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Clinical manifestations;
diagnosis; and treatment of
brucellosis in children

Author Section Editor Deputy Editor

E Dale Everett, MD Morven S Edwards, MD Mary M Torchia,
MD

Last literature review version 17.2: May 2009 | This topic last updated:
June 9, 2008 (More)

INTRODUCTION — Brucellosis (also called undulant, Mediterranean, or Malta

fever) is a zoonotic infection with protean manifestations. Four species,
Brucella melitensis, B. abortus, B. suis and B. canis, are known to cause
disease in humans. Brucella sp. are Gram negative, facultative intracellular
coccobacilli. The clinical manifestations, diagnosis, and treatment of brucellosis
in children are reviewed herein. The clinical manifestations, diagnos, and
treatment of brucellosis in adults and the microbiology and epidemiology of
Brucella are discussed separately. ( See "Clinical manifestations; diagnosis;
and treatment of brucellosis in adults" and see "Microbiology, epidemiology,
and pathogenesis of Brucella" ).

CLINICAL MANIFESTATIONS — Brucellosis is a well-documented cause of

fever of unknown origin, with varied and nonspecific symptoms. In addition to
fever, other prominent symptoms include sweats, malaise, anorexia, fatigue,
weight loss, and depression. The onset of symptoms of brucellosis may be
abrupt or insidious, developing over several days to weeks. (" See "Etiologies
of fever of unknown origin in children" ).

Patients tend to have a multitude of complaints, often without objective

findings except fever. Physical findings, when present, usually are limited to
minimal lymphadenopathy and occasionally hepatosplenomegaly.

Virtually any organ system can be involved with brucellosis, and localization of
the process may cause focal symptoms or findings [ 1,2] . In one report of 530
cases studied prospectively, 32 percent developed a focal complication [ 2] .
Duration of symptoms for more than 30 days before diagnosis was the major
risk factor for developing focal disease.

The most common sites for localization are:

 Osteoarticular, especially sacroiliitis — 20 to 30 percent [ 2,3]
Genitourinary, especially epididymoorchitis — 2 to 40 percent of males
[2,4]
Neurobrucellosis, usually presenting as meningitis — 1 to 2 percent
[2,5,6] ; less common neurologic complications include papilledema,
optic neuropathy, radiculopathy, stroke, and intracerebral hemorrhage
[5]
Endocarditis — 1 percent [ 2,7] ; most cases of endocarditis are
left-sided, and about two-thirds occur on previously damaged valves [ 7]
Hepatic abscess — 1 percent [ 2]

Other less common complications include splenic, thyroid, or epidural abscess;

pneumonitis, pleural effusion or empyema; and uveitis. ( See "Epidemiology;
clinical presentation; and evaluation of parapneumonic effusion and empyema
in children" ).

In one large series of childhood brucellosis, the most common clinical

manifestations among 102 patients were fever (91 percent), arthralgia (73
percent), malaise (60 percent), and weight loss (48 percent) [ 8] . The most
frequent abnormalities on physical examination were arthritis (37 percent),
splenomegaly (35 percent), and hepatomegaly (28 percent). Large joints are
affected most commonly in children with osteoarticular manifestations of
brucellosis [ 9] . Hepatic or splenic abscesses are extremely rare in children
[10] .

A syndrome termed chronic brucellosis manifested by malaise, asthenia, and

depression, was a relatively common diagnosis in the 1950s. However, most
patients who had that diagnosis likely represent the current population
receiving a diagnosis of chronic fatigue syndrome. ( See "Clinical features and
diagnosis of chronic fatigue syndrome" ).

Undiagnosed and untreated brucellosis can be symptomatic for months, and

some previously treated patients may relapse [ 11] .

DIAGNOSIS — The diagnosis of brucellosis should be considered in an adult

with otherwise unexplained chronic fever and nonspecific complaints. Such
patients should be questioned for possible sources of exposure to Brucella,
including contact with animal tissues or ingestion of unpasteurized milk or
cheese. The same sources should be sought for children with suspected
brucellosis. However, in the neonate, transplacental transmission or
breast-milk-borne infection may occur; these modes of transmission are
especially important to consider in highly endemic areas [ 12,13] . The
differential diagnosis varies, depending upon the presence or absence of focal
features.

Routine laboratory studies are nonspecific. White blood cell counts usually are
normal to low (pancytopenia can occur) [ 14,15] , and minor disturbances in
hepatic enzymes are relatively common. Although studies such as
radiographs, bone scans, ultrasound scans, computerized tomography,
magnetic resonance imaging, and echocardiography may be helpful in isolating
or delineating focal disease, they do not provide a definitive diagnosis. In
neurobrucellosis, abnormalities of the cerebrospinal fluid (CSF) typically include
a pleocytosis of 10 to 200 white blood cells that are predominantly
mononuclear, elevated levels of protein and hypoglycorrhachia [ 16] .

Cultures — Both cultures and serologic tests can be used to establish the
diagnosis of brucellosis. Ideally, the diagnosis is made by isolation of the
organism from cultures of blood or other sites, especially bone marrow or liver
biopsy specimens. However, cultures are not always positive; in one large
series, for example, blood cultures were positive in only 80 percent of initial
infections [ 11] .

An important problem is that Brucella sp. tend to be slow growing, which can
lead to erroneous results. Classically, the performance of cultures on biphasic
media (Ruiz-Castaneda) or some modification thereof has been recommended.
Using these techniques, cultures generally become positive between 7 and 21
days but may take up to 35 days. However, the use of biphasic media is not
routine in clinical laboratories, many of which use automated blood culture
systems such as BACTEC, routinely hold bottles for 5 to 7 days, and do not
perform blind subcultures of "negative" bottles. Although some isolates may
grow and be detected in the BACTEC system, cultures are unlikely to be
positive in the 5- to 7-day period. Therefore, febrile patients with unsuspected
brucellosis likely will have negative cultures with standard blood culture
techniques.

Thus, if brucellosis is suspected, the clinician should communicate with the

microbiology laboratory to hold cultures for several weeks, to perform blind
subcultures, or to use lysis centrifugation cultures or biphasic media [ 17-20] .

In addition to blood, a variety of other specimens may provide positive

cultures. They include liver biopsies, aspiration or biopsy of areas of localized
disease, especially bone marrow, pleural fluid or tissue, and occasionally CSF.

Serologic tests — Numerous diagnostic serologic tests have been developed

for the diagnosis of brucellosis:

Serum agglutination (standard tube agglutination)

Complement fixation
Rose Bengal agglutination
Antibrucella Coombs
ELISA (enzyme-linked immunosorbent assay).

Most published results are derived from tube agglutination testing. The
general consensus is that a single titer of >1:160 in the presence of a
compatible illness supports the diagnosis. Demonstration of a fourfold or
greater increase or decrease in agglutinating antibodies over 4 to 12 weeks
provides even stronger evidence for the diagnosis.

An important exception is that infection with B. canis does not produce

antibodies that crossreact with standard brucella antigens. As a result, B.
canis serology should be specifically requested if one suspects the illness is
caused by this species or if brucellosis is suspected but the standard tube
agglutination test is negative [ 1] .

One report compared classic serologic testing with ELISA in 75 patients with
brucellosis [ 7] . All of the patients had positive serologic tests except for five
who had IgM ELISA. Other studies have found that standard tube
agglutination and ELISA are comparable for serologic diagnosis [ 21] . Most
serological studies for diagnosis of Brucellosis are based upon the detection of
antibody. A study has been reported utilizing a sandwich ELISA for the
detection of antigen. One hundred forty six patients with Brucellosis, 264
patients with other diseases, and 1,607 random blood donors were studied.
The specificity was >99 percent in both the infected patients and blood
donors. This study suggests that ELISA would not replace serology but might
be considered instead of blood cultures, as results would be available sooner.

In addition to use for diagnosis, serologic studies also have been used to
attempt to predict cures and relapse of disease. Such studies have involved
treatment of sera with 2-mercaptoethanol or dithiothreitol, both of which
inactivate IgM antibodies. IgM antibodies contribute to the agglutination
reaction in the tube agglutination test and may persist for months to years
after therapy. IgG antibodies tend to decline to low levels over the course of
approximately one year after successful therapy. A similar phenomenon can
be observed by measuring IgM or IgG by ELISA.

Persistently high IgG agglutinating antibodies or IgG levels by ELISA once

were thought to reflect inadequate treatment with persistent infection.
However, the predictive value of persistently elevated IgG titers is limited; it is
not an uncommon finding in cured patients who had high titers or focal
disease on admission [ 21] . On the other hand, rising agglutinating titers or
levels of IgG suggest relapse [ 21] .

Ancillary findings that may prompt ordering of specific cultures or serologic

studies in febrile patients include the presence of granulomatous hepatitis,
hepatic microabscesses, or bone marrow granulomas and/or
hemophagocytosis. In patients with "aseptic meningitis," elevated levels of
adenosine deaminase in CSF suggest the diagnosis of tuberculous or brucella
meningitis [22] .

A test using the polymerase chain reaction shows promise for the detection
and rapid diagnosis of Brucella sp. in human blood specimens [ 23] . Its clinical
role remains to be defined.

TREATMENT — Several regimens have been used to treat brucellosis [ 24,25] .

Doxycycline (100 mg PO BID for six weeks) combined with streptomycin (1 g IM
once daily for 14 to 21 days) or rifampin (600 to 900 mg PO once daily for six
weeks) is the mainstay of therapy in adults. No regimen is 100 percent
effective because some patients will relapse after therapy. Most relapses
occur within three months of stopping therapy and almost all within six
months.

Children — Avoiding the use of tetracyclines in children younger than 8 years

is desirable. One regimen that has been effective in children is oral
trimethoprim-sulfamethoxazole (10 to 12 mg/kg per day of the trimethoprim
component, 50 to 60 mg/kg per day of the sulfa component in two divided
doses) plus rifampin (15 to 20 mg/kg per day of rifampin up to a maximum of
600 mg PO daily in two divided doses) for six weeks; the relapse rate with
this regimen is approximately 3.5 percent [ 26] .

Others have recommended trimethoprim-sulfamethoxazole plus rifampin with

a short course (14 days) of gentamicin for more serious infection or
complications of brucellosis such as endocarditis or meningitis [ 27,28] .

Pregnancy — The treatment of brucellosis in pregnancy is discussed

separately. ( See "Clinical manifestations; diagnosis; and treatment of
brucellosis in adults" , section on Pregnancy).

Neurobrucellosis — Neurobrucellosis requires special attention. Most

authorities recommend two or three drugs that cross the blood-brain-CSF
barrier (such as doxycycline , rifampin, and trimethoprim-sulfamethoxazole ).
The duration of therapy generally is prolonged, varying from 1 to 19 months
[5,6] . Therapy needs to be individualized according to signs and symptoms
but generally should be continued until analysis of the CSF has returned to
normal.

The prognosis is variable in neurobrucellosis. In one report of 18 patients,

only 11 showed complete recovery of neurologic function [ 5] . Corticosteroids
have been used, but their role is not clearly delineated [ 5] .

Endocarditis — Brucella endocarditis rarely is cured by medical therapy alone,

despite therapy with three or four drugs. Thus, most patients need valve
replacement followed by several weeks to months of antimicrobial therapy [ 7] .

Accidental animal vaccine exposure —Another situation that occasionally

arises is accidental injection or eye exposure to animal vaccines. The vaccines
are live attenuated strains that can cause human disease. Should accidental
injection or conjunctival exposure occur, it is recommended that patients
should be treated with a full therapeutic regimen [ 1] .
PREVENTION — Prevention of brucellosis is largely through vaccination of
domesticated herds and flocks and serologic testing and slaughter of infected
animals. Vaccinating cattle with live attenuated vaccines, B. abortus strain 19,
and sheep and goats with B. melitensis Rev-1, are effective measures, but a
sustained vaccination program over several years is required. No vaccine is
available for swine. Other measures include the quarantine of herds and the
slaughter of infected animals.

Pasteurization of milk is very important for the prevention of transmission to

humans. Currently, a brucella vaccine for human use is not available in the
United States.

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REFERENCES

1. Young, ES. An overview of human brucellosis. Clin Infect Dis 1995;

21:283.
2. Colmenero, JD, Reguera, JM, Martos, F, et al. Complications associated
with Brucella melitensis infection: A study of 530 cases. Medicine
(Baltimore) 1996; 75:195.
3. Ariza, J, Pujol, M, Valverde, J, et al. Brucellar sacroiliitis: Findings in 63
episodes and current relevance. Clin Infect Dis 1993; 16:761.
4. Afsar, H, Baydar, I, Sirmatel, F. Epididymo-orchitis due to brucellosis. Br J
Urol 1993; 72:104.
5. McLean, DR, Russell, N, Kahn, MY. Neurobrucellosis: Clinical and
therapeutic features. Clin Infect Dis 1992; 15:582.
6. Bouza, E, de la Torre, MG, Parras, F, et al. Brucella meningitis. Rev Infect
Dis 1987; 9:810.
7. Fernandez-Guerrero, ML. Zoonotic endocarditis. Infect Dis Clin North Am
1993; 7:135.
8. Al-Eissa, YA, Abdulmajeed, MK, Al-Nasser, MN, et al. Childhood
brucellosis: a study of 102 cases. Pediatr Infect Dis J 1990; 9:74.
9. al-Eissa, YA, Kambal, AM, Alrabeeah, AA, et al. Osteoarticular brucellosis
in children. Ann Rheum Dis 1990; 49:896.
10. Vallejo, JG, Stevens, AM, Dutton, RV, Kaplan, SL. Hepatosplenic
abscesses due to Brucella melitensis: report of a case involving a child
and review of the literature. Clin Infect Dis 1996; 22:485.
11. Ariza, J, Corredoira, J, Pallares, R, et al. Characteristics of and risk
factors for relapse of brucellosis in humans. Clin Infect Dis 1995;
20:1241.
12. al-Eissa, YA, al-Mofada, SM. Congenital brucellosis. Pediatr Infect Dis J
 1992; 11:667.
13. Al-Eissa, YA. Probable breast-milk borne brucellosis in a young infant.
Ann Trop Paediatr 1990; 10:305.
14. Karakukcu, M, Patiroglu, T, Ozdemir, MA, et al. Pancytopenia, a Rare
Hematologic Manifestation of Brucellosis in Children. J Pediatr Hematol
Oncol 2004; 26:803.
15. Youssef, AA, Sulaiman, AA, Al-Fawaz, IM, et al. Pancytopenia in children
with brucellosis: Clinical manifestations and bone marrow findings. Acta
Haematol 1993; 89:132.
16. Al Deeb, SM, Yaqub, BA, Sharif, HS, Phadke, JG. Neurobrucellosis: clinical
characteristics, diagnosis, and outcome. Neurology 1989; 39:498.
17. Solomon, HM, Jackson, D. Rapid diagnosis of Brucella melitensis in
blood: Some operational characteristics of the BACT/ALERT. J Clin
Microbiol 1992; 30:222.
18. Gamazo, C, Vitas, AI, Lopez-Goni, I, et al. Factors affecting detection of
Brucella melitensis by BACTEC MR730, a nonradiometric system for
hemocultures. J Clin Microbiol 1993; 31:3200.
19. Navas, E, Guerrero, A, Cobo, J, Loza, E. Faster isolation of Brucella spp.
from blood by isolator compared with BACTEC NR. Diagn Microbiol Infect
Dis 1993; 16:79.
20. Gaviria-Ruiz, MM, Cerdona-Castro, NM. Evaluation and comparison of
different blood culture techniques for bacteriological isolation of
Salmonella typhi and Brucella abortus. J Clin Microbiol 1995; 33:868.
21. Ariza, J, Pellicer, T, Pallares, R, et al. Specific antibody profile in human
brucellosis. Clin Infect Dis 1992; 14:131.
22. Lopez-Cortes, LF, Cruz-Ruiz, M, Gomez-Mateos, J, et al. Adenosine
deaminase activity in the CSF of patients with aseptic meningitis: Utility
in the diagnosis of tuberculous meningitis or neurobrucellosis. Clin
Infect Dis 1995; 20:525.
23. Matar, GM, Khneisser, IA, Abdelnoor, AM. Rapid laboratory confirmation
of human brucellosis by PCR analysis of a target sequence on the
31-kilodalton Brucella antigen DNA. J Clin Microbiol 1996; 34:477.
24. Montejo, JM, Alberola, I, Gloz-Zarate, P, et al. Open, randomized
therapeutic trial of six antimicrobial regimens in the treatment of human
brucellosis. Clin Infect Dis 1993; 16:671.
25. Ariza, J, Gudiol, F, Pallares, R, et al. Treatment of human brucellosis with
doxycycline plus rifampin or doxycycline plus streptomycin. A
randomized, double-blind study. Ann Intern Med 1992; 117:25.
26. Khuri-Bulas, NA, Droud, AN, Azab, SM. Treatment of childhood
brucellosis: Results of a prospective trial on 113 children. Pediatr Infect
Dis J 1993; 12:377.
27. Lubani, MM, Dudin, KI, Sherda, DC, et al. A multicenter therapeutic study
 of 1100 children with brucellosis. Pediatr Infect Dis J 1989; 8:75.
28. American Academy of Pediatrics. Brucellosis. In: Red Book: 2006 Report
of the Committee on Infectious Diseases, 27th ed, Pickering, LK (Ed),
American Academy of Pediatrics, Elk Grove Village, IL 2006. p.235.

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