after one day's treatment. Follow-up examinations according to the rules of the V.S. National Health Service have been negative.
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Benign gonococcemia Case 16 A 47-year-old divorced woman, who had gonorrhea in 1945-1946 with salpingitis, and pregnancy toxicosis in 1961. The last coitus was in the beginning of September. Two weeks afterwards she fell ill during menstruation with general malaise and fainting and a rash on the middle finger of the left hand. Chills and fever 38.3-39.5° continued for 2 days. After a few days of low-grade fever the temperature rose again to 39.5° with myalgia in the left upper arm, rash on the right gluteal region, on the left elbow and the inner side of the right knee. No vaginal discharge appeared, and no signs of cystitis. Upon admission her general condition was unaffected. The temperature was 38.7°, the blood pressure 200/110 mmHg. On the bend of the first phalanx of the left middle finger an efflorescence with a dark crust was seen, 2-3 mm in size; in the right gluteal region 2 hemorrhagic pustules were found and on the inner side of the right knee joint an efflorescence, 2-3 mm in diameter, with a central pustule. No objective joint symptoms were noticed. Two days after admission and before treatment was initiated 3-4 typical eruptions arose on the right lower leg, 1 on the second toe of the right foot and 1 in the nape of the neck and also arthralgia in the right shoulder and right knee. Intense erythema and swelling appeared as well as restriction of movement of the left elbow. Examinations with FA technique of material from the base of vesiculo-papules on the elbow and gluteal region gave positive results and CF with gonococcal antigen was positive in dilution 1: 10 (Dr Dan Danielson, orebro). Cultures for gonococci from blood, cervix, urethra and rectum were negative. WBC 16400, ESR 35 mm, serum iron 54 fAg/IOO ml. Other examinations were negative or gave values within normal limits: AS, ASta, liver and renal function tests and X-ray of lungs. ECG showed slight ST depressions in connexion with tachycardia. The patient was treated with the routine penicillin combination twice daily for 7 days. The fever subsided on the third day of treatment. Follow-up examinations have been normal.
RESULTS Incubation period All women denied knowledge or suspicion of venereal infection; the one male patient stated, however, a suspicion of such. The incubation time could be determined in only a single case in which the occasion of exposure was reported to be 18 days before the onset of illness. The rest of the cases demonstrate the difficulties in this respect. Eight patients reported several possibilities of exposure between 2 and 10 weeks before falling ill. Seven patients either did not know or did not wish to give information on the time of exposure.
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Fever The fever on admission and at start of treatment is illustrated by the following figures: < 37.4° 37.4-37.9° 38-38.9° 39-40°
On admission At start of treatment
2 8
3 3
6 3
5 1
(l patient was not treated with antibiotics)
Four of the patients had fever bouts prior to admission; in 1 case no less than 4 relapses occurred, in another case 2 relapses besides the current fever. The periods of fever occurred between 1 month and 4-5 months before the onset of the current illness. The duration of fever before admission was on the average 4.5 (1-10) days. The fever before admission had been high and remittent in 11 cases. In 3 cases no or merely a slight fever occurred but chills suggested fever of a high remittent type. In 1 case the fever was low and remittent, in another a continuous, moderate increase of temperature had existed. Urogenital symptoms Five patients had signs of cystitis, 3 of these also discharge. Purulent vaginal discharge was found in 6 patients without symptoms of cystitis. Four women and the male patient had neither symptoms of cystitis nor discharge. Salpingitis was found in 1 only out of 12 women gynecologically examined. Nene of the patients was pregnant, but delivery had taken place in 2 cases, 3 and 11 months, respectively, before the onset of the illness. The onset of illness in connection with the menstruation period could be established in 4 cases. Two women were in the menopause and 1 woman had still amenorrhea after delivery. In no case any pelvic operation or gynecologic intervention had taken place. Skin eruptions In all cases skin efflorescenses appeared simultaneously or in close association with the other symptoms of the triad. In 3 cases new eruptions in connection with fever were observed after admission. The efflorescenses were isolated and irregularly distributed with a clear predilection for juxtaarticular regions, In Table I it is shown that in all 16 cases the distal parts of the upper exScand J Infect Dis 2
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Table I. Localization of cutaneous manifestations
Case no.
Face
Body
+
1
2
Upper extremities
Lower extremities
Prox. part
Prox. part
Dist. part
+ + + + + + + + + + + + + + + +
+ +
+
16
11
12
+
3
4
+
+
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5
+
6
7
+
+
+
+
+ +
+
+ +
+
8
9 10 11 12 13
+
14 15 16
Total
+ + 4
9
5
Dist. part
+ + + + + + + + +
+ + + + + + + + + + +
tremities were engaged, in 12 cases the distal parts of the lower extremities. Thereafter followed the proximal parts of the lower extremities and the trunk, while the proximal parts of the upper extremities and the face were affected less often. The number of efflorescenses varied from a few up to about 15. Different stages of development of the rash were observed simultaneously in 13 cases.
Initially discrete erythematous maculae less than 5 mm in diameter occurred in 6 cases; from 5 mm to 2 em in 5; and more than 2 cm in 2 cases. In 2 cases the sizes were not recorded. These maculae developed into papules and vesiculo-pustules, generally (13 cases) with hemorrhagic contents. In one case only pustules appeared and in another only crusts. The completely developed efflorescence constituted a sore vesiculo-pustule with dirty grey necrotic tissue in the center and surrounded by a thin reddish violet edge which in tum was surrounded by a reddish halo. In one case a bullous development could be noticed. Finally, there remained only the central crust which left a brownish discoloration behind. In 1 case erythema nodosum-like efflorescenses appeared and in another case a general erythema. In 2 cases histologic examinations were carried out on excised efflorescenses. In one of these there was a fibrinoid degeneration in the walls and occluding fibrin thrombosis in the lumen of some small arterioles in the corium connective tissue. Some inflammatory cell infiltration in the surrounding area was noted, partly with leucocytes. Also some veins appeared changed, principally with inflammatory cell infiltration. The corium connective tissue was edematous. Also, the subcutis presented signs of inflammation along the vessels. In the second case a dense perivascular inflammatory infiltration containing lymphocytes as well
Table II. Distribution of joint engagements The figures indicate the number of joints with notable changes in the respective region. The figures in parentheses indicate subjective disturbances Case no.
Shoulder
Elbow
Hand
(I)
6
(I)
7
(2)
8 9 10
(I)
(I) (I) 1 1
Knee
Foot
(I) (I)
3 1
(I) (I)
2 1
(I) 2 2
1 I (3)
I 1+(1)
(I)
1
(I)
2+(5)
7+(1)
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(2) (3) (2) (3) (2)
4 (I)
I (3)
5 1 I
(I) 7+(3)
1 1 4 I 1 I 5
I (I)
1 2
2+(3)
No. of joints
3
2
11
Total
Hip
(I)
1
2 3 4 5
12 13 14 15 16
Finger
(I)
8+(4)
5+(3)
(I) 1 (2) 31 +(20)
Benign gonococcemia
Table III. Joint engagement in 16 cases of gonococcemia with cutaneous manifestations No. of affected joints 2
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No. of patients
5
3
4
5
6
7
4
2
2
o
2
as leucocytes was found in the corium connective tissue. In a few places the inflammation was of a granulomatous type with a tendency towards giant cell formation. Several small vessels with similar perivascular infiltrations showed occlusions with fibrin thrombi. No fibrinoid degeneration of the walls could be demonstrated. The perivascular skin changes continued as far down as to the subcutaneous layer. Whether the changes were of the "bacterial embolus" type could neither be ascertained nor excluded.' Changes of the joints
The knee joints were affected most often, thereafter in the following order: finger, elbow, foot, shoulder, hand, and hip joints (Table II). Most of The biopsies were examined by Dr Hans Nordenstam, The Serafimer Hospital, Stockholm.
1
Table IV. Bacteriological and serological findings NO~not
done Serology
Cultivation Case no. I 2 3
Cervix
Urethra
Rectum
ND
NO
+ +
+ +
NO NO
+
+ + +
CF test
+
+
+ +
4 5 6 7
+ + +
8
9 10
+
+
11
+ + +
+ +
12 13 14a 15 16
a The only male individual.
GonoBaIIung
+ +
+ + +
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the cases had polyarticular engagements, while in 5 cases only monoarticular attacks had occurred (Table III), usually in large joints. In 11 cases an exudate occurred in at least one joint. With some exceptions the exudate was scarce and could be used for bacteriological diagnosis in one case only. In only 5 cases there were definite signs of a tenosynovitic engagement. X-ray of affected joints was made in 5 cases. No effusion, swelling of the soft tissue, or skeletal changes could be demonstrated. Other clinical findings In 4 patients the spleen was slightly enlarged and in 5 cases the liver, without changes in liver function tests, however. No signs of meningitis or conjunctivitis were seen. Laboratory findings ESR was raised in all patients but one, and the CRP test was positive, when performed. Half of the patients had leucocytosis (> 10 000 cells/ mm"). No anemia was found but about half of the cases had a low serum iron concentration. In 1 case a slight increase of serum glutamic oxaloacetic transaminases (SGOT) together with positive flocculation reactions and liver enlargement was noticed. These findings were rechecked and found to persist. Further, in 1 case there was an isolated serum glutamic pyruvic transaminase (SGPT) increase which rapidly returned to a normal value. No enlargement of the liver could be found in these patients by palpation or X-ray examination. In 1 case a slight hematuria was present on admission with 3-4 red blood cells per high power field without simultaneous increase of serum creatinine. The serum creatinine value was normal also in the other patients. Hemolytic anemia with icterus or thrombocytopenia did not occur in any case. Bacteriology and serology As is shown in Table IV, 9 out of 15 cases from which cultivations were performed had growth of gonococci from the cervix and / or urethra. In 3 of 14 investigations performed, growth was demonstrated also from the rectum. In spite of the fact that 3-14 blood cultivations were performed on all the patients before the start of treatment, positive blood cultures were Scand J Infect Dis 2
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Table V. Minimum inhibiting concentrations as calculated from the paper disc test according to H. Ericsson (11) Case no. 2 3 5 6 7
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II \2 13
Penicillin (IU/mt) 0.05 0.02 0.2 0.1 0.1 0.01 0.\ >0.1
Streptomycin (mcg/rnl) 0.1 4 6a 4 6a 1
25 b
0.5
Tetracycline (mcg/rnl)
Chloramphenicol (mcg/rnl)
0.1 0.1 0.2 0.1 0.5 0.2 I 0.1
0.5 0.1 0.1 0.2 0.5 0.1 2 0.05
Sulphonamides (mcg/rnl)
0.5
4a 0.2 6a >0.2
a Classified as moderately sensitive. b
Classified as slightly sensitive.
obtained in I case only, namely the case that initiated our investigation. From vesicle contents, direct microscopy was performed in 5, cultivations in 14, and FA tests in 12 cases. These investigations turned out negative for all patients except one, where gonococci were demonstrated with the FA method. In 6 cases cultivation from all sites were negative. In 5 of them the diagnosis was supported through positive serological reactions. The demonstration of gonococci from skin lesions with the FA method in one of the seropositive patients, and a positive cultivation from the sexual partner of another seropositive patient constituted further support for the diagnosis in these cases. Of the 8 cases with positive serology, the GonoBallung was positive in 3 and CF in 5, all the latter belonging to the 6 cases investigated by Dr Dan Danielsson. Of the 8 cases with negative serological findings 5 were followed up with repeated tests but remained negative. The WR reaction was negative in all cases. Joint puncture was made in 2 patients. Exudate was obtained from one of these. Gonococci could not be demonstrated in the exudate. The results of determinations of the sensitivity to antibiotics are reported in Table V. All tested strains were sensitive to between 0.02 and 0.2 IV penicillin/rnl, Three strains showed lowered sensitivity to streptomycin, and so did 2 of 5 strains tested against sulphonamides. In cases in which both sensitivity test and concentration determinations were performed serum concentrations were recorded which exceeded the minimum inhibiting concentration for the particular strain by much more than 10-fold. These Scand J Infect Dis 2
observations corresponded to a rapid effect on the disease in all cases. Electrocardiographic and phonocardiographic examinations In 10 of the 16 patients all ECG and FCG examinations were normal. In no patient were there any definite proofs of myocarditis, endocarditis or pericarditis, although the findings in one patient may raise the suspicion of pericarditis. Auscultation in this case revealed no abnormal findings; only a systolic murmur over the pulmonary artery. FCG on the day after admission (heart rate 100/min) showed a midsystolic murmur over the second left intercostal space of rather low intensity and medium frequency. There was also a faint and short middiastolic murmur and a faint atriosystolic murmur at the same location. One week later, at a heart rate of 85/min, only a very faint short middiastolic murmur could be recorded. The initial ECG showed tachycardia and slight ST-T depressions which were completely absent 1 week later when an ectopic atrial rhythm was present in a part of the recording. The ECG:s thus did not indicate pericarditis. In two other subjects an ectopic atrial rhythm was recorded once during the hospital stay; in one of them this rhythm had also been recorded at a hospital stay 2 years previously. Still another patient showed ectopic atrial rhythm at the control I month after the hospital stay. Premature beats were rare; in one patient only was a premature atrial beat recorded. No ventricular premature beats were observed, neither ST or T changes indicative of myocarditis.
Benign gonococcemia
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Treatment 13 patients were treated with penicillin. 11 of them received a combined preparation for intramuscular injection consisting of 1 million IU benzylpenicillin and 1.2 million IU procaine penicillin. This combination was recommended by the Royal Medical Board Circular of April 30, 1963. However, the daily dose and the period of treatment were increased as recommended for gonorrhea with complications by the Venereal Disease Branch of the US Public Health Service, and accepted also by the Swedish authorities. One patient was treated with benzylpenicillin, one was given penicillin V orally. Penicillin allergy was presumed in 2 patients; one was treated with tetracycline and the other with erythromycin. The patient with negative cultivations but with typical clinical picture was discharged without treatment. The period of treatment was on the average 7.8 days with limit values of 0 and 17 days. Rise of temperature during treatment occurred in one case, probably due to a respiratory infection and/ or mastitis. All patients receiving treatment responded with promt improvement of objective and subjective symptoms. The time of hospitalization was on the average 20.9 days with limit values of 6 and 44 days.
Follow-up examinations All patients had completed the treatment. Subsequent controls with cultures from genital locations were performed in 12 cases, 9 at ambulatory venereologic clinics and 3 at Roslagstull Hospital. Unfortunately, no follow-up cultures were done in 4 cases. Among these were 2 cases which were initially bacteriologically negative. One patient could not be found again. The customary somatic control has been done in 13 cases at 1-7 visits. The longest observation time was 2 years. All control investigations turned out negative.
DISCUSSION Variations in host resistance may be a reason for the difference between the serious and the benign forms of gonococcemia. Also, it could be a question of differences in bacterial virulence (22). On the other hand, the bacteria even in the benign
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form may be of high virulence, namely in the rare case where gonococcemia has been shown in both partners in a sexual relationship (4, 6). Blood cultivation is generally positive in cases of the serious form but as a rule it is negative in the benign type. Probably bacteria reach the blood stream in small numbers and only sporadically. The patients of this series presented symptoms, courses of events and a sexual distribution which were similar to those of previous materials (1-4, 6, 9-10, 12-13, 19, 21, 23, 28-29, 41). Asymptomatic carriers occur more frequently among women than among men. An infection, undiagnosed and consequently not treated for a long time, therefore could cause a gonococcemia more often in women than among men. A support for this hypothesis can be that the syndrome has been more often seen in men during recent years (1, 3, 6, 23,41), at the same time as asymptomatic gonorrhea in males has got more frequent (3, 16, 24-25, 30). It has been assumed that the use of hormonal contraceptive substances might create a greater risk for gonococcemia. Menstruation, pregnancy and delivery have been looked upon as provoking acute exacerbations and generalization of gonococcal infection (4, 6, 21, 28, 35). In some cases in our investigation there was indication that these factors were important. The mean age was rather high, 29 years, in this as well as in some previous materials (20, 32, 41), considering that the maximum frequency of gonorrhea lies in the age group 15-19 years among women in Sweden. Men have their maximum rate above the age of 25 and dominate in frequency over women from this age onwards. The high share of students contrasts to the corresponding figures for narcotic addicts with septicemia in Sweden (36). Narcotic misuse is not believed to exist in our present material. It was through a positive blood culture that our attention was drawn to the triad of symptoms associated with gonococcemia. It is surprising that there is no more case with a positive blood culture in the whole group of patients. The difficulty to isolate gonococci from blood has been stressed in several earlier surveys (1, 12, 23). Besides the intermittent appearance of bacteremia this difficulty may be connected with previous antibiotic treatment. That the syndrome is due to gonococcemia has been confirmed by a large number of investigations where positive blood cultures Scand J Infect Dis 2
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have been obtained (2-4, 6, 18-20,41). The gonococci were demonstrated in our material in most cases from the genital and anal mucous membranes. When the cultivations from these were negative, this implied that the primary localization was already eliminated (1, 4, 13). Like several other investigators (1, 6, 23, 41) we have been unsuccessful in cultivating gonococci from skin lesions. Probably the bacteria succumb very rapidly due to their sensitivity to physical and chemical influences as well as to cellular and humoral defense mechanisms (10). However, gonococci have been sufficiently often demonstrated in cultures from skin efflorescences to ascertain that these are really septic infarctions (1213, 20, 27, 32). Some authors state that it is easier to demonstrate gram-negative diplococci in skin lesions with microscopy of smears than by culture (1, 4). This could not be confirmed by our investigations. Successful results with the FA method have been reported in the last few years (10, 19). This method is not dependent upon viability of the microorganisms which is, of course, the necessary condition for cultivation. Our failures with the FA test in all cases but the last one can be partly explained by a less suitable method for sampling, which has now been abandoned. Since the cultivation frequently fails, the possibility for serological diagnosis becomes important. In this material the microbiological diagnosis was based solely on positive serological reactions in 3 cases. In women gonorrhea is completely free of symptoms in as many as 55 % (16) and sometimes the disturbances are so slight that often a long time elapses before a doctor's help is sought (25). In our study group 4 women were completely without subjective disturbances from the urogenital region. Most, however, had symptoms which ought to motivate a venereological investigation. None of the patients connected their urogenital disturbances with their febrile illness involving rash and arthritis. Our investigation, with only 1 case of gynecologically verified salpingitis, showed that normal gynecologic status is obviously no guarantee that gonorrhea does not exist (20). The only man in the material had no signs of urethritis. Evidently asymptomatic gonorrhea is a factor to reckon with also in men. The number of men with slight symptoms of urethritis is conScand J Infect Dis 2
tinually rising and amounted to 18 % in Sweden in 1966 (16). Fever, one of the components included in the triad, occurred in all patients. The temperature did not describe any typical curve, but fever periods of short duration, often recurring together with simultaneous appearance of cutaneous eruptions, occurred as a rule. Spontaneous abatement of fever was not an unusual phenomenon either, and even definitive healing of the infection without antibacterial therapy was noticed. The skin efflorescences are sufficiently characteristic to lead the observer to the right diagnosis of this disease, which otherwise could appear quite confusing. Besides the demonstration of gonococci in such efflorescences their macroscopic appearance with a central necrosis surrounded innermost by a violet zone caused by extravascular bleeding and by an outer hyperemic halo agrees well with the presumption of a septic infarction. The histopathological findings observed in biopsies of skin efflorescences in 2 of our cases are consistent with an angitis, and similar pictures have also been described in other surveys (4, 12). Further, predominant peripheral localization of the efflorescences is another indication of their embolic origin. Unlike other complications of genital gonorrhea arthritis showed an obvious decline in frequency after the introduction of antibiotic therapy (15, 17). The arthritis has also assumed ;1 tendency more often to be of a polyarticular type (15, 31). It has a predilection for the female sex (15, 21, 31), up to 83 % (15), and it is frequently reversible (15, 31). Joint involvement is an obligatory phenomenon in the benign gonococcemia syndrome. A polyarticular attack, at least initially, is most common (1, 6, 21, 28). This is seldom appreciated and is in contrast to the monoarticular pattern generally observed previously in bacterial infections in general (8) and gonorrheal ones in particular. The initially often mild polyarthritis is characterized by an asymmetrical involvement with slight migrating arthritis or arthralgia. In some cases a gradual intensifying and localizing to one single joint occurs subsequently. Tenosynovitis, which according to certain authors was so common in gonorrheal infection that they used it as a criterion for diagnosis (15, 21, 28), occurred in 5 cases only in our investiga-
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Benign gonococcemia tion. Arthritis and periarticular inflammation were more common in our patients and similar observations have been described in another survey (1). The quantity of exudate, however, was often insufficient for aspiration (21). The fact that cultivation of gonococci from joint exudates is frequently unsuccessful does not contradict the gonorrheal etiology (21, 31). According to Goobar and Clark (15) the agent was isolated from only 25 % of their cases. Keiser et al. (21) have also pointed out that even when the arthritis is associated with clinical, and may be bacteriological, evidence of gonococcal sepsis, isolation of gonococci from the synovial exudate seldom succeeds. Increase in serum transaminases and liver and spleen enlargement, regarded as signs of generalized organ manifestations, were observed in a few of our cases. However, in one of them these findings can be ascribed to alcoholic misuse and in none of the others were there any clinical or anamnestic indications of their being provoked by the gonococcal infection. In the past, the serious variant of gonococcemia was a common cause of acute and subacute endocarditis (37). In a recent material of 95 patients with endocarditis, however, Friedberg et al. (14) did not find anyone with gonococcal infection. The affinity of the gonococci to serous membranes can also cause pericarditis as a metastatic infection. Among 414 patients with purulent pericarditis Boyle et al. (7) observed 2 cases associated with gonococci, and Vietzke (39) reported 2 cases of pericarditis in patients with gonococcal arthritis. Myocarditis does not seem to be a common complication. Keiser et al. (21) did not find myocarditis in any of 24 patients with gonococcal septicemia. The present study does not reveal any definite cardiac complications. In one patient the FCG showed murmurs of too low intensity to be heard on auscultation, timed in midsystole, middiastole and in presystole and recordable only over the second left intercostal space. This is not a quite normal finding and should in this case be suggestive rather of an extracardiac friction rub than of a relative or absolute tricuspid stenosis. As the ECG showed no signs of pericarditis and the patient had no clinical symptoms the diagnosis is not clear. Ectopic atrial rhythm as a transient finding in 4 out of the 16 patients seems to be a
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high frequency. However, it is an unspecific finding highly influenced by vegetative factors and does not suffice for the diagnosis of acute myocarditis. In one of the patients this rhythm was present also before this study. The general and local symptoms were less impressive than is usually the case in generalized infections. The milder course of events in benign gonococcemia has also been pointed out by other authors (26). An unaffected general condition without progress of the symptoms and the absence of complications during the time of observation emphasize the benign character of the disease. Many cases during the last few years which, according to their clinical pictures, have been interpreted as cases of low grade staphylococcal sepsis may very well have been cases of the benign gonococcal syndrome. Differential diagnosis must distinguish also between other forms of sepsis, among others meningococcemia, where similar skin manifestations and similar clinical pictures have been described (33). Among other differential diagnoses can be named typhoid fever, tuberculosis, Henoch-Schonlein's purpura, systemic lupus erythematodes, periarteritis nodosa, drug allergies and some viral diseases. In 14 cases described by Abu-Nassar et al. the most common misdiagnoses were rheumatic fever and nongonorrheal endocarditis with bacteremia (1). Over half of our cases were referred under the suspicion of septicemia but only one case as suspected gonorrhea. The others arrived with the diagnosis of cystopyelitis or rheumatic infection, erythema nodosum, rheumatic fever or lues, "exanthema and arthritis" and, in 3 cases, "fever of unknown origin". Penicillin is the drug of choice and the few patients who have been found to harbour strains with lowered sensitivity to penicillin or who showed allergy to penicillin could be successfully treated with other antibiotics. The relatively short time of treatment necessary deviates considerably from that called for in other forms of septicemia (1).
REFERENCES 1. Abu-Nassar, H., Hill, N., Fred, H. L. & Yow, E. M.: Cutaneous manifestations of gonococcemia: a review of 14 cases. Arch Intern Med (Chicago) 112: 731, 1963. 2. Ackerman, A. B.: Hemorrhagic bullae in gonococcemia. New Eng J Med 282: 793, 1970.
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3. Ackerman, A. R & Calabria, C.: Asymptomatic gonorrhea, the gonococcal carrier state, and gonococcemia in men. JAMA 196: 101, 1966. 4. Ackerman, A. R, Miller, R. C. & Shapiro, L.: Gonococcemia and its cutaneous manifestations. Arch Derm (Chicago) 91: 227, 1965. 5. Audry, c.: Gonococcie metastatique de la peau (angiodermite suppuree a gonocoques). Ann Derm Syph (Paris) 6: 544, 1905. 6. Bjornberg, A. & Gisslen, H.: Benign gonococcal sepsis with skin lesions. Brit J Vener Dis 42: 100, 1966. 7. Boyle, J. D., Pearce, J. D. & Guze, L. R: Purulent pericarditis. Medicine (Bait) 40: 119, 1961. 8. Chartier, Y., Martin, W. J. & Kelly, P. J.: Bacterial arthritis: Experiences in the treatment of 77 patients. Ann Intern Med 50: 1462, 1959. 9. Cowan, L.: Gonococcal ulceration of the tongue in the gonococcal dermatitis syndrome. Brit J Vener Dis 45: 228, 1969. 10. Danielsson, D. & Michaelsson, G.: The gonococcal dermatitis syndrome. Acta Dermatovener (Stockholm) 46: 257, 1966. 11. Ericsson, H.: Rational use of antibiotics in hospitals. Scand J Clin Lab Invest, Suppl. 50, 1960. 12. Fred, H. L., Eiband, J. M., Martincheck, L. A & Yow, E. M.: More on gonococcal dermatitis. Arch Intern Med (Chicago) 115: 191, 1965. 13. Frichot, R C. & Everett, M. A: Gonorrhea: arthritis, septicemia and cutaneous manifestations. A case report. J Okla Med Ass 60: 597, 1967. 14. Friedberg, C. K, Goldman, H. M. & Field, L. E.: Study of bacterial endocarditis. Arch Intern Med (Chicago) 107: 74, 1961. 15. Goobar, J. E. & Clark, G. M.: Rheumatological manifestations of gonorrhea. Arch Interam Rheum 7: 1, 1964. 16. Hansson, S.: Transactions of the Annual Meeting of the Swedish Medical Society, Stockholm 1968. 17. Hench, P. S. & Boland, E. W.: The management of chronic arthritis and other rheumatic diseases among soldiers of the United States Army. Ann Intern Med 24: 808, 1946. 18. Hewes, H. T.: Two cases of gonorrheal rheumatism with specific bacterial organisms in the blood. Boston Med Surg J 131: 515, 1894. 19. Kahn, G. & Danielsson, D.: Septic gonococcal dermatitis. Demonstration of gonococci and gonococcal antigens in skin lesions by immunofluorescense. Arch Derm (Chicago) 99: 421, 1969. 20. Keil, H.: A type of gonococcal bacteriaemia with characteristic haemorrhagic vesiculopustular and bullous skin lesions. Quart J Med 7: 1, 1938. 21. Keiser, H., Ruben, F. L., Wolinsky, E. & Kushner, I.: Clinical forms of gonococcal arthritis. New Eng J Med 279: 234, 1968. 22. Kellog, D. S., Jr, Peacock, W. L., Jr, Deacon, N. E., Brown, L. & Pirkle, C. I.: Neisseria gonorrhoeae: virulence genetically linked to clonal variation. J Bact 85: 1274, 1963. 23. Kvoming, S. A.: Acute skin eruptions in generalized gonorrhoea. Danish Med Bull 10: 188, 1963.
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24. Landsman, G. S. & Gelmi, 0.: Asymptomatic gonorrhea in the male. Southern Med J 52: 750, 1959. 25. Liden, S.: Gonorrefallen fortsatter at! oka - betydelsen av medicinska faktorer. Lakartidn 66: 907, 1969. 26. Lomholt, S.: Generalized gonococcal infection. In: Venereal Diseases in General Practice, p. 163. H. K. Lewis & Co. Ltd., London 1946. 27. Margolin, E. S.: Gonorrheal dermatitis as part of systemic gonorrhea. Urol Cutan Rev 47: 512, 1943. 28. Montgomery, M. M. & Poske, R. M.: Dermal disorders and rheumatic diseases. Med Clin N Amer 49: 85, 1965. 29. O'Sullivan, E. P.: Gonorrhoea in skin. Brit Med J 1: 1508, 1964. 30. Pariser, H., Farmer, A. D. & Marino, A: Asymptomatic gonorrhea in the male. Southern Med J 57: 688, 1964. 31. Partain, J. 0., Catchart, E. S. & Cohen, A. S.: Arthritis associated with gonorrhoea. Ann Rheum Dis 27: 156, 1968. 32. Reitzel, R. J. & Kohl, C.: Identification of gonococci in complications of gonorrhea. JAMA 110: 1095, 1938. 33. Robinson, S. S.: Septicemic eruptions: With special reference to the differentiation of septic and drug eruptions. Urol Cutan Rev 41: 490, 1937. 34. Selle: Medicina clinica 1781. Quoted from Buschke, A: Hautkrankheiten bei Gonorrhoe, In: Handbuch der Geschlechtskrankheiten, p. 276 (eds. E. Finger, J. Jadassohn, S. Ehrman & I. Gross). A HOlder, Wien and Leipzig 1912. 35. Spink, W. W. & Keefer, C. S.: Latent gonorrhea as cause of acute polyarticular arthritis. JAMA 109: 325, 1937. 36. Svanbom, M., Bengtsson, E., Strandell, T. & Tunevall, G.: Septicemia in narcotic addicts. To be published. 37. Thayer, W. S.: Gonococcal endocarditis. Edinburgh Med J 38: 314, 1931. 38. Thayer, J. D. & Martin, J. E., Jr.: A selective medium for the cultivation of N. gonorrhoea and N. meningitidis. Public Health Rep 79: 49, 1964. 39. Vietzke, W. M.: Gonococcal arthritis with pericarditis. Arch Intern Med (Chicago) 117: 270, 1966. 40. Wallmark, G.: Personal communication. 41. Wolff, C. B., Goodman, H. V. & Vahrman, J.: Gonorrhoea with skin and joint manifestations. Brit Med J 2: 271, 1970.
M. Svanbom, M.D., Roslagstulls sjukhus, Box 5901, S-11489 Stockholm, Sweden
