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NDT Advance Access originally published online on January 4, 2008
Nephrology Dialysis Transplantation 2008 23(7):2344-2349; doi:10.1093/ndt/gfm925
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Brucellosis in cases of end-stage renal disease

Tuba Turunç1, Yusuf Ziya Demiroglu1, Hikmet Aliskan2, Sule Çolakoglu2, Funda Timurkaynak1, Nurhan Özdemir3 and Hande Arslan1

1 Departments of Infectious Diseases and Clinical Microbiology 2 Departments of Clinical Microbiology and Microbiology 3 Departments of Nephrology, Baskent University Faculty of Medicine, 06490 Ankara, Turkey

Correspondence and offprint requests to: Tuba Turunç, Baskent University Faculty of Medicine, Adana Teaching and Medical Research Center, Department of Infectious Diseases and Clinical Microbiology, Dadaloglu Mah, 39 Sok, No. 6, 01250 Yuregir, Adana, Turkey. Tel: +90-322-3272727; Fax: +90-322-3271276; E-mail: tubaturunc{at}yahoo.com



   Abstract
Top
 Abstract
Short summary
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. Patients with brucellosis frequently present with joint and bone pain. However, brucellosis may be overlooked in patients with end-stage renal disease (ESRD) who undergo dialysis since amyloidosis due to renal osteodystrophy and beta-2 microglobulinaemia may cause bone pain as well. Only four cases of end-stage renal failure accompanied by brucellosis have been reported in the literature. We evaluated clinical and laboratory characteristics and organ involvement of seven brucellosis patients with end-stage renal failure and compared them with brucellosis cases without any renal diseases.

Methods. This is a prospective study and involved 158 patients diagnosed with brucellosis. All the patients were divided into two groups: brucellosis patients with ESRD (Group 1) and brucellosis patients without any renal disease (Group 2).

Results. Group 1 included 7 patients (5 males and 2 females with the mean age 52.1 ± 14 years) and Group 2 included 151 patients (62 males and 89 females with the mean age 45.4 ± 16 years). Out of seven patients in Group 1, one had neurobrucellosis, one had paravertebral abscess, one had epidural abscess and one had peripheral arthritis. In addition, one patient in Group 1 with accompanying sickle cell anaemia presented with pain crisis and was diagnosed with brucellosis on admission. Serological tests were negative for brucellosis, but Brucella melitensis was isolated in blood cultures in another patient with accompanying continuous ambulatory peritoneal dialysis. Group 1 more frequently had joint pain and malaise. B. melitensis was isolated in blood cultures in blood taken in the absence of fever in half of the cases in Group 1 positive for B. melitensis in blood cultures on admission.

Conclusion. B. melitensis can be isolated in blood cultures even in the absence of high fever. In fact, in the present study, B. melitensis was isolated in most of the cases without high fever. For this reason, blood cultures should be performed in cases of end-stage renal diseases suspected of having brucellosis although fever is not present. In addition, brucellosis can present various clinical forms in endemic areas, mimics several diseases and can be characterized with severe complications.

Keywords: brucellosis; end-stage renal diseases



   Short summary
Top
 Abstract
 Short summary
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Brucellosis may mimic various diseases. For this reason, brucellosis should be kept in mind in cases of end-stage renal diseases presenting with joint and bone pain especially in endemic regions. The disease may cause severe organ involvement.



   Introduction
Top
 Abstract
 Short summary
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Brucellosis is a zoonosis that can affect all the systems and organs in the body although it frequently involves the musculoskeletal system. Patients with brucellosis most frequently present with joint and bone pain [1]. Brucellosis may be overlooked in end-stage renal disease (ESRD) patients who undergo dialysis since amyloidosis owing to renal osteodystrophy and beta-2 microglobulinaemia may cause bone pain in this population [2]. To our knowledge, there have been only four reports of ESRD patients with brucellosis [3–6]. Unlike other studies, in this study, we reviewed clinical and laboratory features, organ involvement and treatment outcomes in seven brucellosis patients with ESRD and compared them with brucellosis patients without renal diseases.



   Patients and methods
Top
 Abstract
 Short summary
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Hospital setting and study population
Baskent University Faculty of Medicine Adana Teaching and Research Medical Center is a 535-bed tertiary-care hospital in Adana, Turkey. This prospective study was performed in the Department of Infectious Diseases and Clinical Microbiology between January 2001 and March 2006. Patients with brucellosis in this study were aged 16 years or older. This is a prospective study that involved 158 patients with brucellosis. The patients were divided into two groups: Group 1 (brucellosis patients with ESRD) and Group 2 (brucellosis patients without renal diseases).

Brucellosis was diagnosed on the basis of one of the following criteria: (1) isolation of Brucella species in blood, other body fluids, or tissue samples or (2) a compatible clinical picture such as arthralgia, fever, sweating, chills, headache and malaise supported detection of specific antibodies at significant titres and/or demonstration of an at least fourfold rise in antibody titre in serum specimens taken 2 or 3 weeks apart. Antibody titres of ≥1/160 on a standard tube agglutination test were considered significant.

Demographic data and results of medical history, physical examination, laboratory analyses, imaging studies, treatment and follow-up were recorded on individual forms.

Based on the duration of complaints, patients were classified as having acute brucellosis (<2 months), subacute brucellosis (2–12 months) or chronic brucellosis (>12 months).

The diagnosis of nervous system involvement was based on the presence of at least one of the following findings: isolation of Brucella spp. from the cerebrospinal fluid (CSF) or demonstration of antibodies to Brucella in CSF (at any titre) in the presence of any abnormality in CSF (presence of >10 cells per mm3; protein levels of >45 g/L or blood glucose levels of <40%). Cranial computed tomography (CT) was also performed for the differential diagnosis in patients with neurobrucellosis.

Radiological findings of sacroiliitis were a poorly defined subchondral osseous line, narrowing or widening of the interosseous line and narrowing or widening of the interosseous space. Radiographic findings of spondylitis were epiphysitis of the anterosuperior angle of the vertebra, narrowing of the disc space, erosion, sclerosis, vertebral collapse and osteomyelitis. Diagnoses of spondylitis and sacroiliitis were confirmed by CT or magnetic resonance imaging (MRI).

The diagnosis of the genitourinary complications was based on physical examination and scrotal ultrasonography and transrectal ultrasonography performed when necessary.

The patients were treated with various combinations of antibiotics. The regimens included the following antibiotics (for brucellosis cases without focal involvement):

  1. Oral doxycycline 100 mg every 12 h and oral rifampicin 600 mg every 24 h for 45 days.
  2. Oral doxycycline 100 mg every 12 h for 45 days plus streptomycin (1 g/day i.m.) for the first 21 days.
  3. Oral ciprofloxacin 500 mg every 12 h and oral rifampicin 600 mg every 24 h for 45 days.

Antibiotic treatment for spondylodiscitis initially consisted of streptomycin (1 g/day i.m.) plus doxycycline (100 mg p.o. b.i.d.). At the end of the third week of treatment, streptomycin was discontinued and a regimen of rifampicin (600 mg/day p.o.) plus doxycycline was administered up to the end of the sixth month.

Antibiotic treatment for neurobrucellosis was planned for 4 months and in the first month, the treatment consisted of ceftriaxone (2 g i.v., b.i.d.), rifampicin (600 mg/day p.o.) and doxycycline (100 mg p.o., b.i.d.). At the end of the first month, ceftriaxone was discontinued and a regimen of doxycycline plus rifampicin was administered until the end of the fourth month.

The patients were invited for the check-up in the first, third and sixth months of treatment and in the 12th month after the completion of the treatment.

Relapse was assessed by a recurrence of symptoms and signs of the disease, a positive blood culture or rising antibody titre after treatment in the absence of re-exposure to infection.

Statistical analyses
The data obtained were analysed using the Statistical Package for the Social Sciences (SPSS). The {chi}2 test and Fisher's exact test (when appropriate) were used for categorical variables, and Student's t-test was used to compare mean values.



   Results
Top
 Abstract
 Short summary
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Demographics and clinical features
Of the 343 ESRD patients followed in the nephrology unit of our hospital during the study period, 285 underwent haemodialysis and 58 underwent peritoneal dialysis (PD). Of all the ESRD patients, seven (2.04%; five males and two females with the mean age of 52.1 ± 14 years; range: 24–70 years) were diagnosed as having brucellosis and were treated in our clinic. Six patients received haemodialysis three times a week and one underwent continuous ambulatory PD (CAPD). Comparison of demographics between the groups revealed that the patients were more frequently male and stockbreeding farmers. Also, most of the cases in Group 1 were found to be followed for acute brucellosis. Patient characteristics and risk factors for patients in both groups are shown in Table 1.


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  		Table 1 Patient characteristics and risk factors

 
All ESRD patients with brucellosis complained about joint pain, particularly pain in the hip and knee joints, and weakness and three patients (42.8%) had also accompanying high fever.

In order of frequency, the most common complaints were arthralgia, malaise, sweating, fever, and lower-back pain in Group 2 (Table 2). Patients in Group 1 had fewer complaints about fever but more complaints of joint pain and malaise.


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  		Table 2 Symptoms in 158 patients

 
In Group 1, one patient had accompanying sickle cell anaemia and B. melitensis was isolated in blood cultures performed to determine the cause of a high fever when the patient was hospitalized for a pain crisis.

Musculoskeletal involvement was the most frequent complication in all groups and it was more frequent in Group 1. The most frequent musculoskeletal involvement was spondylodiscitis in all cases (66.6% of the cases in Group 1 and 58.8% of the cases in Group 2). It was most frequently located in the lumbar region in Group 2. Spondylodiscitis was accompanied by epidural and paravertebral abscess in two ESRD patients and one of them had multiple involvements including the thoracic and lumbar vertebrae.

In Group 1, one case (14.2%) had peripheral arthritis and right knee involvement. Five cases in Group 2 (9.8%) had peripheral arthritis. The most frequently involved peripheral joints were hip and shoulder joints. The second most frequent involvement was central nervous system involvement in both groups. Table 3 shows the complications due to brucellosis observed in both groups.


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  		Table 3 Complications due to brucellosis

 
Laboratory findings
Table 4 shows the laboratory findings of all the cases. None of the patients in Group 1 had leucopaenia, thrombocytopaenia or increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT), but all cases had a high erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Both groups had a similar frequency of lymphocytosis. Although blood cultures were not carried out in 26 cases in Group 2 for various reasons, B. melitensis was isolated in 64 (51.2%) out of 125 cases in which blood cultures were performed. Blood cultures were carried out in all seven cases of Group 1 and B. melitensis was isolated in four cases (57.1%). B. melitensis was isolated in blood cultures in blood taken in the absence of fever in half of the cases in Group 1 positive for B. melitensis in blood cultures on admission.


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  		Table 4 Laboratory analyses at initial examination in 158 patients with brucellosis

 
Although STA was negative in one case in Group 1 (14.2%), the B. melitensis was isolated in blood cultures. Also, STA was performed at higher dilutions to avoid prozone and it was negative for brucellosis. To exclude the presence of blocking antibodies, Coombs’ brucella agglutination test was done. Both Coombs’ test and SAT performed at 10-day intervals were negative for brucellosis. In addition, in Group 1, four cases (57.1%) had positive titres of 1/1280 or over, one case (14.2%) had positive titres of 1/640 and another case (14.2%) had positive titres of 1/320. In Group 2, STA was negative for B. melitensis but blood cultures were positive in one case (0.6%); 31 cases (20.5%) had positive titres of 1/160, 21 cases (13.9%) had positive titres of 1/320, 22 cases (14.6%) had positive titres of 1/640 and 75 cases (49.7%) had positive titres of 1/1280 or over.

Treatment
Taking into account the complications, side effects of the drugs and patient characteristics, we used seven different treatment regimens. The most frequently preferred treatment regimen in Group 2 was doxycycline 100 mg twice daily combined with rifampicin 600 mg once daily for 6 weeks in 68 cases (45%). The second most frequently used treatment regimen was streptomycin 1 g daily intramuscularly for the first 3 weeks of treatment combined with rifampicin plus doxycycline for 6 months in 22 cases (14.6%). This treatment regimen was mostly used for the patients with spondylodiscitis. Eighteen cases (11.9%) received streptomycin 1 g daily intramuscularly for 21 days combined with doxycycline plus rifampicin for 6 weeks. Most of these patients had sacroiliitis and/or peripheral arthritis. The third most commonly used treatment regimen was ciprofloxacin 500 mg twice daily combined with rifampicin. It was used for 30 days in 15 cases (9.9%) and for 45 days in another 15 cases (9.9%). Eight out of 9 cases with neurobrucellosis received the combination of doxycycline and rifampicin for 6 months and ceftriaxone 4 g daily intravenously for the first month of the treatment. One case with neurobrucellosis received co-trimoxazole 160/800 mg twice daily and the combination of doxycycline plus rifampicin for 6 months. Treatment regimens were changed in some patients due to side effects.

As for the treatment for Group 1, three patients without focal organ involvement were administered the combination of doxycycline 100 mg twice daily and rifampicin 600 mg once daily. Surgery was not performed in two patients with spondylodiscitis accompanied by epidural and paravertebral abscess since one of them did not have neurological involvement and the other was at a high risk of anaesthesia complications. These patients were given doxycycline 100 mg twice daily, rifampicin 600 mg once daily and co-trimoxazole 80/400 mg once daily for 6 months. One patient with neurobrucellosis was administered ceftriaxone 2 g twice daily intravenously and the combination of doxycycline plus rifampicin for 30 days. At the end 30 days, ceftriaxone was discontinued, but the combination of doxycycline plus rifampicin was continued for three more months. One patient with peripheral arthritis was treated with the combination of doxycycline plus rifampicin for 4 months.

During follow-up, none of the patients in Group 1 had relapses, but in Group 2, 12 patients (7.9%) had relapses and 3 patients (2%) did not respond to treatment.

Patient characteristics in Group 1 are shown in Table 5.


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  		Table 5 Characteristics of patients with end-stage renal diseases accompanied by brucellosis

 


   Discussion
Top
 Abstract
 Short summary
 Introduction
 Patients and methods
 Results
 Discussion
References
 
Brucellosis is an anthropozoonosis with a worldwide distribution. The disease causes high morbidity both in animals and humans and heavy financial burden, and represents a serious public health problem in many developing countries. [6]. Brucellosis, a zoonotic infection, is still endemic in Turkey as well as in the Middle East and Latin America. The disease has been prevalent in Turkey for years and there were 14 572 cases of human brucellosis in 2003 according to data from the Ministry of Health [7]. At this time the incidence of human brucellosis was two cases per 100 000 people in the region where the present study was performed. According to data from the World Health Organization, 500 000 people are diagnosed with brucellosis every year [8]. The incidence of the disease is thought to be higher than the number of reported cases because the clinical presentation of brucellosis varies widely and the disease can easily be misdiagnosed [9,10]. According to data from the Ministry of Health, there were 24 803 patients who underwent haemodialysis and 6222 who underwent CAPD in Turkey in 2003 [7].

Brucella spp. are small Gram-negative bacteria capable of surviving, and even multiplying, within the cells of the mononuclear phagocytic system, which could explain the high frequency of a long disease, complications and relapses. As in other infections, brucellosis may appear in various clinical pictures in ESRD patients. To our knowledge, there have been four cases of ESRD accompanied by brucellosis [3–6]. In this study, clinical features, laboratory results, treatment regimens and treatment outcomes were compared among seven cases of ESRD accompanied by brucellosis and its large series.

Brucellosis may appear at any age. The mean age of the patients was 52.1 ± 14 years in Group 1 and 45.4 ± 16 years (15–79 years) in Group 2. Although more than half of the patients in Group 2 were female (58.9% of the patients were female and 41.1% male), neither of the genders was preponderant. However, some studies revealed male preponderance, while others showed female preponderance [10,11].

Brucella infections may be difficult to diagnose because of their wide spectrum of clinical manifestations. For this reason, brucellosis is frequently included in the differential diagnosis of a variety of clinical pictures. Symptoms suggesting brucellosis include fever, headache, arthralgia, myalgia, back pain, sweat, malaise, fatigue and weight loss [10–12]. In the present study, the patients in both groups most frequently presented with joint pain and malaise, but the patients in Group 1 less frequently complained about fever. Amyloidosis due to renal osteodystrophy and beta-2-microglobulinemia may cause bone pain in ESRD patients [2]. For this reason, brucellosis may be overlooked in dialysis patients. Also, in the present study, one patient with ESRD and sickle cell anaemia presented with pain crisis and B. melitensis was isolated in blood culture. As far as we know, there have been no such cases reported in the literature.

Brucellosis most frequently causes musculoskeletal complications. It has been reported from different series that 19–69% of the brucellosis cases have musculoskeletal complications [10–13]. We found that the most frequent complication was musculoskeletal complications in both groups and the most frequent musculoskeletal complication was spondylodiscitis. The location and the frequency of musculoskeletal involvement vary. Consistent with the literature, some studies have revealed that the most frequent musculoskeletal involvement is spondylodiscitis, while the others have revealed that sacroiliitis is the most frequent musculoskeletal complication [10–14]. This tendency for axial involvement in adults may be due to the closure of the metaphysis, change in bone vascularization and redistribution of the bone marrow from the long to the axial bones, which begins in the second decade of life. Spondylodiscitis was accompanied by epidural and paravertebral abscess in two ESRD patients and one patient had multiple involvements including the thoracic and lumbar vertebrae. To our knowledge, there have been only three cases similar to our case reported in this study [15–17].

Neurological involvement is reported in 2–5% of brucellosis cases [18]. Although infrequent, neurologic complications are of marked clinical importance because they cause severe morbidity and sequelae [19]. The lesions are located mainly in the meninges, where a diffuse inflammatory infiltrate can be observed extending to the perineurium of the nerve sheaths and to the vessel walls. These pathologic findings explain the wide clinical polymorphisim of neurobrucellosis. The clinical picture may include meningitis, encephalitis, meningoencephalitis, radiculitis, myelitis and neuritis. The cranial nerves commonly involved are the optic, oculomotor, abducens, facial and vestibulocochlear [19,20]. In this study, nine patients in Group 2 (6%) had neurological involvement. Out of nine patients with neurobrucellosis, two had acute meningitis and seven had chronic meningitis. One case of ESRD accompanied by neurobrucellosis presented with diplopia and was found to have paralysis of the sixth cranial nerve on physical examination. The cases of neurobrucellosis in both groups recovered without any sequelae.

Routine laboratory tests are usually unremarkable or nonspecific. The white blood cell count and the ESR may be normal or elevated [21,22]. In Group 2, 51.7% of the patients had anaemia, 44.4% had lymphocytosis, 6.6% had leucopaenia, 2% had thrombocytopaenia and 61.6% had an increased ESR. All the cases in Group 1 had an increased ESR and high CRP levels. A higher rate of patients with anaemia in Group 1 can be ascribed to ESRD. Since Brucella is a facultative, intracellular pathogen that affects the reticuloendothelial system, it frequently causes liver involvement. Despite the high frequency of liver involvement, liver enzymes are normal or only moderately increased [22]. In the present study, 15% of the patients in Group 2 had high levels of ALT and AST. However, none of the cases of ESRD had increased levels of AST and ALT. Isolation of the causative agent helps to make a firm diagnosis of brucellosis. Colmenero et al. reported that Brucella spp. was isolated in 68.8% of the cases and Aygen et al. reported that the rate of positivity was 41.1% in one study and 22.6% in another study [10,11]. In the present study, B. melitensis was isolated in two out of four cases of ESRD in that blood cultures showed bacterial growth when the body temperature was <37°C. Therefore, blood cultures should be performed in ESRD patients with typical signs of brucellosis even if they do not have fever.

At present, brucellosis is most frequently diagnosed with serological tests. In the present study, SAT and Coombs’ brucella agglutination test were negative for B. melitensis in two cases (one in Group 1 and the other in Group 2), but the causative agent was isolated in blood cultures. This may be due to an excess of antigens (the phenomenon of prozone) or the presence of blocking antibodies. For this reason, the tests were repeated at high dilutions and Coombs’ brucella agglutination test was also done to rule out blocking antibodies in the above mentioned two cases. There have been two cases in the literature similar to the ones in the present study [26,27]. However, consistent with this study, Coombs’ brucella agglutination test was repeated for only one case at certain intervals.

The purpose of chemotherapy for brucellosis is to decrease symptoms, reduce complications and prevent relapses. Optimal treatment regimens for brucellosis should include at least one agent with good intracellular penetration [23–27]. Despite treatment including several antibiotic regimens, relapse is estimated to occur in 5–40% of the patients with acute brucellosis in the following year depending on antibiotic use, duration of treatment and combination of antibiotics [27]. In this study, the patients were given various regimens. The duration of the therapy was based an organ involvement. No therapeutic failure was observed in Group 1. A doxycycline–rifampicin combination is the best alternative to the common doxycycline–streptomycin combination. The doxycycline plus streptomycin regimen could prove to be more effective than the doxycycline plus rifampicin regimen in patients with spondylitis [28].

Forty-five percent of the patients in Group 2 were administered the combination of doxycycline and rifampicin. 11.7% of the patients administered this combination had relapses. Agalar et al. also reported that 10% of the patients receiving the combination of doxycycline plus rifampicin had relapses [28].

In conclusion, brucellosis is a zoonosis that may appear in a wide variety of clinical pictures and therefore, it may mimic various diseases. For this reason, brucellosis should be kept in mind in cases of ESRD presenting with joint and bone pain especially in endemic regions. The disease may cause severe organ involvement. In the present study, B. melitensis was isolated in the majority of the cases (57.2%) without fever. Blood cultures should be performed in cases of ESRD suspected of having brucellosis even if fever is not present.

The limitation of this study is that the number of patients with ESRD accompanied by brucellosis is low. Therefore, studies with larger sample sizes are needed.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Short summary
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Received for publication: 14. 8.07
Accepted in revised form: 11.12.07


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