Brucellosis in Saudi Arabia: Diverse Manifestations of an Important Cause of Pyrexial Illness

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1 Brucellosis in Saudi Arabia: Diverse Manifestations of an Important Cause of Pyrexial Illness Hussein M. Al-Freihi, MD*, Suliman A. Al-Mohaya, MD, Mohamed F. A. Al-Mohsen, MS Ezzeldin M. Ibrahim, MRCP, Mohamed O. Al-Sohaibani, MD, Kingsley Twum-Danso, MRCPath, Hassan Y. Al-Idrissi, Facharzt# * Assistant Professor of Medicine; Assistant Professor of Medicine; Lecturer in Medicine; Assistant Professor of Medicine; Assistant Professor of Pathology; Associate Professor of Microbiology; # Assistant Professor of Medicine; College of Medicine and Medical Sciences, King Faisal University, P.O. Box 214, Dammam, Saudi Arabia ABSTRACT A retrospective analysis of the medical records of 70 patients with brucellosis seen at King Fahd Hospital of King Faisal University was carried out. Male to female ratio was 2.3:1, with a median age of 35 years (range = 5-70 years). Eighty-seven percent were Saudi. Fever, back and joint pain, and excessive sweating were the commonest presenting symptoms, occurring in 95%, 36% and 34%, respectively. Splenomegaly, hepatomegaly, and lymphadenopathy were detected in 27%, 23% and 10%, respectively, and 16% had signs of arthropathy. Sixty-four percent of the patients were found to be anemic. Leukopenia, neutropenia and leukocytosis were found in 31%, 30% and 10% of patients. Blood cultures for Brucella were positive in 28 out of 55 tested patients (51%). In a retrospective analysis of 231 patients with pyrexia without an apparent etiology, brucellosis was found to be the commonest cause, accounting for 23% of all reviewed cases. In the text we compared some of our data with data reported recently from Riyadh. We conclude that human brucellosis has diverse clinical manifestations and high index of suspicion is needed for its early recognition. We also conclude that it represents a frequent cause of pyrexial illness. HM Al-Freihi, SA Al-Mohaya, MFA Al-Mohsen, EM Ibrahim, MO Al-Sohaibani, K Twum-Danso, HY Al-Idrissi, Brucellosis in Saudi Arabia: Diverse Manifestations of an Important Cause of Pyrexial Illness. 1986; 6(2): MeSH KEYWORDS: Brucellosis-Saudi Arabia Fever Introduction BRUCELLOSIS, remains one of the most widespread and economically ravaging of the worldwide zoonoses. 1 In some countries it has been successfully eradicated, 2 while in others attempts to control the disease have centered around the vaccination of young animals as well as testing and slaughtering older animals with serologic evidence of disease. 3 Human brucellosis also has worldwide distribution. 4 In Saudi Arabia, recent evidence has shown that the disease is a major health problem in both urban and rural areas. 5,6 However, because of its diverse clinical manifestations, many patients with human brucellosis escape early or correct recognition. 4 In this retrospective study we analyzed all patients with a proven diagnosis of brucellosis seen at King Fahd Hospital (KFH) of King Faisal University, Al-Khobar, Eastern Province, Saudi Arabia. We compared our data with that from other centers in the Kingdom and it illustrated the diverse clinical features of the disease. Finally, the relative importance of brucellosis as a cause of pyrexial illness without apparent etiology was assessed. Patients and Methods The medical records of all patients with a proven diagnosis of brucellosis seen at KFH between June 1981 and July 1985 were reviewed. The diagnosis was considered definite if it was made on the basis of a clinical picture compatible with brucellosis together with brucella agglutination titers 1:160 or 1 four-fold rise in titer, or isolation of Brucella organisms from blood cultures or both. In addition, to determine the relative frequency of brucellosis in the etiology of pyrexial illness, the medical records of all patients seen at KFH with fever of unknown origin were retrospectively reviewed. Pyrexial illness without an apparent etiology was defined as a rise in temperature to 38 C or more with no definite cause, after careful history, physical examination and routine laboratory investigations. Also included were those patients that would fulfill the criteria of pyrexia of unknown origin (PUO); i.e., pyrexia with a temperature of 38 C or more for at least two weeks, in whom diagnosis could not be made during at least one week of intensive investigations. For serological diagnosis, the standard brucella agglutination (using Difco antigen preparation) was performed on sera of all suspected cases of brucellosis with each serum diluted to 1:320. Each batch of tests is accompanied by

2 positive control serum of titer 80 and a negative control serum (Difco). For blood cultures, 3 to 5 ml of blood from every case of suspected brucellosis was inoculated into 30 ml of hypertonic trypticase soy broth with 10% sucrose in rubber stoppered bottles. Where there had been previous antimicrobial medication a second inoculation of 3-5 ml blood was made into a similar broth medium containing, in addition, resins. The broth cultures were incubated at 37 C for 24 hours, on a shaker to encourage bacterial multiplication, and then examined for evidence of bacterial growth using the Bactec Model 460 (Johnston Laboratories) by measuring radioactive CO 2 in the supernatant gas in the bottle and the cultures were returned to the incubator with the shaker for a second 24-hour period before a reexamination with the Bactec machine. Cultures were subsequently incubated without shaking, and examined daily with the Bactec machine. Any cultures showing evidence of growth were subcultured into freshly prepared sheep blood agar with Columbia blood agar base and incubated in a CO 2 incubator at 37 C for 48 hours. Gram stains also were made and examined for organisms. No further examinations were done on broth cultures that showed no evidence of growth by Bactec machine after a further 3 weeks incubation. Identification of isolates on the blood agar plates was done by Analytical Profile Index (API20) method. Then the Brucella species was serotyped by slide agglutination (using sera prepared by Wellcome). Results Medical records of 70 patients with a proven diagnosis of brucellosis were reviewed. Table 1 shows the distribution by age, sex and nationality. Male to female ratio was 2.3:1, and the median age was 35 years (range = 5-70 years). The disease was relatively uncommon in children below the age of 9 years. The median duration of symptoms was 3 weeks (range = 2-7 weeks). The clinical manifestations of all patients are summarized in Table 2. Fever, back and joint pain, excessive sweating, and headaches were the most common presenting symptoms. Splenomegaly, hepatomegaly and lymphadenopathy occurred in 27%, 23%, and 10% of patients, respectively. Signs of arthropathy were relatively uncommon compared to other local series. One young female developed clinical evidence of endocarditis, and her illness was further complicated by disseminated intravascular coagulopathy. Anemia, defined by a hematocrit less than 37% for women and less than 40% for men, was noted in 64% of our patients. A total white cell count of 4,500-9,500/cu mm was considered normal. Leukopenia was noted in 31% of patients, neutropenia (<2,000/cu mm) in 30%, leukocytosis in 10%, and a raised erythrocyte sedimentation rate (>30 mm/h) occurred in 49% of the patients. Table 1. Age, sex and nationality* distribution Age groups (years) Males Females > Total (%) 49(70%) 21(30%) *Nationality: Saudi Patients = 61 (87%) Non-Saudi patients = 9 (13%)

3 Table 2. Clinical manifestations in 70 patients Clinical datum No. of patients (%) Symptoms Fever 64(90%) Back and joint pain 24(34%) Night sweating 23(33%) Headaches 21(30%) Anorexia 12(17%) Nausea and vomiting 8(11%) Hematuria 1(1.5%) History of raw milk ingestion 36(51%) History of occupational exposure 3 (4%) Signs Fever 66(94%) Splenomegaly 29(37%) Hepatomegaly 16(23%) Active arthritis 11(16%) Lymphadenopathy 7(10%) Jaundice 1(1.5%) Endocarditis 1(1.5%) One or more abnormalities in liver function tests were demonstrated in 46 patients (65%). Elevated values of alkaline phosphatase, gamma glutamyl transpeptidase, lactic dehydrogenase and the transaminases were found in 23%, 29%, 53% and 58% of patients, respectively. Follow-up on liver function status could not be determined in 37 patients (53%), in whom the tests were not reevaluated or the patients were lost to follow-up. Among the remaining 33 patients (47%), 29 with initially abnormal liver function normalized over a median period of 3 weeks and a range of 1 to 14 weeks following therapy. In 68 (97%) patients, diagnostic brucella agglutination titers of 1:160 were detected. The remaining 2 patients were serologically negative, but they all had positive blood cultures for Brucella, and their serology was not repeated. Fifty-five patients had blood cultured for Brucella organisms. The cultures were positive in 28 patients (51%). Brucella melitensis was identified in 11 patients, and Brucella abortus in 2. In 15 patients the species was not identifiable. A retrospective analysis of the medical records of patients with PUO seen at KFH between June 1981 and July 1985, identified 231 patients. In about 75%, the etiology could not be determined initially by history, physical examination and routine laboratory workup. The remaining 25% had pyrexial illness that would fit the definition stated earlier for PUO. Of all those patients, brucellosis was the commonest disease entity occurring in 53 patients (23%), followed by salmonellosis in 33 patients (14%). Malaria and tuberculosis were relatively uncommon causes as they ocurred in only 15 (6.5%) and 8 (3%) of the patients, respectively (Table 3).

4 Table 3. Retrospective analysis of the etiology of PUO in 231patients Diagnosis No. of patients (%) Brucellosis 53(23%) Salmonellosis 33(14%) Atypical pneumonia and upper respiratory tract infection 30(13%) Urinary tract infection 27(12%) Malaria 15(6.5%) Tuberculosis 8(3.5%) Rheumatic fever 8(3.5%) Lymphoma 8(3.5%) Pyogenic abscess 7 (3%) Infective endocarditis 6(2.5%) Anicteric hepatitis 6(2.5%) Meningitis 6(2.5%) Solid tumors 5(2.5%) Drug fever 5(2.5%) Collagen-vascular disease 4(2%) Miscellaneous 10(4%) Total 231 (100%) Fifty-six patients were treated with a combination of oral tetracycline (0.5 gm six hourly) and intramuscular streptomycin (1 gm daily) for an average of 3 weeks. Oral tetracycline alone was continued for another 2-3 weeks. With the exception of one patient, all other 55 patients demonstrated a favorable clinical and laboratory response within 5 to 10 days. No significant drug-related toxicity was noted. The only patient who failed to respond was treated successfully with co-trimoxazole (each tablet contains trimethoprim 80 mg and sulfamethoxazole 400 mg) three tablets twice daily for 2 weeks followed by two tablets twice daily for another 4 weeks. There was no incidence of relapse in the patients treated. Co-trimoxazole was also used alone in the same dosage as the initial line of therapy in 3 pregnant (second and third trimester) and 2 lactating women. Dramatic response was achieved within 7-10 days. The three pregnant women had normal pregnancies without maternal or fetal complications. Oral tetracycline (2 gm daily for 3-6 weeks) was used alone in the treatment of nine patients resulting in complete but slow response. One patient was readmitted after 6 weeks with evidence of relapse or reinfection. The young female who developed endocarditis and disseminated intravascular coagulation was treated successfully with a combination of tetracycline and gentamicin in addition to anticoagulation and other supportive therapy. It is worth mentioning that the patient had no previous history of valvular heart disease. Discussion Epidemiologic studies have shown that human brucellosis is closely linked to the endemicity of animal infection, standards of hygiene, and man s food habits. In many rural areas in Saudi Arabia, brucellosis has been found to be endemic in domestic animals. 7 This high animal endemicity rate as well as the prevailing social habits among Saudis of drinking raw milk and milk products have resulted in a high incidence of human brucellosis in the Kingdom. 5, 6 Despite this high incidence, human brucellosis tends to be underdiagnosed. The clinical symptoms and physical findings of the disease are often nonspecific, nonacute, and also present for prolonged periods. Furthermore, the onset of symptoms is often insidious in almost 50% of the patients, 8 and in addition, the disease is usually characterized by a paucity of physical signs. 9 In our series, only 4 patients (6%) were under the age of 15 years, suggesting that the disease is rather uncommon in children. This low incidence was similar to that reported in another series from the Kingdom. 5 In contrast, however, other studies have concluded that childhood brucellosis is not uncommon in areas where the disease is endemic. 10,11 In our study, manifestations in the joints were relatively uncommon, compared to a recent report from Riyadh. 5 Back and joint pains and signs of arthropathy were documented in 36% and 16% of patients, respectively, compared

5 to 64% and 40%, respectively, in the Riyadh series. However, the incidence of bone and joint manifestations in human brucellosis in Saudi Arabia seems to be significantly more common than elsewhere. In a large series reported from Peru, joint and bone complications were documented in only 15% of patients. 12 The varying frequency of this complication has been attributed to differences in the species of infecting organism, with B. melitensis, the most common isolate in our study, producing the most serious illness. 13 The frequency rates of hepatosplenomegaly and lymphadenopathy in our series were higher than other reports from the Kingdom 5 and abroad. 14 Furthermore, the high incidence of hepatitis, as demonstrated by the mild to moderate impairment of the liver function tests in 65% of the patients, is significantly more frequent than the usual pattern of hepatitis associated with brucellosis. Hepatitis is usually less common and associated with only mild abnormalities demonstrable by liver function tests. 15,16 Subacute hepatitis was seen in only 23% of patients in the Riyadh series. 5 However, in neither study could other causes for hepatitis or impairment of liver function be ruled out. Liver biopsy was not done in any of our patients to demonstrate the presence of the hepatic Brucella granulomas. Normalization of the liver function following treatment was documented in 29 patients. However, the lack of histological confirmation in all patients with abnormal liver function and the lack of follow-up on another 17 patients precludes an accurate evaluation of subacute hepatitis in human brucellosis. Furthermore, it is conceivable that the impairment of liver function could be attributed to other etiologies. The standard agglutination method that has been used in our study might have missed some cases of chronic brucellosis where the immunoglobulin G. levels may be too low to be detected. However, since most of the cases in this series had active disease, it is not very likely that the number missed would be high. The negative serological reactions in two patients despite positive blood cultures could not be due to prozone phenomenon, since all sera were routinely diluted to 1:320. Furthermore, if there was a possibility of prozone at 1:320, the particular serum was further diluted to 1:1280. One possibility is that these were the cases that presented at a very early stage when antibody levels would not be high enough to be detected. Unfortunately, neither patient had a repeat serology to determine antibody production at a later stage in the course of their illness. The isolation rate of Brucella organisms in our series (51%) is comparatively high. This may be due to the fact that the laboratory uses freshly prepared sheep blood agar which is not stored for more than two days. More interesting perhaps is the isolation of B. abortus which, to our knowledge, has not been reported before in Saudi Arabia. The high incidence of anemia in our patients is in keeping with other series. 17 Diverse hematologic abnormalities have been linked to human brucellosis; however, the lack of a consistent pattern has minimized their diagnostic value. 14,17,18,19,20 In our retrospective analysis, human brucellosis was found to be present in almost one-fourth of all patients with pyrexia without an apparent etiology and also among some patients with classical PUO. Its frequency rate was more common than salmonellosis, malaria, or tuberculosis. A high index of suspicion is required for early recognition of this highly curable malady. In view of a recent surge in the prevalence of brucellosis in Saudi Arabia, a nationwide control program is warranted. REFERENCES 1. Abdulssalam M, Fein DA. Brucellosis as a world problem. In: International symposium on brucellosis (II). Dev Biol Stand 1976;31: Bjorkman G, Bengtson H. Eradication of bovine brucellosis in Sweden. J Am Vet Med Assoc 1962; 140: Scottish brucellosis symposium. Scott Med J 1970; 21: Wise RI. Brucellosis in the United States. Past, present and future. JAMA 1980; 244(20): Madkour MM, Rahman A, Mohamed E, et al. Brucellosis in Saudi Arabia. Saudi Med J 1985; 6(4) Kambal AM, Mahgoub ES, Jamjoom GA, Chowdhury MN. Brucellosis in Riyadh, Saudi Arabia. A microbiological and clinical study. Trans R Soc Trop Med Hyg 1983; 77(6): Radwan Al, Asmar JA, Frerichs WM, et al. Incidence of brucellosis in domestic livestock in Saudi Arabia. Trop Anim Health Prod 1983; 15(3): Center for Disease Control: brucellosis surveillance, annual summary Atlanta: Center for Disease Control, Spink WW. The nature of brucellosis. Minneapolis: University of Minnesota Press, 1956: Hagebusch OE, Frei CF. Undulant fever in children. Am J Clin Pathol 1941; 11:

6 11. Feiz J, Sabbaghian H, Miralai M. Brucellosis due to B. melitensis in children. Clinical and epidemiologic observations on 95 patients studied in central Iran. Clin Pediatr (Phila) 1978; 17(12): Aguilar JA, Elvidge AR. Intervertebral disk disease caused by the Brucella organism. J Neurosurg 1961; 18: Keenan JD, Metz CW Jr. Brucella spondylitis. A brief review and case report. Clin Orthop 1972; 82: Schirger A, Nichols DR, Martin WJ, et al. Brucellosis: experience with 224 patients. Ann Intern Med 1960; 52: McCullough NB, Eisele CW. Brucella hepatitis leading to cirrhosis of the liver. Arch Intern Med 1951; 88: Young EJ. Brucella melitensis hepatitis: the absence of granulomas. Ann Intern Med 1979; 91(3): Crosby E, Llosa L, Miro Quesada M, et al. Hematologic changes in brucellosis. J Infect Dis 1984; 150(3): Calder RM, Steen C, Baker L. Blood studies in brucellosis. JAMA 1939; 112: Spink WW. Clinical aspects of human brucellosis. In: Brucellosis: a symposium under the joint auspices of the National Institutes of Health, United States Department of Agriculture, and National Research Council. Washington, DC: American Association for the Advancement of Science, 1950: Young EJ. Human brucellosis. Reviews infect Dis 1983; 5(5):