A Complication of Brucellosis: Epididymoorchitis

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provided by Elsevier - Publisher Connector International Journal of Infectious Diseases (2006) 10, 171—177

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A complication of brucellosis: Epididymoorchitis

Esragu¨l Akıncı a,*,Hu¨rrem Bodur a, Mustafa Aydın C¸evik a, Ays¸e Erbay a, Selim Sırrı Eren a,I˙pek Zıraman b, Neriman Balaban c, Ali Atan d,Gu¨lu¨s¸an Ergu¨l e

a Department of Infectious Diseases and Clinical Microbiology, Ankara Numune Education and Research Hospital, Ankara, Turkey b Department of Radiology, Ankara Numune Education and Research Hospital, Ankara, Turkey c Department of Microbiology, Ankara Numune Education and Research Hospital, Ankara, Turkey d Department of Urology, Ankara Numune Education and Research Hospital, Ankara, Turkey e Department of Pathology, Ankara Numune Education and Research Hospital, Ankara, Turkey

Received 18 October 2004; received in revised form 28 January 2005; accepted 24 February 2005 Corresponding Editor: Marguerite Neill, Pawtucket, USA

KEYWORDS Summary Brucellosis; Brucella mellitensis; Background: Epididymoorchitis is the most frequent genitourinary complication of Brucella abortus; brucellosis. Epididymoorchitis; Methods: This prospective study was conducted between February 2001 and January Genitourinary 2004, prospectively. Male patients diagnosed with brucellosis were included in this infections study and evaluated for testicular involvement. Results: Epididymoorchitis was detected in 17 out of 134 (12.7%) male patients with brucellosis. Mean age of the patients was 36.9 Æ 7.1 years. Twelve patients (70.6%) had acute, four patients (23.5%) had subacute, and one patient (5.9%) had chronic brucellosis. The most common symptoms were scrotal pain (94%) and swelling (82%). Elevenpatientshadunilateralepididymoorchitis,fourhadunilateralorchitisandtwohad unilateral epididymitis. A testicular abscess was detected in one patient. Sperm analysis was performed on 14 patients. Five patients had aspermia and eight had oligospermia. Combined antibiotic therapy was started and continued for 6—8 weeks. Orchiectomy was required for two patients and granulomatous orchitis was detected in the resected specimens. Relapse occurred in only one patient. Three patients had permanent oligospermia and one patient had permanent aspermia after the antibiotic therapy. Younger age, high C-reactive protein level and blood culture positivity were statistically sig- niﬁcant differences between the patients with and without epididymoorchitis.

* Corresponding author. Present address: Department of Infectious Diseases and Clinical Microbiolgy, Numune Education and Research Hospital, C¸igdem Mahallesi, Segmen Sitesi, A Blok, No: 15, 06530 Karakusunlar, Ankara, Turkey. Tel.: +90 3122878183. E-mail address: [email protected] (E. Akıncı).

Conclusions: Brucellosis should be considered in the diagnosis of scrotal diseases in endemic areas. A conservative approach is usually adequate for managing brucellar epididymoorchitis. However, infertility problems may develop in these patients. Well- designed further investigations are needed to explain the relationship between brucellar epididymoorchitis and infertility in man. # 2005 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Introduction tenderness) and ultrasonographic examination. Mumps, testicular malignancies and other bacterial Brucellosis is a systemic infection in which any organ infections were excluded by: absence of history of orsystemofthebodycanbeinvolved.1 Inmen,various parotitis, genitourinary tract disease, genitourinary genitourinary infections including epididymoorchitis, tract manipulation, urethral discharge, and sexual prostatitis, testicular abscess and seminal vesiculitis exposure; negative mumps IgM with ELISA test; have been attributed to brucellosis.2 The most fre- normal serum amylase, alpha-fetoprotein and quent genitourinary complication of brucellosis is beta-human chorionic gonadotropin levels and epididymoorchitis. It was first described by Hardy negative scrotal ultrasonographic findings compati- as a cause of granulomatous orchitis in 1928.3 ble with testis tumor. Brucellosis is an endemic disease in Turkey. The Demographic data, clinical and laboratory seropositivity rate is 1.8% in the healthy population.4 findings, treatment, outcome and follow-up of Itisfrequentespeciallyintheruralareasofthemiddle the patients were recorded. The patients with and southeastern regions and Brucella melitensis is epididymoorchitis were followed up at least six the most prevalent strain.5—8 In this study, clinical months after the completion of the antibiotic characteristics and outcomes of 17 patients with therapy by clinical, laboratory and ultrasono- brucellar epididymoorchitis are presented and com- graphic findings. Outcomes were classified as fail- pared with male patients without epididymoorchitis. ure, relapse or cure. Relapse was defined as reappearance of signs and symptoms within six months after the completion of antibiotic therapy. Patients and methods Sperm analysis was also done before and after treatment to evaluate the effect of the infection The hospital setting and study population on fertility. Due to financial and other reasons, scrotal ultrasonography and sperm analysis could Ankara Numune Education and Research Hospital is a not be performed on the patients without epidi- 1100-bed referral and tertiary-care hospital in Tur- diymoorchitis. key. This study was conducted in the Infectious Dis- eases and Clinical Microbiology Clinic between Ultrasonographic examination and February 2001 and January 2004, prospectively. Male technique patients diagnosed with brucellosis were included in this study and evaluated for testicular involvement. On admission, all of the patients with epididymoorchitis underwent bilateral scrotal ultrasonography. In nine of them, the vascularity of the testis was Clinical assessment and definitions evaluated by color Doppler ultrasonography. Control scrotal ultrasonographic examination after the com- Definitive diagnosis of brucellosis was made by iso- pletion of the treatment was planned for all patients lation of Brucella species from the blood cultures. In with epididymoorchitis but it could be done in only the absence of positive blood culture, presumptive eight patients. diagnosis was made serologically by positive serum The sonographic studies, including gray-scale standard tube agglutination test (SAT) together with ultrasonography and color Doppler and power Dop- compatible clinical signs and symptoms of brucel- pler examinations, were performed by the same losis.1 According to the duration of symptoms, physician with a General Electric Logic-9 System patients were classified as having acute (<2 (GE Medical Systems, Solingen, Germany) using 5— months), subacute (2—12 months) or chronic bru- 14 mHz linear array transducer.The examination was cellosis (>12 months).9 Among these patients with performed with the patients in a supine position. brucellosis, the diagnosis of epididymoorchitis was Serial transverse and sagittal images of each testis based on clinical findings (scrotal swelling, pain or and epididymis were obtained in addition to at least A complication of brucellosis 173 one image showing both testes for direct compar- 7.0 (College Station, TX) was used for the statistical ison and the following parameters were assessed: analysis. epididymal echogenicity; testicular echogenicity and size; presence and characteristics of hydrocele. For color Doppler and power Doppler exam- Results ination, while the clinically inflamed testis was studied, the machine settings were adjusted to Between February 2001 and January 2004, a total of optimize the detection of blood flow. We evaluated 134 male patients with brucellosis were followed up. the scrotum of each patient by subjective side-by- The diagnosis was bacteriologically confirmed in 45 side comparison; abnormal blood flow was defined patients. In the remaining 89 patients, serological as a subjective increase or decrease in number, diagnoses were made. Of these 134 male patients, 17 size or length of visible vessels in the affected (12.7%) had brucellar epididymoorchitis. Mean age of testis compared with the unaffected testis. the patients with epididymoorchitis was 36.9 Æ 7.1 (range 23—45) years. Fifteen (88.2%) were married Microbiologic studies and had children. A total of 11 patients (64.7%) lived in rural areas; 13 patients (76.5%) were breeding Blood samples were cultured by use of an automated cattle and 15 patients (88.2%) had consumed unpas- culture system (Organon Tecnica BacT/Alert Bio- teurized dairy products. Occupational exposure was Merieux, France). Biotyping of the strains was car- detected in two patients (11.8%) who were working in ried out at the reference laboratory (Pendik the microbiology laboratory. Veterinary Research Laboratory, Istanbul, Turkey). At admission, duration of epididymoorchitis was a Standard tube agglutination tests and Coombs tests mean 11.8 Æ 12 (range 1—40) days. Twelve patients were performed. An agglutination titer of 1/160 (70.6%) had acute, four patients (23.5%) had suba- was accepted as positive.1,4,10 cute and one patient (5.9%) had chronic brucellosis. In one patient, brucellar epididymoorchitis Statistical analysis developed while he was on combined antibiotic therapy for brucellosis (on the 26th day) and in In statistical analysis Student’s t-test, Fisher’s exact another patient it developed just after the comple- test and the x2 test were used. A p value of <0.05 tion of the antibiotic therapy. These two patients was accepted as significant. Software package STATA had used the antibiotics irregularly.

Table 1 Characteristics of patients with and without brucellar epididymoorchitis. Characteristics of Patients with Patients without p Value the patients epididymoorchitis (n = 17) epididymoorchitis (n = 117) No. (%) No. (%) Mean age, years (SD) 36.9 (7.1) 46.8 (18.4) 0.03 Mean duration of symptoms, 60.7 (91.9) 82.1 (92.7) 0.38 days (SD) Scrotal pain 16 (94) 0 — Scrotal swelling 14 (82) 0 — Night sweats 10 (59) 0 — Scrotal redness 9 (53) 0 — Fever 9 (53) 54 (46) 0.60 Arthralgia 9 (53) 61 (52) 0.95 Headache 8 (47) 41 (35) 0.34 Hepatomegaly 6 (35) 19 (16) 0.06 Weakness 6 (35) 44 (38) 0.85 Dysuria 6 (35) 0 — Splenomegaly 5 (29) 19 (16) 0.19 Weight loss 4 (24) 38 (32) 0.33 Anorexia 3 (18) 29 (25) 0.38 Vomiting 3 (18) 18 (15) 0.52 Hepatosplenomegaly 2 (12) 13 (11) 0.60 Abdominal pain 2 (12) 0 — Frequent urination 1 (6) 0 — Hematuria 1 (6) 0 — 174 E. Akıncı et al.

Table 2 Laboratory ﬁndings in patients with and without brucellar epididymoorchitis. Laboratory ﬁndings Patients with Patients without p Value epididymoorchitis (n = 17) epididymoorchitis (n = 117) No. (%) No. (%) CRP >5 mg/dl 17 (100) 94 (80) — Mean CRP, mg/dl (SD) 68.4 (54.3) 35 (39.5) 0.01 ESR >20 mm/h 14 (82) 88 (75) 0.38 Mean ESR, mm/h (SD) 35.2 (17.4) 35 (26.4) 0.98 ALT and AST >40 IU/l 6 (35) 33 (28) 0.55 GGT >50 IU/l 5 (29) 19 (16) 0.19 ALP >150 IU/l 3 (18) 22 (19) 0.61 WBC >10.5 Â 109/l 3 (18) 14 (12) 0.37 Platelets <150 Â 109/l 3 (18) 14 (12) 0.37 Total bilirubin >1 mg/dl 2 (12) 4 (3) 0.33 Positive blood culture 10 (59) 35 (30) 0.04

The most common symptoms were scrotal pain Comparison of clinical and laboratory character- and swelling in the patients with epididymoorchitis istics of the patients with and without epididymoor- (Table 1). Eight (47.1%) patients had urinary tract chitis revealed that younger age, high CRP level and symptoms including dysuria, frequent urination and rate of the blood culture positivity were statistically hematuria. There were no clinical symptoms sug- signiﬁcant differences between these two groups gestive of urethritis. C-reactive protein (CRP) levels (Tables 1 and 2). were high (mean 68.4 mg/dl; range 8—187 mg/dl) in According to ultrasonographic examination, ele- all of the patients with epididymoorchitis (Table 2). ven patients had unilateral involvement of epididy- Erythrocyte sedimentation rates (ESRs) were mis and testis, four had unilateral involvement of between 11 and 75 mm/h (mean, 35.2 mm/h) and testis only and two had unilateral involvement of 14 patients had an ESR level above 20 mm/h. Ane- epididymis only. Bilateral involvement was not seen mia (hemoglobin <12 g/dl), severe thrombocytope- in any patients. Enlargement and hypoechoic echo- nia (thrombocytes <50 Â 109/l) and leukopenia texture were detected in the affected testis and (leukocytes <4.5 Â 109/l) were not detected in epididymis (Figure 1). A testicular abscess was found any of the patients. Three patients had platelet in one patient. Three patients had focal hypoechoic counts between 50 Â 109/l and 150 Â 109/l. The lesions in the involved testis. Hydroceles were pre- Brucella tube agglutination test was positive for sent in eight patients. Three patients had compli- all patients. Brucella spp were yielded from the cated hydroceles. Color and power Doppler imaging blood cultures of ten (58.8%) patients with epididy- showed hypervascularity of the testis and epididymoorchitis. Nine were Brucella melitensis and one mis of the affected side compared with the opposite was Brucella abortus. No growth was detected in side. Such a hypervascularity could not be shown in urine cultures. Urine analysis was normal in all any of the healthy opposite-side testes. patients except one who had hematuria. Alpha- fetoprotein and beta-human chorionic gonadotropin Table 3 Results of sperm analysis. levels were within normal ranges. Patient No. Sperm count (million/cm3) Motility (%) 115 50 20 — 30 — 41 90 510 30 616 90 7 0.2 0 80 — 940 60 10 0.2 0 11 10 40 12 8 0 Figure 1 Ultrasonographic imaging of orchitis due to 13 0 — Brucella melitensis. Right testis is enlarged and hypoe- 14 0 — choic compared to the left testis. A complication of brucellosis 175

Sperm analysis was carried out for 14 patients Discussion before antibiotic therapy was commenced (Table 3). Three patients were unable to give specimens for Brucellar epididymoorchitis has been described in 2— analysis. Five patients had aspermia and eight had 20% of patients with brucellosis.11 It is a relatively oligospermia (spermatozoa count <20 million/ common cause of epididymoorchitis in endemic cm3). Motility was normal (>50%) in only four areas.12,13 In the present study, epididymoorchitis patients. occurred in 12.7% of male patients with brucellosis. Ten patients were treated with rifampin plus The mean age of the patients was 36.9 years and they doxycycline, four patients with doxycycline plus were significantly younger than the patients without streptomycin, one patient with rifampin plus strep- epididymoorchitis. In other studies, patients with tomycin, one patient with streptomycin plus tri- brucellar epididymoorchitis were also found to be methoprim—sulfamethoxazole and one patient young,2,3,11,12 and it appears that brucellar epididy- with ciprofloxacin plus rifampin combination. Anti- moorchitis occurs most commonly in young males. biotic therapy was continued for 6—8 weeks. Clinical Most patients had an acute brucellosis when signs and symptoms were resolved in 15 (88.2%) epididymoorchitis occurred. Some studies support patients by medical treatment. Orchiectomy was this finding as it has been reported that patients required for two patients. One of these patients had with epididymoorchitis generally had acute a testicular abscess and pathological examination onset.3,11 But in one study, it was suggested that revealed necrotizing granulomatous orchitis. The the onset of brucellar epididymoorchitis was mostly other patient underwent orchiectomy because his insidious.14 However, according to some references, complaints did not resolve with the antibiotic ther- the acute, subacute and chronic classifications are apy. Granulomatous orchitis was detected in the arbitrary time periods and they may overlap.1 resected specimen. Relapse occurred in only one The most common symptoms were scrotal pain patient, in the previously unaffected testis, three and swelling. Fever was detected in more than half months after antibiotic therapy. of the patients. These symptoms were reported as Control ultrasonography and sperm analysis were the most frequent symptoms of brucellar epididy- carried out on eight patients between one and four moorchitis in the literature.3,11,12,14 Urinary tract months after the completion of antibiotic therapy. symptoms were present in 47% of the patients in this Hydrocele had completely resolved in all control study. Similarly, urinary tract symptoms were patients but hypoechoic echotexture did not disap- reported at a high level of 64% in one study.12 pear in four of them, although the symptoms had Nevertheless, the rate was lower in other stu- subsided and vascularity was decreased (Figure 2). dies.3,11 In all of these studies, urine analysis and The patient who relapsed developed fibrous bands urine cultures were normal in most of the patients, and bilateral testicular atrophy. Sperm counts which is also the case in our study. improved to normal levels (>20 million/cm3) in four Leukocytosis has generally been reported as not patients. Aspermia persisted in the patient with being a typical feature of brucellosis. In this study, bilateral testicular atrophy and three patients had leukocytosis was detected in 18% of the patients. permanent oligospermia (sperm counts, 0.6, 6 and Some studies presented leukocytosis (>10 Â 109/l) 15 million/cm3). as an important feature of brucellar epididymoorchitis.12,15 However, in other studies, leukocytosis was detected at lower rates.3,11,14 These results indicate that leukocytosis cannot be used to differ- entiate brucellar epididymoorchitis from nonspeci- fic epididymoorchitis. All patients had unilateral involvement and most of them had epididymoorchitis. These results were compatible with the literature.2,3,11—14 In the majority of cases, unilateral involvement of both epididymis and testis were reported. Bilateral involvement was rarely detected. Sperm analyses were subnormal in almost all patients at the acute phase of the infection. After antibiotic therapy, four patients had permanent Figure 2 Control ultrasonography after antibiotic ther- aspermia or oligospermia. Fifteen patients (88.2%) apy. Right testis contains hypoechoic area in the upper that had children were assumed to be fertile before pole. infection. According to these results, it may be 176 E. Akıncı et al. hypothesized that brucellosis causes decreased testicular lesions that are suspected of being neo- sperm counts and possibly infertility. But in this plasm.13 An unnecessary orchiectomy could be pre- study, scrotal ultrasonography and semen analyses vented as a consequence. could not be performed on patients without epidi- This study suggests that younger age is an impor- dymoorchitis. Further studies, with well-designed tant risk factor for the development of brucellar control groups, are needed to investigate the pos- epididymoorchitis. CRP level and rate of the blood sibility that brucellar epididymoorchitis causes culture positivity were also significantly higher in infertility in man. these patients. This is probably associated with the The interesting aspect of our results was the fact acute onset of the disease. that clinically unilateral infection of testis resulted In conclusion, brucellosis should be considered in aspermia and oligospermia. Osegbe found similar for the diagnosis of scrotal diseases in endemic results in patients with unilateral epididymoorchitis areas. A conservative approach with administration and performed bilateral testicular biopsies.16 The of combined antibiotic therapy is usually adequate biopsies indicated that infection caused bilateral for managing brucellar epididymoorchitis. However, gonadal damage. He suggested that prolonged infertility problems may develop in these patients. infection was the major cause of testicular loss There are no studies on this subject and well- and the consequent failure of the testis to regain designed further investigations are needed to spermatogenic function in the patients. Also, explain the relationship between brucellar epididy- research by Ingerslev et al. found a causal link moorchitis and infertility in man. between acute epididymitis and the development Conflict of interest: No conflict of interest to of antisperm antibodies.17 Although these studies declare. did not include patients with brucellar epididymoorchitis, the same mechanisms may also occur in brucellar epididymoorchitis. This could be investi- gated in further studies. References Human brucellosis continues to pose a therapeutic problem. The institution of a proper combination of 1. Young EJ. Brucella species. In: Mandell GL, Douglas RG, Bennett JE, Dolin R, editors. 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