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  1. 1. CLINICAL PROFILE AND MANAGEMENT OF BRUCELLOSIS IN TEHRAN – IRAN 11 Original Article CLINICAL PROFILE AND MANAGEMENT OF BRUCELLOSIS IN TEHRAN – IRAN A. Hadadi1, M. Rasoulinejad2, M. HajiAbdolbaghi2, M. Mohraz2, P. Khashayar3 Key words: brucellosis, clinical features, therapy, Iran ABSTRACT months in 83.85% of the patients prior to being examined in our centre. While sweating and fever Background- Brucellosis is one of the most were the most common symptoms, peripheral frequent infectious diseases in many regions of Iran. arthritis, sacroiliitis and splenomegaly were the The purpose of this study was to evaluate different most frequently reported signs. Rifampin plus clinical, laboratory and therapeutic aspects of this cotrimoxazole was the most common regimen disease. administered in these cases (32%) and relapse was Method- This retrospective descriptive study also more frequently seen in this group of patients was performed on patients referred to two teaching (13.8%), whilst doxycycline and cotrimoxazole led hospitals in Tehran/Iran with brucellosis diagnosis to the least number of relapses (2.5%). during the years 1998 - 2005. Patients’ signs and Conclusion- Brucellosis is known to have various symptoms, laboratory findings and clinical responses manifestations, so it should be considered as one were evaluated during the study period. of the differential diagnoses of any patient referred Results- More than half of the 415 patients with different organs involvement accompanied with enrolled in this study were female. The duration or without fever. Relapse is one of the complications of the symptoms was reported to be less than 2 reported even following an appropriate treatment. ––––––––––––––– 1 Associate Professor of Infectious Diseases, INTRODUCTION Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran; 2 Full Professor of Infectious Diseases – Brucellosis has remained a health catastrophe and Iranian Research Center of HIV/AIDS- a socio-economic problem in many Mediterranean Imam Khomeini Hospital, countries (1, 2). It is the most common zoonosis; as a Tehran University of Medical Sciences, result, it cannot be controlled unless it is eradicated in Tehran, Iran; 3 General Practitioner, animal populations. The disease has different manifes- Research and Development Center, tations which can be presented variably. This may lead Sina Hospital Tehran University of Medical Sciences, to delayed diagnoses as well as erroneous treatments Tehran, Iran in many cases; so it should be considered as a differ- Address for Correspondence: ential diagnosis of many infectious and non-infectious Dr Azar Hadadi diseases. Sina Hospital Brucellosis is a known endaemic disease in Iran. Imam Khomeini Street According to the reports published by the Center for Tehran, Iran Disease Control of the Ministry of Health, more than Tel: +98 (21) 66 71 65 46 Fax: +98 (21) 66 71 65 46 23,558 cases of brucellosis were diagnosed in Iran dur- E-mail: hadadiaz@ ing the year 2005. It also revealed the incidence rate Acta Clinica Belgica, 2009; 64-1
  2. 2. 12 CLINICAL PROFILE AND MANAGEMENT OF BRUCELLOSIS IN TEHRAN – IRAN of brucellosis to be 2 in 100,000 inhabitants of Tehran, years (35%). Neither of the studied cases was preg- the capital of Iran, where our study was performed nant. (3). The purpose of this study was to describe differ- The findings revealed that 76.4% of the patients ent aspects of this disease (epidemiologic, clinical, and had exposure to dairy products (CI: 71.94-80.33). Sev- therapeutic) in our country. enty-one patients (17.4%) had a positive history of oc- cupational exposure to cattle (95% CI: 13.68-21.16). A positive family history of brucellosis was seen in 19.5% MATERIALS AND METHODS of the cases (95% CI: 15.87-23.72). The incidence of the disease in different seasons was as follows: sum- Records of patients, presented to the infectious mer (32%), spring (30%), fall (21%) and winter (17%). diseases clinics and departments of the 2 main teach- June and July were reported to be the months with the ing hospitals affiliated to Tehran University of Medical highest incidence of this disease. Sciences, with brucellosis diagnosis between the years The duration of the symptoms was reported to be 1998 and 2005 were reviewed, retrospectively. Diag- less than 2 months in 83.85% of the patients prior noses were made based on the presence of clinical signs, to visiting our centre; this period ranged between 2 symptoms and radiologic findings with the evidence of months and 1 year in 13.3% of the cases and more brucella infection in addition to a serology equal to or than a year in only 0.5%. Sweating and fever were the greater than 1:80 using Standard Tube Agglutination most common symptoms; fever, peripheral arthritis, Test (SAT), a positive 2 mercaptoethanol test (2ME) or sacroiliitis and splenomegaly were the most frequent- Coombs Wright equal to or greater than 1:40 (3). ly reported signs (Table 1). Information on the demographic data, occupation, Three of the cases presented with fever of unknown history of consumption of non-pasteurized dairy, fam- origin (FUO) as the sole presentation; after perform- ily history, duration of the complaints, clinical presen- ing the required serologic tests and echocardiography, tations, laboratory findings, treatment regimen admin- all were diagnosed with endocarditis with aortic valve istered, response to treatment and recurrence were ex- vegetation. tracted from the patients’ records. Cases with general Meningoencephalitis (6 cases) was reported to be manifestations without any organ involvement were subacute (4 cases) or chronic (2 cases) in our patients. defined as ‘uncomplicated’ cases; on the other hand, The analysis of CSF revealed high amounts of protein those with localized involvement were considered as in all of these cases. Cell count was lower than 500 ‘complicated’ cases (meningoencephalitis, arthritis with lymphocytes as the prominent cells in all of the and endocarditis). samples. CSFs glucose was lower than normal in only Anaemia was defined as a haemoglobin level lower 2 cases. than 13 g/dL in men and lower than 12 g/dL in wom- Leukocytosis was reported in 13% of the studied in- en; thrombocytopaenia was defined as a platelet level dividuals. Laboratory findings are outlined in Table 2. lower than 150000/μl and leukopaenia was considered Five different drug regimens had been administered as a leukocyte count lower than 4000/μl. to the patients, among which rifampin + cotrimoxa- Statistical analyses were done using SPSS 11.5 soft- zole (RC) was the most common (n= 133, 32%), fol- ware (SPSS Inc., Chicago,IL). Continuous variables were lowed by rifampin + doxycycline (RD, n =124, 30%), ri- expressed as the mean ± standard deviation (SD) as fampin + cotrimoxazole + gentamycine (RCG, n= 112, well as minimum and maximum while frequency and 27%), doxycycline + cotrimoxazole (DC, n= 42, 10%) 95% confidence interval (95%CI) were computed for and doxycycline + rifampin + cotrimoxazole (DRC, n= qualitative variables. 4, 1%). The DRC regimen had been administered to just meningoencephalitis and endocarditis patients. Endocarditis patients had also undergone valvoplasty. RESULTS The patients were recommended to use the prescribed regimen for 8 weeks in uncomplicated cases and up to Four-hundred and fifteen patients were enrolled in 4-6 months in complicated subjects. All of the records this study; 52.5% of whom were female. The mean age had at least 6 months of follow-up and the median and of the patients was 35.5 ± 11.3 years (range: 12 - 80 maximum follow-up durations were 7 and 24 months, yrs). The patients were included in 3 age groups: under respectively. During this period, the patients had been 20 years old (20.5%), 20-40 years (44%) and above 40 assessed in regard with clinical manifestations. In case Acta Clinica Belgica, 2009; 64-1
  3. 3. CLINICAL PROFILE AND MANAGEMENT OF BRUCELLOSIS IN TEHRAN – IRAN 13 Table 1 Frequency of clinical signs and symptoms DISCUSSION of patients with brucellosis In this study, we tried to present a good descrip- Symptoms & Sings No (%) 95% CI tion of the characteristics of brucellosis patients in Symptoms Fever 279(67.22) 62.44-71.68 Sweating 304(73.25) 68.67-77.39 our country and their outcome. Age and sex distribu- Malaise-fatigue 268(64.54) 59.70-69.11 tion of the patients and the seasonal pattern of the Arthralgia 255(61.44) 56.55-66.11 disease incidence were rather similar to the studies in Headache 187(45) 40.16-49.93 other countries (4, 5). The evaluation of the presence Weight loss 121(29.15) 24.87-33.82 of the history for well-known transmission modes of Low back pain 175(42.16) 37.38-47.08 the disease showed that 76% of the patients report Signs Fever 235(56.62) 51.69-61.42 the consumption of non-pasteurized dairy which was Arthritis 84(21.6) 17.8025.94 reported to be 67% and 88% in different other studies Sacroiliitis 48(11.56) 8.72-15.13 Splenomegaly 97(23.37) 19.44-27.8 (5, 6). Occupational exposure was present in only 17% Spondylitis 11(2.6) 1.49-4.68 of our cases while a higher rate (34.2%, 58.7% and Erythema nodo- 3(0.7) 0.25-2.10 27.0%) was reported in other similar studies (4, 7-8). sum This could be due to the result that the majority of the Meningo- 6(1.4) 0.66-3.12 cases presented in the very study were housekeepers Complications encephalitis and urban habitants and the cattlemen comprised a Endocarditis 3(0.7) 0.25-2.10 Epididymo-orchitis 31(7.4) 5.18-10.47 smaller group of the patients. Another characteristic we evaluated was the fam- ily history of the disease which was positive in 19.5% of the cases. Other studies performed in Iran report- Table 2 Frequency of laboratory findings in ed the positive familial history to be 11.1% (95%CI: brucellosis 8-14%) (8), while reports from other countries show that the infection rate among family members is 19% No (%) 95%CI Anaemia 25 (6.02) 4.01-8.88 (9). According to the transmission way of the disease, Leucopaenia 14 (3.37) 2.02-5.58 the simultaneous infection of different members of a Leukocytosis 62 (13.00) 11.78-18.89 family could be possible. This finding can lead to the Lymphomonocytosis 17 (4.10) 2.57-6.46 fact that screening family members of an acute case Thrombocytopaenia 2 (0.48) 0.13-1.74 of brucellosis can help the early detection of cases in Positive CRP 240 (57.83) 52.91-62.61 order to prevent disease complications. However, the cost-effectiveness of this screening strategy needs to be investigated (10). Brucellosis usually manifests as an acute (< 2 of the relapse of signs and symptoms, serological tests months) or subacute (2-12 months) febrile illness, had been taken to confirm relapse diagnosis and if so, which may persist and progress to a chronic one (> 1 the treatment was re-initiated. year). Similar to other studies, most of our cases were Following the treatment, all patients had become reported to have an acute presentation with non-spe- symptom-free showing the initial response to the cific manifestations including sweating, fever, malaise treatment; however, relapse was seen in 40 of the and fatigue (11). patients in the follow-up duration. Relapses had oc- Haji Abdolbaghi et al., demonstrated hepatomegaly curred at the rate of about 13.8% in patients taking and splenomegaly to be present in 42% and 32% of RC regimens (95% CI: 8.2-20.5), whilst DC had led to the 505 hospitalized cases enrolled in their study from the least number of relapses (2.5%, 95% CI: 0-12.5). 1990-99 (9).However, hepatosplenomegaly was less Patients in whom RD and RCG was administered, re- frequent in our study. It may be due to the time trend lapse had been reported in 10% (95% CI: 5.1-16.3) and of the difference between study samples, as they have 8.3% of the cases (95% CI: 3.7-14.7), respectively. No studied admitted patients whose diseases might be mortality secondary to brucellosis occurred within the more chronic, severe or complicated. follow-up period of the present study. In general, the osteoarticular involvement including arthritis, spondylitis, osteomyelitis, tenosynovitis and bursitis was present in 20%-60% of the cases; how- Acta Clinica Belgica, 2009; 64-1
  4. 4. 14 CLINICAL PROFILE AND MANAGEMENT OF BRUCELLOSIS IN TEHRAN – IRAN ever, various involvement rates are reported in differ- less relapses in our study. A clinical trial performed in ent studies because of different criteria used to define Babol – Iran (1998-2001) compared the efficacy and osteoarticular involvements (2, 12-13). Osteoarticu- therapeutic responses of using DC and RC regimens. lar involvement was reported in 34.5% of our cases. Failure of treatments plus relapses were seen in 15.7% Therefore, brucellosis should be considered in patients and 26.4% of the cases treated with DC and RC, re- consulting with physicians about their low back pain, spectively (19). arthritis and arthralgia especially in endaemic areas like Another study carried out in Iran revealed the least Iran. number of relapses following the use of doxycycline – Tuberculosis and brucellosis are the most impor- cotrimoxazole regimen (20). tant differential diagnoses in patients with subacute Several interactions have been listed for rifampin; or chronic mononuclear meningitis in our country. moreover, the administration of rifampin for brucello- Meningo-encephalitis was the most common form of sis is accompanied by a higher risk of resistance if this cerebral involvement in our study (1.4%). Neurobru- drug is used in tuberculosis. It could be concluded that cellosis formed 6% of the subjects of another study the administration of rifampin free regimens is recom- performed in Iran (5). In a study performed on 18 mended for treating brucellosis. The superiority of DC cases of neurobrucellosis by Maclean et al., 11 cases regimen could allow the exclusive use of rifampin as had meningitis alone or accompanied by oedema of the drug for tuberculosis. Further clinical trials should papilla, optic neuritis and radiculopathy (14). confirm this superiority. Unilateral epididymo-orchitis is one of the most It is noteworthy that some limitations may have af- common complications of genitourinary brucellosis, fected our results as the records which did not contain affecting 2% to 20% of the males with brucellosis. complete information on the patients’ history, labora- Although the prognosis of the very complication is tory and radiologic findings or the ones which were not usually good, delay in diagnosis or inappropriate man- followed-up for at least 6 months, were excluded from agement may lead to orchiectomy (15). Epididymo- this study. However, these records comprised less than orchitis was present in 7% of our cases. 5% of all records evaluated and therefore, the nega- Although brucella endocarditis is a rare entity, found tive effect of this selection bias could be considered in less than 2% of these patients, it is associated with negligible. Furthermore, culture results would not be high mortality rates, especially in endaemic areas. Na- at hand in less than 4-6 weeks. Moreover, Bactec is not tive aortic valve is involved in 50%-70% of the cases. routinely performed in our country. As a result, serol- This complication is the major cause of death in this ogy was the only laboratory test used in this study. group of patients (16). Endocarditis was seen in 0.7% In addition, the hospitals under study are university of the cases of the present study. affiliated ones. There is no specific referral pattern to Significant haematologic changes were absent in these hospitals’ outpatient clinics; some patients are the majority of the cases of the present study; in other presented for the first diagnosis, whereas others are words, most of the cases had a normal CBC. Roushan complicated cases referred from other hospitals. They et al. reported normal WBC to be present in 84.5%, might not be a good representative sample of all bru- normal haemoglobin in 80.8%, normal ESR in 80.7% cellosis patients since the studied patients might be a and positive CRP in 60.4% of the cases (17). In a study biased selected group. Therefore, regarding the sever- conducted in Turkey lymphocytosis was documented ity of illness, presence of complications, or their socio- in 58.8%, anaemia in 33.3% and leukopaenia in 21.7% economic status, we should be cautious in interpreting of the patients (18). these findings. Overall, we should consider that the Regarding the treatment regimens administered to complicated cases in our studied patients are more the patients, rifampin + cotrimoxazole was the most prevalent compared to the population of all brucellosis common regimen prescribed in our study. This regimen patients of the country. is the regimen of choice by the Iranian Disease Control Committee (3). It is noteworthy that rifampin + cotri- moxazole are the regimens of choice prescribed by the CONCLUSION WHO. While RC and RD are the most common regi- mens used in Iran, RCG and DC are the other accepted It could be concluded that brucellosis has various regimens empirically used in our country. manifestations, so it should be considered as one of Doxycycline + cotrimoxazole was accompanied by the differential diagnoses of any patient referred with Acta Clinica Belgica, 2009; 64-1
  5. 5. CLINICAL PROFILE AND MANAGEMENT OF BRUCELLOSIS IN TEHRAN – IRAN 15 different organ involvement accompanied with or 7. Serra Alvarez J, Godoy Garcia P. Incidence, etiology and epide- without fever. In addition, screening the family of the miology of brucellosis in a rural area of the province of LIeida. Rev Esp Salud Publica 2000;74(1):45-53. affected patients can help with the early diagnosis and 8. HajiAbdolbaghi M, Rasoulinejad M. Epidemiologic, clinical, di- prevent related complications. agnostic and therapeutic survey in 505 cases with brucellosis. J Med Uni of Tehran 2000; 4: 34-46. 9. Alsubaie S, Almuneef M, Alshaalan M, et al. Acute brucellosis in Saudi families: Relationship between brucella serology and ACKNOWLEDGEMENT clinical symptoms. Int J Infect Dis 2005; 9: 218-24. 10. Sharifi Mood B, Metanat M, Alavi Naini R. Screening of the fam- We are indebted to the Research and Development ily Members of patients with acute brucellosis in Southeast Center of Sina Hospital for their support. The authors Iran. Indian J Med Microbiol 2007; 25(2):176-7. 11. Malik GM. A clinical study of brucellosis in adults in the Asir gratefully acknowledge Dr. Zeinali, the dean of the region of southern Saudi Arabia. Am J Trop Med Hyg 1997; Committee of Contagious Diseases of the Ministry of 56(4):375-7. Health, Treatment and Medical Education for his help- 12. Bosilkovski M, Keteva L, Caparoska S, Dimzova M. Osteoarticu- ful comments. The authors also would like to thank Dr. lar involvement in brucellosis: study of 196 cases in the repub- Parvin Tajik for reviewing the article and for her useful lic of Macedonia. CMJ 2004; 45(6): 727-33. 13. Geyik MF, Gur A, Nas K, et al. Musculoskeletal involvement in comments. brucellosis in different age groups: a study of 195 cases. Swiss Med Wkly 2002; 132: 98-105. 14. Maclean RD, Russell N, Yossuf khan M. Neurobrocellosis. Clin Infect Dis 1992; 15: 582-90. REFERENCES 15. Colmenero JD, Munoz Roca NL, Bermudez P, Plata A, Villalobos A, Reguera JM. Clinical findings, diagnostic approach, and out- 1. Bosilkovski M, Krteva L, Caparoska S, Dimzova M. Hip arthritis come of Brucella melitensis epididymo-orchitis. Diagn Micro- in brucellosis: a study of 33 cases in the Republic of Macedonia biol Infect Dis 2007; 57: 367-72. (FYROM). Int J Clin Pract 2004; 58(11): 1023-7. 16. Purwar S, Metgud SC, Darshan A, Mutnal MB, Nagmoti MB. 2. Pourbagher A, Pourbagher MA, Savas L, et al. Epidemiologic, Infective endocarditis due to brucella. Indian J Med Microbiol Clinical, and Imaging Findings in Brucellosis patients with oste- 2006; 24(4): 286-88. oarticular involvement. AJR 2006; 187: 873-80. 17. Hassanjani Roushan MR, Gangi SM, Ahmadi M. The Compari- 3. National guidelines for brucellosis control. Iranian Ministery of son of skeletal complications in patients with brucellosis. J Med Health and Medical Education. Health deputy center for dis- Univ Babol 2002; 5(1): 21-6. eases control. Zoonoses Office, 2007. 18. Fallatah SM, Oduloju AJ, Al-Dusari SN, Fakunle YM. Hu- 4. Elbeltagy KE. An epidemiological profile of brucellosis in Tabuk man brucellosis in Northern Saudi Arabia. Saudi Med J 2005; Province, Saudi Arabia. East Mediterr Health J 2001; 7(4-5):791- 26(10):1562-6. 8. 19. Hassanjani Roushan MR, Gangi SM, Ahmadi SA. Comparison of 5. Hasanjani Roushan MR, Mohrez M, Smailnejad Gangi SM, So- the efficacy of two months of treatment with co-trimoxazole leimani Amiri MJ, Hajiahmadi M. Epidemiological features and plus doxycycline vs. co trimoxazole plus rifampin in brucellosis. clinical manifestations in 469 adult patients with brucellosis in Swiss Med Wkly 2004. 18; 134(37-38):564-8. Babol, Northern Iran. Epidemiol Infect 2004; 132(6):1109-14. 20. Hadadi A, Mohraz M, Marefati M. The efficacy of different regi- 6. Tasbakan MI, Yamazhan T, Gokengin D, et al. Brucellosis: a retro- mens in treating Brucellosis in Imam Khomeini Hospital. J Trop spective evaluation. Trop Doct 2003; 33(3):151-3. Infect Dis 2003; 20: 29-32. Acta Clinica Belgica, 2009; 64-1