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    Col Me Nero 1996

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    Enzo Furtado

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    © All Rights Reserved
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    Cit © 108 ty Witans & Wane Print in US Complications Associated with Brucella melitensis Infection: A Study of 530 Cases J.D. Coumenero, J. M. REGUERA, F. Martos, D. SANCHEZ-DE-Mora, M. DELGADO, M. CAUSE, A. Martix-FARFAN, AND C. JUAREZ Introduction Brucellosis is an anthropozoonosis with a world- wide distribution (82). Its high degree of morbidity, both for animals and humans, is an important cause of economic losses and represents a serious public health problem in many developing countries (9, 56, 64). Brucellae are small Gram-negative bacteria capa- ble of surviving, and even multiplying, within the cells of the mononuclear phagocytic system, which could explain the high frequency of long illnesses, complications, and relapses (98, 120). Although in many developed countries the current incidence of brucellosis is low (24, 126), the growing phenomena of international tourism and migration, together with the variable incubation period of the disease, may cause symptoms to develop in a differ- cent area or even country from where the infection ‘was contracted (15, 124). Infection by organisms of the genus Brucella has a wide clinical polymorphism, and almost every organ can be affected (121). For this reason, brucellosis is frequently included in the differential diagnosis of a variety of clinical pictures that involve many medical specialists. In Spain, brucellosis is primarily due to B. melitensis, which is carried by sheep and goats. B. suis and B. abortus, pathogens of swine and cat- tle, respectively, are rarely found in this locale. A few reports provide a general overview of the clinical aspects of the disease (25, 89, 102, 107, 128) or analyze some of its specific complications (20, 23, 26, 35, 50, 58, 104, 106). However, discrepancies in the incidence and diagnostic criteria of focal forms or complications of brucellosis are common (33, 128), Moreover, no reports analyze the possible fac- tors associated with the appearance of com- plications, From the Unit of infectious Diseases, Internal Medicine Depart- ‘ment, Regional Hospital, Malaga, Spain. Abbreviations used in this paper: ALAT, alanine aminotransfer- ase; CI, confidence interval; CSF, cerebrospinal fd; CT, com ‘Bted tomography; ELISA, enzyme-linked immunosorbent assay; ESR, erythrocyte sedimentation rate; GGT, gamma glutamyl- ‘transpeptidase; IFA, indirect immunofluorescence; OR, odds ratio. 195 In this study we carry out a comprehensive analy- sis of the focal forms of Brucella melitensis infec- tion in adults, analyze the possible factors related to their occurrence, and review the literature. Methods ‘Study population Five hundred thiry patients older than 14 years of age with active brucellosis diagnosed between January 1983 and December 1909 in the Infectious Diseases Unit of the Malaga Regional Hospi- tal were included in the study. Patients younger than 14 years of, age were excluded. Partial data on epidemiology and osteoarticu- lar complications of a subgroup of patients in this series have ‘been previously reported (32, 99), ‘Malaga Regional Hospital is a 1,350-bed tertiary care center, situated in southern Spain, which serves a population of 350,000 Inhabitants and provides referral attention to 1,250,000 people ‘mainly working inthe tourist and service industry, in the coastal ‘eas, or in farming and stockbreeding of sheep and goats inthe less populated interior areas. Diagnosis of brucellosis was established by isolation of Bi calla spp in blood or any other body fluid or tissue or a compatible clinical picture with the detection of specific antibodies at signi ‘cant tters or demonstration of an at least ‘fold rise in antibody titer in serum specimens drawn 2 to 3 weeks apart. Significant Liters were considered to be ay ofthe following: Wright's seroag slutination test 2 1/160, indirect immunofluorescence (IFA) 2 V/ 100, nonagglutinating antibodies by using Coombs test for Bru- cella 2 120. Al patients were enrolled in a prospective study that included a complete history and physical examination; complete blood cell count; erythrocyte sedimentation rate (ESR) (Westergren); chemistry profile (glucose, serum electrolytes, creatinine, total protein and protein electrophoresis, liver profile); routine urine biochemical analysis and sediment; and radiographs of chest, abdomen, lumbar spine, both sacroiliac joints in the prone post tion, and any other osteoarticular location suspected of being affected. For deep locations (spine, sacroiliac, and hip joints), a radionuctide bone scan with technetium-£9 methylene diphospho- nate (555 MBq) was performed when there was a high clinical suspicion and radiographic examination was normal Microbiological study Serologic tests included agglutination in porta with antigen stained with rose Bengal, Wrights seroagalutinaton, and IFA. From 1990 onward, an enzyme-linked immunosorbent assay 196 COLMENERO ET AL. (ELISA), previously validated by our group, substituted for TFA. (31). Coombs test was used only in those cases with indeterminate iagnosis after the previous tests. All tests were carried out ac- conting to previously described techniques (10, 42, 70, 86). Blood cultures were perforned and processed following usual techniques (71, 139) For blood culture, biphasic Ruiz Castaneda, ‘medium (Materiales y Reactivos SA, Madrid, Spain) was used ‘until 1988. After 1988, nonradiometric BACTEC NR 730 system, (Becton-Dickinson Diagnostic Instrument Systems, Towson, MD, USA) was used. After the inital isolation and identification, all, strains of Brucella were sent to the Laboratorio de Referencia de Brucelosis (Valladolid, Spain) for confirmation and biotyping. Treatment schedules Patients were treated with several therapeutic schedules, mod- ified over the study period according to advances in treatment of Dicellosis. Until the end of 1985, patients were treated with either tetracycline (600 mg/6 hr po) or doxycycline (100 mg/12 hr po) for 30 days along with streptomycin (1 gid IM) for the fist 21 days. From January 1986 to December 1987, the patients were treated randomly with doxyeyeline (100 mg/12 hr po) for 30 days. along with streptomycin (1 4 IM) for the first 21 days or rifampin, (15 mg/kg/d po) plus doxyeyeline (100 mg/12 hr po), both for 45, days, as part of a clinical trial. The results of this trial were previously reported (30), From 1988, patients were treated with oxyeyeline (100 mg/12 hr po) for 45 days plus streptomycin (1 8/4 IN) for 3 weeks. In patients with focal forms, doxyeycline was maintained for at least 2 months, except in patients with spondilts, who were treated for 3 months. Special consideration was also given to endocarditis or neuromeningeal complications, Which were treated using 3 drugs: doxyeycline and rifampin for ‘S months and streptomycin for the frst 3 weeks, extending doxy- cyeline and rifampin until normalization of biological parameters in cerebrospinal fluid (CSF) for cases with meningeal involve- ‘ment. On completion of treatment, all patents were followed by 2 ofthe authors (CJD and RIM) for a period of a least 6 months. ‘This follow-up took place monthly in cases of improvement and whenever necessary if there were complications or relapses. Definitions Focal form or complication was defined as the presence of ‘symptoms or physical signs of infection ata particular anatomic site that lasted for atleast 7 days ina patient with active brucello- sis. Osteoarticular complication was defined as pain and two or ‘more inflammatory signs in any peripheral joint (heat, redness, ‘swelling, definite restriction of movement) or inflammatory pain (Pain unrelieved with rest) together with radiologic alteration, ‘and/or radionuclide uptake in a deep location evaluated by both ‘the clinician and the radiologist independently. Hepatic complica- tion was defined as the presence of hepatic abscess or a 5fold for greater rise in normal levels of alanine aminotransferase (ALAT or aspartate aminotransferase or a old or greater rise in the level of alkaline phosphatase (AP) or gamma glutamyl- transpeptidase (GGT) together with the presence of pain in the right upper quadrant or jaundice. Neurologic complication was, defined as any neurologic symptom or sign not attributable to ‘other causes with simultaneous isolation of Brucella spp in the central nervous system or demonstration of intrathecal synthesis, ‘of specific antibodies. Neurologic alterations caused by neigh- boring processes or asymptomatic alterations of CSF not accom: panied by other inclusion eriteria were excluded. Hematologic ‘complications were considered only as those with a defined clini ‘al expression, excluding asymptomatic or poorly symptomatic ‘ytopenias or coagulation disturbances. Cutaneous involvement ‘was only diagnosed ifskin abscesses not produced by inoculation ‘were present. Failure of treatment was defined asthe persistence of intial symptoms after 2 weeks of appropriate treatment for rnoncomplicated forms and after 8 weeks for focal forms. Relapse ‘was defined as the reappearance of symptoms oF a postive blood ccalture after the treatment was concluded. Statistical analysis Statistical analysis was cartied out using the statistical pack- ages EPIINFO 5.1 (Center for Disease Control and Prevention, Ailanta, GA, USA) and SPSS/PC+ 4.01 (Microsoft Com, Licensed {638058 SDC, Hospital Regional, Mélaga, Spain). For quantitative variables, the comparison vas performed using twortailed St dent test for independent variables. Comparison of values of qualitative variables was carried out by chisquare or Kruskall- Wills tests after adjustment of the variables to normality. p < (0.05 was considered statistically signifcant In univariate analysis, ‘orks ratio (OR) was calculated as the quotient of crossed prod ucts. The variables that showed statistical significance inthe uni- variate analysis were evaluated by logistic multiple regression for the determination of OR (p of inclusion = 0.15, p of exchusion = (020) through the forward stepwise method. Determination ofthe respective 95% confidence intervals (CD) of OR was made with the formula Cl'= oft "-s2%s, where © represents the base of neperian logarithms, Bis the logistic regression coefficient, t—a/ 2s the value ofthe theore statistics for a = 0.05 tworaile, and eis the standard error of the logistic regression coefficient, Case Reports Bone and joint involvement Case 1: Spondylitis and psoas abscess: An 18-year-old male farmer was referred to our center because of a 2-month febrile syndrome of unknown origin with chills, sweating, malaise, and arthralgias. Three weeks before admission, he developed an in- tense inflammatory pain in the lower lumbar region and right buttock. The physical examination was normal except for the presence of splenomegaly, intense lumbar paravertebral muscle spasm, and pain over the right sacroliae joint during sacroiliac ‘maneuvers. Two blood cultures were negative, a rose Bengal test ‘was positive, and Wright's seroaggutination test and Coombs test for Brucella were positive at titers of 1/160 and 1/1280, respec- tively. A plain roentgenogram showed signs of right sacrolits, ‘anda lumbar computed tomography (CT) showed data suggesting spondylitis at L-1A level, with a big left psoas abscess (Figure 1). The patient was operated on, and the culture of pus obtained both by percutaneous drainage and during the operation yielded B. melitensis, Aver surgery and a 3-month course of doxyeyeline, ‘ith streptomycin during the first 3 weeks, he was cured with- cout sequelae. Comment: This patient illustrates that B. meti- tensis spondylitis, although more frequent in people older than 40 years, may occur in younger patients with highly destructive lesions with paravertebral FOCAL FORMS OF BRUCELLA MELITENSIS INFE Fic. 1. Large osteolytc lesion of the third lumbar vertebrae witha large left multiloculated abscess, abscesses frequently requiring surgi ent This is also an example of the frequently observed coexistence of sacroiliitis and spondylitis. Case 2: Sacroititis: A 26-year-old male farmer developed re- iting fever of up to 40°C, intense chills, profuse sweating, ma aise, arthralgias, myalgias, and nonproductive cough. He was treated with erythromycin for a suspected lower respiratory tract infection. Fever and associated symptoms disappeared almost completely. Two weeks later, the same symptoms recurred, to- gether with an intense pain inthe right groin radiating tothe right posterior thigh. On admission, the patient appeared severely il, had a temperature of 405°C, tachyeardia, hepatomegaly, and in- tense pain during left sacroiliae palpation. Lumbar spine, hip, and sacroiliac joints appeared normal on plain roentgenogram. A radionuclide bone sean with technetiurn-0 methylene diphospho- nate (655 MBq) showed tracer accumulation over the right sacroil- lac joint. A sacroiliac CT showed signs of severe right sacroilts (Figure 2). Wright's seroagglutination test was positive ata ‘of V/640. On the 9th day of admission, a blood culture drawn at ‘entry grew B. melitensis. After a course of doxyeyeline for 45 days plus streptomycin for 21 days, he was cured without sequelae Comment: This patient initially had an undifferen- tiated febrile syndrome that subsided after antibiot treatment prescribed for a suspected lower respira- tory tract infection. The indiscriminate use of antibi- oties in patients with fever of unknown nature fre- quently masks Brucella infection, because this bacterium is sensitive to a wide range of antimicro- bial agents that, however, do not eradicate the infet tion. The infection usually manifests again after sev- eral weeks, frequently as a focal complication. This patient's course is also an example of the low sensi tivity of plain roentgenogram for the diagnosis of Fic. 2 Sacroiliac joint CT showing loss of the articular space ‘and muliple subchondral erosions in the right sacroiliac joint in patient with normal plain roentgenogram. sacroiliitis, even in the presence of severe symptoms and lesions detected by CT. Genitourinary complications Case 3: Orchiepididymitis and testicular abscess: A 25-year old male farmer, who occasionally consumed fresh goat cheese, presented witha 3:month history of fever, preceded by chills and accompanied by profuse sweating and constitutional symptoms ‘A month later, he developed painful swelling ofthe let testicle, nausea, and vomiting. He received amoxicilin and gentamicin for 10 days, after which he noted only partial improvement. On admission, the patient was febrile (38°C). On physical examina tion, hepatomegaly was evident, as well a an enlarged and tense left testicle, which was slightly tender on palpation. The complete blood cell count and leukocyte differential count were normal ESR was 63 mavhr. The levels of ALAT, adenosine deaminase, @2 globulin, and C-reactive protein were increased. Urinalysis ‘was normal, and blood and urine cultures were negative. Wright's Seroagglutination test was positive at titer of 1/920 and Coombs test for Brucella was positive ata titer of 15,120. Doppler ultraso- rogram of the left testicle disclosed an enlarged testicle with thickened covering membranes, increased vascularization and hypoechoic lesion compatible with abscess (Figure 3). He was treated with doxycycline, streptomycin, and naproxen, after hich he gradually improved during the first month of treatment luni full recovery. Comment: This case shows the usual clinical course of Brucella orchiepididymitis and its frequent initial confusion with nonspecific orchitis. However, in contrast to the latter, Brucella orchiepididymitis is usually more insidious, the fever and systemic symptoms precede by days or weeks the testicular symptoms, and the urinalysis and culture are usually negative. Even in the presence of abscesses, local inflammatory signs are usually mild or absent, as in this case. Medical treatment is usually effective; surgical management is rarely indicated. 198 COLMENERO ET AL, Fic. 3. Ultrasonographic image of the lft testicle showing thick ‘ened tuniea and a large hypoechoic area suggest Neurologic complications Case 4; Meningoencephatitis and hysrocephatus: 4 22-year ‘old male bricklayer sought consultation for 8 days of a remitting, febrile syndrome with chills and profuse sweating, headache, and vomiting, Three days later he fel sleepy, with memory li difficulty in communicating. He had no medical or surgical history and occasionally consumed fresh goat cheese. On admission he ‘was alert, disoriented, with diminished short-term memory, motor aphasia, horizontal nystagmus, and bilateral papilledema CT of the brain showed significant dilation of the lateral ventricle, with normal third and fourth ventricles. CSF analysis showed 240 lew ocytes/mL, TO%lymphocytes, glucose 28 mg/d, and total protein 200 mgidl. Empiric treatment with cefotaxime and dexametha- sone was begun, and a CSF drainage catheter was inserted, ater, Which the level of consciousness improved. Rose Bengal test, Wright's seroagglutination test, and Coombs test for Brucella all ‘of them performed in serum and in CSF samples, were repeatedly negative. The patient had fluctuating consciousness, and apneic spells were observed. An endotracheal tube was inserted and assisted ventilation was begun. On the ninth hospital day, blood and CSP cultures yielded B. melitensis, Doxycycline, streptomy. ‘in, and rifampin were begun, but the patient developed left hemi plegia. CT revealed the presence of multiple hypodense lesions, some of them with bleeding, suggesting hemorthagic infarctions, (Figure 4), The patient died on the OLst hospital day a8 a conse ‘quence of nosocomial Pseudomonas aeruginosa meningitis, Comment: This patient illustrates a very dis- tressing clinical event: rapid onset meningoenceph litis and hydrocephalus with a rapidly progressive clinical course and fatal outcome. Although menin- geal involvement is a constant feature of neurobru- Cellosis, it occasionally manifests with no meningeal signs, which may delay the diagnosis. If encephalic involvement develops, as in the patient above, multi- ple infaretions secondary to cerebral vasculitis may occur. Finally, itis important to remember that, al- though exceptional (0.6% of cases in our experi- ence), serologic response to B. melitensis infection Fic. 4 Cranial CT showing a ventricular drain inserted in the right lateral ventricle and a hemorrhagic infarction in thalamus and internal capsule, iay be absent, which obliges the clinician, in ex- posed patients or high prevalence areas, to suspect the infection and to try to isolate the organism in every case. Heart complications Case 5: Aortic endocarditis: A 21-year-old man developed fe ver, hills, drenching sweats, arthralgia, and myalgia 2 months before adrission. The patient was given cloxacilin for several days and then gentamicin but did not improve. Two weeks before admission, the patient experienced progressive exertional dys ‘pea, which became dyspnea at rest during the last few days. The patient wasa student, had no past medical history, and occasion: ally consumed rave milk and cheese. On admission he was tachy: cardiae, with blood pressure of 170/60 and had orthopnea, a rap lly rising “water-hammer” pulse, and trill In the aortic valve Anintense aortic regurgitation murmur was auscultated and hepa tosplenomegaly was felt. A chest Xray film showed cardiomegaly, signs of pulmonary congestion, and Kerley B- lines. A transtho- racic echocardiography showed an oscillating intracardiac mas that obstructed the outflow tract of the left ventricle. Wright's seroagglutination test was positive at a titer of 1/320 and B. met tensis was isolated in two blood cultures, Doxycycline, rifampin, ‘and streptomycin were begun, and the aortic valve was replaced by @ St Jude 21 prosthetic valve. In the course ofthe operation, 1 vegetation on the noncoronary valve and a total rupture ofthe tricuspid valve were observed. After the valve replacement, the FOCAL FORMS OF BRUCELLA Mi patient improved satisfactorily. To date, 5 years after the opera- tion, he has remained asymptomatic. Comment: This case exemplifies a Brucella endo- carditis course. The patient had aortic valve endocar- ditis which involved a previously healthy native valve, producing highly destructive lesions and sec- ondary hemodynamic instability that required valve replacement. After the operation, he improved with a 3drug regimen, 2 of which were maintained for more than 3 months. Gastrointestinal complications Case 6: Liver abscess: A A-yearold male bricklayer presented. with a history of gastric ulcer, unilateral hearing loss secondary toprevious episodes of otitis, and nephrolithiasis. He occasionally ‘consumed raw goat milk, Ten weeks before entry, he noticed fever, chills, and sweats. A diagnosis of brucellosis was made. The patient first received trimethoprim sulfamethoxazole and then tetracyeline plus rifampin without improvement. The patient was referred to our center hecause of persistent fever right upper ‘quadrant abdominal pain, nausea, and vomiting. On physical ex amination, the patient showed a marked toxic appearance. very large and tender liver was palpable. An abdominal ultrasono- graphic study showed a Gem hypoechoic lesion with il-defined borders and calcified densities. A percutaneous drainage evact ated 75 ml, of dense and greenish pus, in which B melitensis was isolated. Despite the percutaneous drainage and institution ‘of doxycycline and rifampin, the patient remained febrile, with right upper quadrant pain and elevated levels of C-reactive pro- tein. Five days later, an abdominal CT showed the persistence of | large heterogeneous hypoattenuated area with calcium densities and blurred margins (Figure 5A), A laparotomy with resection of| a multiloculated thick-walled mass that occupied the left lobe of the liver (all of the IIT and part of the IV liver segment) and contained purulent material was performed. The histopathologic ‘examination of the surgial specimen showedl an intense necrotiz: granulomatous inflammation (Figure 5B). After the operation and completion of the antibiotic treatment, the patient improved, Comment: Although liver involvement in brucello- is is frequent, the presence of a liver abscess is very rare. The existence of calcifications within many of these lesions suggests that they are due to reactiva- tion of a previously silent infection. The failure of percutaneous drainage seen in our case suggests that extensive and complex lesions require surgical drainage for resolution. Case 7: Subacute cholecystitis: The patient was a 58-year-old male sheep and goat shepherd with a history of sinus node dys- function and colonic polyposis. Three years before, he had an episode of brucellosis that was treated with doxycyeline for 45 ‘days and streptomycin for 21 days. He has been well until 20 ‘days before entry, when remitting fever, chills, profuse sweating, asthenia, anorexia, abdominal pain in the right upper quadrant, nausea, and voriting developed. Physical examination revealed hepatomegaly and Murphy's sign. The white cell count was 4,940 ‘er mum? with 35%6 lymphocytes and 13% monocytes, and ESR was 15 muh. Wright's seroagglutination test was positive at titer INFECTION 199 INI of 1/160 and an ELISA test to Brucella showed increased IgG levels. Blood cultures were repeatedly positive for B. melitensis. ‘An abdominal ultrasonogram disclosed a thick-walled gallbladder Containing 1 stone and echogenic material suggestive of pus or biliary sludge. A second course of doxyeycline and streptomycin was begun, and fever and systemic symptoms diminished, but pain inthe right upper quadrant persisted. Cholecystectomy’ was performed 7 days later. The gallbladder had a thick wall and contained purulent material, The histopathologic examination showed signs of chronic cholecystitis wit the presence of numer- ous granulomas (Figure 6), Culture of the bile was negative Comment: This patient is an illustrative case of Brucella reinfection, which occurs infrequently. Al- though the organism was not isolated from bile (the patient was operated on a week after the initiation of antibiotic treatment), the repeated isolation of Brucelia in blood cultures and the presence of granu- Fic. 5. A Abdominal CT demonstrating a big multiloculated hnypodense lesion in the le. liver lobe with central calcification. B Liver tissue with epithelioid granulomas, central necrosis, and peripheral lymphocytic reaction (hematoxylin and eosin stain, original magnification > 400 oF 1,000). 200 ‘COLMENERO ET AL. Jomas in the gallbladder wall strongly support the diagnosis of Brucella cholecystitis. The focal form is rare today, but its existence shows the wide poly- morphism of brucellosis, which ean involve almost every organ. Results Epidemiology Five hundred thirty patients were included in the study: 372 (70.29%) were male and 158 (29.8%) female. ‘The mean age was 37.5 * 16.6 years (range, 14-85). Eighty-eight patients (16.6%) were between 14 and 20 years old, 114 (21.6%) between 21 and 30, 106 (20%) between 31 and 40, 81 (15.3%) between 41 and 50, 80 (15%) between 51 and 60, and 61 (11.5%) were over the age of 60 years. One hundred sixty-five patients (339%) were live- stock producers, shepherds, farmers, veterinarians, or laboratory workers, with a professional risk of acquiring the infection; 164 (30.9%) worked in pro- fessions without recognized risk; and the remaining 196 (37%) were housekeepers, students, or retired. The possible source of infection was identified in 472 cases (89.1%); 37 patients (7%) had direct contact wiht sheep or goats, 27 (5.196) worked with products derived from sheep or goats, and 126 (23.6%) com- sumed unpasteurized milk or cheese. In 286 cases (63.29), the posible source of infection was multiple, and in the remaining 58 cases (10.9%), it was not identified. Clinical findings Signs and symptoms of brucellosis in this series reflected a combination of systemic illness with cer- tain manifestations (Table 1). The mean duration of, the symptoms before diagnosis was 44 + 77 days. In 249 cases (47%), it was less than 2 weeks, in 119 (22.59%) between 2 weeks and 1 month, in 107 (20.2%) between 1 and 3 months, and in the remaining 55 (16.36) over 3 months. Routine hematologic and biochemical testing yielded no specific findings to suggest the diagnosis of uncomplicated or focal brucellosis (Table 2). In particular, most patients had normal leukocyte and lymphocyte counts, were not thrombocytopenic, and. had normal or mostly elevated ESRs. Of the 483 patients in whom a complete urinalysis was prac- ticed, 95 (19.7%) had some abnormal result: 27 (5.5%) mild to moderate proteinuria, which in none of the cases was within nephrotic range; 37 (7.6%) micro- hematuria or pyuria; and 32 (6.6%) had both alterations. Microbiological and serologic findings ‘Two or more blood cultures were drawn in 421 patients, of which 360 (85.5%) were performed under ideal conditions (absence of antibiotic treatment in the previous 72 hr and incubation for 30 days or more). Of these, 247 (68.8%) were positive, B. meli- tensis being the only isolated species (85.3% biovar 1, 11.2% biovar 2, and 3.5% biovar 3). At first consultation, 500 patients (94.3%) had 1 or more positive serologic tests. Of the remaining 30 (6.7%), 20 (3.8%) were diagnosed by Brucella isola- tion (16 blood isolations, 2 in vertebral tissue, and 1 case each in articular fluid and CSF) and 10 (1.9%) by seroconversion. Of those cases with negative se- rologic titers at first consultation but positive isola- tion, 17 (85%) seroconverted, and in 3 (0.6% of the ‘TABLE 1. Summary of symptoms and signs of patients with brucellosis ‘Symptoms Fever® his Sweating Constitutional symptoms Arthralgias Myalgias Lambar pain ‘Testicular pain Bpistaxis| Signs Hepatomegaly Splenomegaly ‘Adenopathy Osteoarticular involvement Relative bradicardia ‘Skin lesions Neurological signs No, of Cases % 520 98.1 458 86 450 B49 387 3 260 502 203 387 125 26 4 2 202 us 48 27 1m 18 48 * Fever = axillary temperature higher than 378°. + Constitutional symptoms = 2or more ofthe following: anorexia, asthenia, and malaise FOCAL FORMS OF BRUCELLA MELITENSIS INFECTION 201 TABLE 2. Summary of initial hematologic and biochemical data No.of Patients % Mean = SD Leucocytes, fl, er = 2837 120 o 98. ‘Total bilirubin, mal 085 = 047 30 days (OR 2.0, 95% CI, 1.5-2.7), ESR > 40 mun/hr, (OR 1.9, 95% CI, 1.2-3.0), and d-2 globulin > 7.5 g/L. (OR 6.8, 95% CT, 2.2-20.7). Outcome Five hundred nineteen patients (97.996) completed 204 COLMENERO ET AL. ‘TABLE 5. Clinical, hematologic, biochemical, and microbiological characteristics of patients with and without complications with ‘Without eee Complications Complications oe eo B 508 09 1 08.17 os 402 0.1 339 372 4 og21 026 661 78 Fever 976 989) 05 ore2 027 Duration of symptoms, 30 days 51s. 767 29 195 6.0000001 220 days 472 2a ills 839 875, 07 0413 0.26 Sweating Bad srs. 07 0412 0.25 Constitutional symptoms* 708 Bs 09, 05.13 046 Hepatomegaly| 308 ais. 06, 0409 0 Splenomegaly 172 27 06. 0409 0.05 Hematologic ‘Lencocytes > 10,500/mL. a7 22 0859 oo7 Iymphocytes < 1,500/m, 307 15 0924 0.08 ESR > 40 manwhr 24 22 3a 0.0001 Biochemical ‘ALAT > 200 U/L 53 ut 0426 os7 ASAT > 200 U/L 48 09 03-25 088 Alcphosphatase > 500 U/L 29 09 02-31 079 Gor > 150 UL. BL 21 LI46 003 Serum protein < 65 g/L au o7 oa 018 ‘a2-globulin > 75 g/L 197 20 1292 0.001 Gamma globulin > 16 9/1. M1 u 08.25 016 Microbiologie and serologic Seroagglutination > 820+ 600 es u ors oot IPL1gG > 2007 642 08 2 06-21 0.69 Coombs test > 640+ 27 5A 22 or 020 Positive blood culture 655 70 08. 05.13 040 * Constitutional symptoms + Expressed as reciprocal of titers. the treatment and the 6-month follow-up period. Eleven (2.1%), all without complications, completed the treatment but were lost to follow-up. All were contacted by phone 6 months after the end of the treatment and reported a good state of health. Four hundred ninety-one (94.6%) received medical treat- ment alone and 28 (5.39%) required surgical treatment as well (20 spondylitis, 5 endocarditis, 1 arach- noiditis, 1 cholecystitis, and 1 liver abscess), Seven patients (1.7%), all with focal forms, had therapeutic failures, being cured after changing the therapeutic schedule, and 20 (3.9%) had I or more relapses. Four patients (0.8%) died as a direct conse- ‘quence of the infection: 1 with cervical spondylitis and epidural abscess, | aortic endocarditis with rup- ture of Valsalva sinus, 1 meningoencephalitis, and 1 lumbar spondylitis that produced secondary aortitis and mesenteric artery thrombosis. ‘oF more of the following: anorexia, asthenia, and malaise ‘The relapse rate was 3.6% for those patients with- ‘out complications and 4.1% for patients with focal forms (not significant; p > 0.05). However, when therapeutic failure, relapses, and mortality were con- sidered together, the risk of an unfavorable clinical course was significantly greater in patients with fo- cal forms (10.6% versus 3.6%) in patients without complications (OR 19, 95% CI 1.4-7.1, p < 0.005) (Table 7). Discussion Brucellosis is still a serious health problem in developing countries. The incubation period is be- ‘tween 7 days and 3 months (85, 124), although incu- bation periods of as long as 10 months have been reported (46), thereby explaining the fact that symp- FOCAL FORMS OF BRUCELLA MELITENSIS INFECTION 205 TABLE 6. Final logistic regression model for determination of factors independently associated with complications Duration of symptoms > 30 days Leucocytes > 10,500/ml, Ger > 150 UL 2-globulin > 75 gi. tomatology can start in a different locale to that of infection (15). Brucellosis is a systemic infection with a wide clinical spectrum, ranging from asymptomatic forms to severe cases causing death (25, 61, 121, 128). The infection usually manifests itself as a febrile syn- drome with no apparent focus, chills, profuse sweat- ing, asthenia, adynamia, malaise, arthralgia, and my- algia (25, 32, 89, 102, 107, 128). Of our patients, 73.1% first consulted because of fever without apparent focus. Brucellosis can affect virtually any organ or system causing focal forms with long clinical courses, which are considered true complications of the infection. Notable discrepancies exist in the incidence rate and clinical spectrum of focal forms. Reported incidence rates range from less than 1% in some series (25) to more than 50% in others (107). Some authors consider these discrepancies to be a consequence of the lesser virulence of some Bru- cella spp, especially B. abortus. However, this fact does not explain the low incidence of focal forms in some reports referring to B. melitensis (102), ‘Therefore, these discrepancies seem to be mainly related to the retrospective character of the reports and the lack of uniform definitions and diagnosis of focal forms. In our series, 31% of patients had focal forms, rates similar to those reported recently by others (22, 77, 107). Multivariate Adjusted oR 95% CI B 20 1527 ‘0.000 18 07-51 035 45 09-25 010 rm 06-2 070 19 1230 001 24 09-62 021 68. 22-207 0.0007 13 743 021 A possible bias of the present report is the selec- tion bias derived from the recruitment of patients in a hospital setting, which may overestimate the incidence of focal forms, usually referred to hospi- tals, Unfortunately, most large series previously re- ported are also based on hospital populations (12, 51, 61, 7, 89, 102, 107, 118). There are few clinical reports outside the hospital setting, and they are biased by an earlier diagnosis in bouts of the disease ‘occurring in restricted professional or family groups (15, 25, 94). On the other hand, in a recent report that included all cases of brucellosis diagnosed over 1 year in a province in southern Spain, the percent- age of focal forms was 32%, similar to that reported by us (108) Bone and joint involvement Among focal forms, those affecting the musculo- skeletal system are the most common (11, 50, 90). There are striking differences in the reported inci- dence of osteoarticular forms, ranging from 0% (25) to 72.5% (107). In our series, osteoarticular complica- tions were present in 21.3% of patients, representing 66.9% of focal forms (11, 51, 77, 119). As is the case for other focal forms of brucellosis, clinical features, of osteoarticular complications are rather non- specific. Only the presence of some suggestive symp- toms, such as the insidious onset of illness, remitting TABLE 7. Differences of outcome between patients with ‘and without complications With ‘Complications (= 169) ‘Therapeutic failure 7 a1) Relapse 741%), Mortality 424%) Total 18 10.0%) "ND = not done because of zero value. Without Complications OR 95% CI p nasa 0 NDe 13@O% 120483075 0 ND 13GOH 19 147A 0.005 206 (COLMENERO ET AL. fever, chills, profuse sweating, and the involvement of the axial skeleton, allows the clinician to suspect that Brucella is responsible for the clinical picture, when facing a differential diagnosis that includes other processes due to collagen-vascular disease or other infections, ‘The disease can affect the musculoskeletal system at virtually any site (109), but in adults the axial skeleton is the most frequently involved (11). Sacroi- liitis and spondylitis account for more than 80% of our patients with osteoarticular involvement (13, 119). This tendency for axial involvement in adults may be related to closure of the metaphysis, change in bone vascularization, and redistribution of the bone marrow from the long to the axial bones, which ‘occurs from the second decade of life (39). In spondylitis, the lumbar segment is the most frequently involved, followed by the thoracic, and finally the cervical segments (11, 29, 76). Multiple level involvement is rare, accounting for only 3.2% of our cases. Although Brucella spondylitis is considered a mild form of infectious spondylitis in some reports (84, 105, 117), in others, and in our own experience, it causes highly destructive lesions (29). Thirty-two percent of our patients with spondylitis required sur- gical treatment because of the development of para- vertebral and/or epidural masses, spinal cord or ra- dicular compression, or instability of the column. ‘The frequent appearance of therapeutic failures in patients with spondylitis, together with its potential gravity, suggests that treatment must be prolonged for 3 oF more months (11, 29). Sacroilitis, together with spondylitis, is the most frequent osteoarticular involvement in adult patients (23, 34, 115, 119). It almost invariably occurs unilat- erally, and in those cases of bilateral involvement, itis usually asymmetric (32), which helps to differen tiate it from noninfectious sacroilitis. Sacroilitis often produces a lower lumbar pain that needs to be differentiated from that of spondyli tis (34, 78), but in the former, both the response to treatment and the prognosis are usually good. The treatment of these cases can therefore be similar to noncomplicated cases (13, 28, 33, 119). Peripheral arthritis isa frequent form of osteoarti- cular brucellosis (8, 22, 72). The knee and ankle are the most frequently affected joints. In our series, the frequency of peripheral arthritis was 14.1%, two- thirds of which were monoarthritis and one-third oligoarthritis. These figures are considerably lower than those reported by others (8, 50, 72, 90) but similar to the 16.2% and 13.2% reported in 2 recently published extensive series (13, 119). These discrep- ancies may possibly be due to the percentage of ic patients included. In the present report, tient age with peripheral involvement or sacroili- itis was significantly lower than in the spondylitis -ases, as has been previously reported in many stud- ies (11, 29, 76, 109), supporting this hypothesis. sternoclavicular involvement has been rarely re- ported until recent years (19, 33, 57, 74). Extra-artic- ular involvement is not exceptional in brucellosis (11, 33, 49), representing 1.8% of our patients with osteoarticular involvement. Osteomyelitis, relatively frequent some decades ago (68), is exceptional today 1, 33, 50, 119). Genitourinary complications Second\in frequency to osteoarticular are genito- urinary complications, with an incidence of between 6% and 17.5% (12, 82, 100, 107, 108, 112). The marked affinity of different Brucella spp in reproductive sys- tems of cows; goats, and sheep has been known for a long time. The tropism for the genital organs of rumiants may be related to the high concentrations, in these locations of erythritol, a carbohydrate that allows Brucella to grow (69). Although in humans the concentration of erythritol in seminal fluid and prostatic secretions is far lower than that found in rumiants (128), there are high concentrations of other carbohydrates (79), which might explain the fact that genitourinary complications are also fre- quent in humans, Inourstudy, the overall incidence of genitourinary complications was 3.4% (5.1% when only the male population was considered). Epididymitis and or- chiepididymitis start subacutely, and in contrast to nonspecific orchiepididymitis, frequently have asso- ciated systemic symptoms, minimal urinary symp- toms, lower white blood cell counts, and fewer alter- ations in the urine sediment (58). Cystitis and pyelonephritis are exceptional (1, 67, 128). The geni- tourinary complications of brucellosis usually re- spond favorably to treatment, but testicular atrophy and abscesses requiring surgical treatment have been described (71). Renal involvement in brucellosis is relatively com- mon. Pfischner et al. (102) isolated Brucella in the urine of 39% of 224 patients with active brucellosis. However, as is clearly shown by our study, these alterations are usually mild and asymptomatic, do not affect renal function, and respond well to medi- cal treatment. On rare occasions, renal involvement severely compromises renal function and even the life of the patient. The pathogenic mechanism of renal involvement is multiple. In most cases, lesions are secondary to interstitial nephritis caused by di- rect invasion of the bacteria (96). In other cases, the renal lesion has a glomerular predilection as a consequence of the deposition of circulating im- mune complexes (36). In these cases, the coexis- tence of an underlying endocarditis is frequent. FOCAL FORMS OF BRUCELLA MELITENSIS INFECTION 207 Neurologic complications ‘The reported incidence rates of neurologic com- plications ranges from 0% to 25% (2, 25, 32, 112, 128). ‘These marked discrepancies derive mainly from the inclusion in some of the series of spinal cord and radicular compressions produced by contiguous 0s- teoarticular processes (107, 112). In the present study, the incidence was 2%, similar to that reported in other studies using similar diagnostic criteria (4, 23, 43, 97, 116). Although infrequent, neurologic complications are of marked clinical importance due to their severity and important sequelae (23, 43, 83). The lesions are located mainly in the meninges, where a diffuse in- flammatory infiltrate can be observed extending to the perineurium of the nerve sheaths and to the ves- sel walls. These pathologic findings explain the wide clinical polymorphism of neurobrucellosis (7, 17, 41, 92, 99, 113). Inflammatory changes of CSF are a constant fea- ture of neurobrucellosis (4, 23, 43, 83, 97, 116). Most patients have lymphocytic pleocytosis (between 20 and 500 cellsvmL), elevated total protein, and hypo- glycorthachia. Brucella is isolated from CSF in 35%- 50% of cases of meningitis or meningoencephalitis, (4, 43, 83, 97). Between 75% and 100% of patients with neurobrucellosis have specific antibodies in CSF (41, 43, 116). Antibody titers in CSF are usually lower than in blood, and sometimes more than I serologic testis necessary for their detection (4, 23, 43, 83, 87). ‘There isno general consensus concerning the best treatment for neurobrucellosis (2, 23, 83, 97). The severity of this location and the low penetration of streptomycin in CSF warrant the addition of a third drug with a good diffusion to CNS. This can be achieved satisfactorily with rifampin or trimetho- prim-sulfamethoxazole, This treatment should be prolonged for at least 3 months. We usually prolong. the treatment until biological normalization of CSF occurs, a criterion also used by other authors (4, 23, 43, 83, 87). In cases of encephalic involvement, ephalus, myelorradiculitis, and spinal arach- , short courses of corticosteroids should be adequate. ‘The prognosis of meningitis is usually good; how- ever, in those cases of encephalic or spinal cord involvement, mortality is not negligible and sequelae are frequent (83, 116), Heart complications Cardiac involvement is rare, occurring in 0% to 2% in large series (20, 25, 32, 77, 89, 102, 107) and 1.5% in our series. Endocarditis is the most common car- diovascular complication, and a large proportion of ‘eases, more than 50% in some series (20, 62), involve a previously healthy native valve. The aortic valve wolved in more than 75% of cases (40, 62, 98). Mitral endocarditis occurs more rarely and generally, affects a previously damaged valve (59). Cases of endocarditis caused by B. melitensis, B. abortus, and B. swis have been reported. Irrespec- tive of the causative species, Brucella endocarditis produces highly destructive lesions of the valve structures (20, 40, 62). Although a complete cure has ‘occasionally been achieved with medical treatment alone (27, 103), most require surgical treatment be- ‘cause of hemodynamic instability (5, 20, 40, 62). Al- though overall mortality from brucellosis is low, en- docarditis is a severe complication and accounts for about 80% of deaths (100). Two of 4 deaths in our study were due to cardiovascular complications. The treatment for Brucella endocarditis has not been well established, due basically to the low num- ber of reported cases. Most authors recommend a prolonged course of treatment (20, 40, 59). In our ‘unit, we use a combined treatment of doxycycline plus rifampin for at least 3 months and streptomycin (1 g/d) for the first 3 weeks. No relapses occurred with this schedule in the 5 patients who completed the treatment. Pericardial and myocardial involvement is rela- tively common in patients with Brucella endocarditis, (200, 128) but can also happen as isolated events (48, 51, 100, 123), in which case the prognosis is more favorable (48, 123). Gastrointestinal complications Brucella is a facultative intracellular bacteria, and Killing the organism involves mainly the mononu- clear phagocytic system (38). Thus, liver involve- ment is very frequent in brucellosis, although this involvement usually has little clinical importance and is usually limited to soft painless hepatomegaly or slight increases in levels of aminotransferase (26, 82, 60, 127, 128). These clinical and biochemical ab- normalities are completely reversed with adequate treatment. We do not believe they represent a true complication of the disease. The concept of hepatic complication should be reserved for those cases with clinical expression (right upper quadrant pain and/or jaundice) in the presence of severe distur- bances of the biochemical liver parameters or liver abscess. Defined in these terms, 2.4% of our patients had hepatic complications (26, 60, 107). Histologic examination usually reveals the existence of a non- specific reactive hepatitis with or without granulo- mas (75). Some studies have associated the presence of hepatic granulomas to the infection by B. abortus (227). However, others have also found granulomas in 60%-70% of patients with hepatitis caused by B. 208 COLMENERO EP AL. ‘melitensis (26, 75), which is similar to our data. Tt is possible that the presence or absence of granulo- mas has a closer relation with the immune response ‘of the host than with the species of Brucella involved in the infection (125). Liver abscess is uncommon in brucellosis. It has been associated with infection by B. swis (91, 125). However, many cases of liver abscesses have been reported in infections by B. melitensis (73, 91). In addition to hepatic involvement, digestive sys- ‘tem complications of brucellosis are exceptional, al- though cholecystitis (87), ileitis (96), colitis (65), and pancreatitis (3) have been reported. Cutaneous involvement Cutaneous manifestations of brucellosis are rare (21), Over the last 3 decades, litle attention has been paid to them, with only isolated case reports or small, series (18, 45, 47, 106). In our study, 3.8% of patients, had skin involvement, although only 1 had a true skin complication. In 90% of cases, the lesions were maculopapular or papulonodulary exanthema, in- volving predominantly the lower limbs and trunk. Usually, these lesions were not pruritic and spared the face, palms, and soles, as in other reports (14). Of patients with rash, 28% had some purpuric ele- ment. The appearance of purpuric lesions has been related to the presence of leukocytoclastic vasculitis, due to the deposit of immune complexes (129) Paniculitis resembling erythema nodosum has been previously reported (47), accounting for up to 11% of cutaneous manifestations in some series (14). In our experience, they accounted for 5% of the skin lesions and, as in previously reported cases, were cured with conventional treatment, rest, and nonste- roidal anti-inflammatory drugs (14). ‘The pathogenic mechanism involved in cutaneous lesions of brucellosis can be multiple. Lesions pro- duced by direct inoculation (63, 80), hypersensitivity phenomena (122), deposit of immune complexes, and direct invasion by the organism reaching the skin hematogenously have been reported (14, 45), Pulmonary complications Although classic descriptions refer to a high rate of pulmonary complications, they are in fact exeep- tional in the antibiotic era (11, 25, 32, 50, 77, 89, 102, 107, 128). The route of contagion does not infiuence the development of pulmonary involvement (25, 66). ‘The presence of a dry or scarcely productive cough is a frequent symptom in patients with brucellosis but does not imply the existence of a focal complica- tion (24, 32). Only 1 of our patients with cough had a definite pulmonary complication. The spectrum of pulmonary complications of brucellosis is wide; cases of unilateral or bilateral bronchopneumonia, cavitated pneumonia, pulmonary nodules, hilar lymphadenopathy, and empyema have been de- scribed (44, 54, 104). Hematologic complications Hematologic alterations in brucellosis are com- mon (16, 35, 81), but they rarely constitute a true complication and resolve promptly with treatment. Leukopenia and relative lymphocytosis are the most common hematologic finding (82, 114). It was de- tected in 28.7% of our patients. Leukocytosis is rarely found, and its presence in a febrile patient with no apparent focus should point the clinician toward other etiologic possibilities (35). Pancytopenia oc- cours in 5%-20% of patients with brucellosis (35, 114), 6% in the present series. Although pancytopenia may be secondary to hemophagocytosis (81), the cause may be multifactorial, because hypersplenism (16, 35) and presence of granulomas in bone marrow are well

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