Clinical Features , Complications and Treatment Outcome of Brucella infection : Ten Years ' Experience in an Endemic Area

Purpose: Brucellosis is a multi-systemic infection that is endemic in some parts of the world. The purpose of this study was to examine the epidemiology as well as the clinical and haematological characteristics, complications, and treatment outcome of patients with brucellosis at the King Fahd Hospital of the University Alkhobar, Saudi Arabia. Methods: A descriptive case assessment of all adult patients (aged 13 years and above) with brucellosis over a period of 10 years between 1998 and 2007 was undertaken. Results: The diagnosis of brucellosis in 84 patients was made by clinical findings, positive agglutination titre, and/or the isolation of Brucella species. The number of patients with brucellosis presenting at our hospital reduced over the study period, with a much smaller proportion of cases occurring after the year 2000. Most of the patients had fever (73%) and musculoskeletal symptoms (64%). Splenomegaly was recorded in 13% and hepatomegaly in 11% of patients. Seven patients (8%) had epididymo-orchitis. Two patients presented with fever of unknown origin with negative serology and only bone marrow culture was positive for Brucella mellitensis. Two patients presented with menstrual associated recurrent fever. One previously healthy patient presented with jaundice and spontaneous peritonitis. No therapeutic failure was observed but relapse occurred in six patients (7%). None of the patients who received streptomycin or ciprofloxacin as part of their antibiotic regimen had a relapse. Conclusion: Brucellosis has a wide range of clinical manifestations. Although the number of patients with brucellosis presenting at our hospital has reduced, continuous organized effort is necessary for brucellosis control.


INTRODUCTION
Brucellosis is a disease of domestic and wild animals that can be transmitted to humans (zoonosis).The disease exists worldwide, particularly in the Mediterranean basin, the Arabian Peninsula, the Indian subcontinent, and in parts of Mexico and Central and South America 1 .Consumption of contaminated foods and occupational contact remain the main sources of infection 1 .Human brucellosis may present with protean clinical manifestations that require broad differential diagnosis, including many infectious and noninfectious diseases.It is a systemic infection that can affect any organ in the body¹.The onset of disease is insidious in approximately half of all cases.It is characterized by several somatic complaints such as fever, sweats, anorexia, and weight loss.By contrast, there can be few abnormal physical findings.Occasionally, symptoms related to a single organ predominate.The aim of this study was to examine the epidemiological features, clinical and haematological characteristics, complications, and treatment outcomes of brucellosis in an endemic region.

Study population
Between 1998 and 2007, a descriptive case assessment of 84 adult patients with brucellosis presented to King Fahd Hospital of the University, Alkhobar, in a longitudinal prospective study.The university hospital is a secondary-tertiary care hospital in the Eastern Province of Saudi Arabia.

Diagnostic criteria
The diagnosis of brucellosis was based on the clinical findings characteristic of the disease and on either positive cultures that tested for Brucella species or a titre of ≥ 1: 160 antibodies by tube agglutination.Complete blood count, sedimentation rate, liver function tests, and in some patients detection of immunoglobulin (IgM and IgG) antibodies by ELISA were also performed.

Treatment and outcome
Various treatment combinations of anti-Brucella antimicrobials (streptomycin, doxycycline, co-trimoxazole, rifampicin, ciprofloxacin) were used, depending on the patient's age and pregnancy status.The mean follow-up period was one year, although this was not possible for all patients because of the nomadic nature of the patient population.Relapse was defined as an initial improvement followed by reappearance of symptoms and signs during the treatment period or within 2 months of discontinuation of treatment.A cure was defined as no recurrence of symptoms and signs during the 12-month follow-up period.

RESULTS
A total of 84 patients were diagnosed with brucellosis during the 10-year study.The number of patients with brucellosis reduced during the study period, with a much smaller number of cases occurring after 2000 (Fig. 1).The median age of patients was 32±9 years (range: 13-81 years).Males were more often affected than females and the male-to-female ratio was 3:1.Of the 84 patients, two presented with a relapse, while the other 82 were diagnosed with brucellosis for the first time.Fifty four patients (64%) gave history of contact with animals, sixteen patients (19%) gave history of drinking raw milk, five patients (6%) were involved in slaughtering animals particularly during Hajj season, three patients (4%) were laboratory workers, and six patients (7%) denied any risk factors for acquiring brucellosis.The occupations of the patients varied from farmers (21 males and 2 females), Sheppard (12 males, and 1 female), students (8 males and 4 females), teachers (6 males and 3 female), laboratory workers (2 males, and 1 female), engineer (I male), housemaid (1 female), housewives (18 females), and unemployed (4 males).
The clinical characteristics of the 84 patients with brucellosis are described in Table 1.A history of fever was obtained from 95% of patients, but it was positive in 73% of patients.A substantial number of patients (64%) developed arthritis or arthralgia.Splenomegaly was recorded in 13 (16%) and hepatomegaly in 9 (11%) patients.Two patients presented with fever of unknown origin with negative serology and only bone marrow culture was positive for Brucella mellitensis.Two patients presented with recurrent fever associated with menstruation.
ELISA was performed to test for IgM and IgG antibodies in 28 patients, and only 18 (64%) were positive for IgM or IgG antibodies.A positive result was noted in 8 of 23 patients (34%) for culture-confirmed brucellosis.

Treatment and rate of relapse
Treatment regimens for the 84 patients consisted of combinations of two or three agents: streptomycin plus doxycycline (18%); doxycycline plus rifampicin (18%); doxycycline plus co-trimoxazole (12%); rifampicin plus cotrimoxazole (2%); doxycycline plus ciprofloxacin (31%); and streptomycin plus doxycycline plus ciprofloxacin (19%).Streptomycin was administered for 15 days.Treatment with other antimicrobial agents varied according to clinical response and the development of complications (mainly arthritis).Spondylitis is recognized as the most common and one of the most debilitating forms of focal brucellosis and there is no consensus on the best therapeutic regimens, so we chose triple therapy (doxycycline, streptomycin, and ciprofloxacin) to treat patients with Brucella spondylitis.A total of 61 patients (73%) had long-term follow-up (12 months).Six patients (7%) suffered a relapse after completion of therapy with no osteoarticular or nervous system involvement.Three of these six patients had received doxycycline and co-trimoxazole.Isolates from two patients were found to be resistant to co-trimoxazole and the isolate from the third patient failed to grow.Three patients relapsed after receiving doxycycline and rifampicin.Blood cultures of both of these patients tested negative for Brucella.None of the patients who received streptomycin or ciprofloxacin in combination with doxycycline suffered a relapse (Table 2). .The likely culprits are poor compliance and the wide use of rifampin and streptomycin for the treatment of brucellosis and other conditions.
Alternative drug combinations have been used, including other aminoglycosides (e.g., gentamicin and netilmicin), trimethoprimsulfamethoxazole combination and quinolones.A recent meta-analysis of the efficacy of various combinations to treat spondylitis advocated treatment for at least three months; however, the superiority of one specific regimen could not be proved 24 , but preliminary results indicate that quinolones may be cost-effective in spondylitis 26 .In this study, patients received various chemotherapy regimens.The duration of therapy was based on the level of organ involvement.No therapeutic failure was observed with any of the regimens, but the relapse rate was 7%.None of the patients who received streptomycin or ciprofloxacin in combination with doxycycline had a relapse.A regimen of doxycycline and ciprofloxacin is significantly more expensive than the traditional regimens.However, when the protracted duration of other treatment regimens, the economic impact of the residual damage and the economic consequences are considered, the combination of doxycycline and ciprofloxacin may prove cost-effective.

CONCLUSION
The clinical presentations among our patients emphasize the wide and unexpected spectrum of this disease.Timely diagnosis and treatment of patients with brucellosis require clinical awareness of the full spectrum of signs and symptoms associated with brucellosis, as delay in treatment can result in significant morbidity.

Table 1 :
Clinical characteristics and laboratory findings of 84 patients with brucellosis SAT -standard tube agglutination test, ALT -alanine aminotransferase, AST -aspartate aminotransferase

Table 2 :
Treatment and outcome for 84 patients with brucellosis