Published online May 1, 2008
PEDIATRICS Vol. 121 No. 5 May 2008, pp. e1178-e1183 (doi:10.1542/peds.2007-1874)
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ARTICLE

Diagnostic and Therapeutic Challenges of Childhood Brucellosis in a Nonendemic Country

Mark W. Shen, MD

Department of Pediatrics, University of Texas Medical Branch, Austin, Texas


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. The goal to define the current epidemiology, clinical manifestations, and course of childhood brucellosis in the United States.

METHODS. A retrospective chart review was performed of 20 patients who received a diagnosis of brucellosis over a period of 13 years at a large, tertiary care children's hospital in Dallas, Texas. Diagnostic criteria, epidemiology, clinical presentations, and outcomes were recorded.

RESULTS. Ninety-five percent of the patients had a recent history of either travel to Mexico or ingestion of unpasteurized milk products from Mexico. Fever was an initial complaint in 80% of the patients, and 50% of the patients presented with arthritis. Diagnosis was made via the identification of Brucella melitensis in the blood cultures of 18 patients. Five patients experienced relapse, and 3 experienced treatment failure.

CONCLUSIONS. Childhood brucellosis in the United States is now an imported disease, primarily from Mexico. In the context of this epidemiologic link, the diagnosis should be entertained for a patient who presents with signs of systemic inflammation and arthritis. Therapeutic challenges remain.

Key Words: brucellosis • child • United States • Mexico • epidemiology • zoonoses

Abbreviations: ICD-9-CM—International Classification of Diseases, Ninth Revision, Clinical Modification • SAT—serum agglutination test • TMP-SMX—trimethoprim-sulfamethoxazole

Brucellosis is thought to be the most common zoonosis worldwide.1 Human disease is typically protean in its manifestations and can present in almost any organ system of the body. Morbidity in untreated disease is substantial; thus, early consideration and diagnosis of brucellosis are important for minimizing untoward outcomes. Maintaining a high index of suspicion for this disease may be difficult in nonendemic areas such as the United States, where decades of intensive efforts to control the disease in animals resulted in a great decline in the incidence of human brucellosis. As a result, what was once an occupational disease in animal husbandry and abattoir workers is now a disease associated with the ingestion of unpasteurized milk products. This changing epidemiology has been documented, with a link to the Hispanic populations in California and Texas, 2 states with the highest incidence of disease2–5; however, the specific impact of this shift on the children of the United States has not been examined. Almost all data continue to come from countries where brucellosis remains endemic and the incidence remains high. We sought to define risk factors for this disease in a nonendemic area. The purpose of this study was to examine the epidemiology, manifestations, and treatment of childhood brucellosis in the United States by reviewing presentations to a large, tertiary care children's hospital in Dallas, Texas.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
A retrospective chart review was conducted via the Medical Records Department at Children's Medical Center of Dallas. Inpatient and outpatient encounters from January 1993 to January 2006 were searched for the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 023 (023.0–023.9). A searchable database of ICD-9-CM codes was not available for patients who presented before 1993. Inclusion in the review was based on a final clinical and laboratory-supported diagnosis of brucellosis, followed by appropriate antimicrobial therapy. An automated BacT/Alert culture system had been in place before 1993 and was used by the laboratory during all study years. All positive blood cultures had been sent to the Texas Department of Health for confirmation and typing. In the absence of a positive culture, a single positive serum agglutination test titer (SAT) of ≥1:160 was considered sufficient for diagnosis in the presence of supportive clinical evidence of disease. For differentiation between the common findings of arthritis and arthralgias, the former was defined by the documentation of an objective finding of swelling, tenderness, or limitation of movement in a joint, whereas the latter was defined by a complaint of joint discomfort without objective findings. Organomegaly was defined by a documented assessment of abnormal size after the physical examination was performed. Relapse was defined by the presence of a clinical picture compatible with brucellosis, after a symptom-free interval after previous treatment. Treatment failure was defined as persistence of symptoms or the development of new symptoms of brucellosis before the end of treatment. Information was obtained solely through documentation in the medical chart.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Twenty patients received a diagnosis of and were treated for brucellosis from 1993 through 2005 (Table 1). Diagnosis was confirmed via blood culture for 18 (90%) patients. All 18 positive blood cultures grew Brucella melitensis. For 2 patients with negative blood cultures, serology was used for diagnosis. Patient 14 presented with 6 weeks of fever, sweating, and sacroiliitis with a markedly elevated SAT of >1:1260. Patient 9 had traveled to rural Thailand for 1 month and presented with 2 weeks of fever, a maculopapular rash, elevated liver enzymes, and a SAT of 1:160. There was no documentation of previous residence in an endemic area. After discussion with the Infectious Disease service, a decision was made to treat the patient for brucellosis. Intravenous gentamicin was administered for 7 days, and oral doxycycline and rifampin were prescribed for 6 weeks. Symptoms resolved rapidly after the initiation of antibiotic therapy.


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  		TABLE 1 Cases of Brucellosis at Children's Medical Center of Dallas, 1993–2005

 
Ages ranged from 2 to 18 years, and there were equal numbers of male and female patients. Nineteen (95%) of the 20 patients were classified as Hispanic, and 16 (80%) had reported travel to Mexico within the previous year. Thirteen of these 16 patients also consumed unpasteurized milk or cheese products while in Mexico. During their stays, 6 children also spent time on ranches or farms, where they had exposure to cows, goats, horses, or pigs. Of the 4 patients who did not have a history of travel to Mexico, 2 had consumed fresh homemade cheese directly transported from Mexico, 1 child had traveled to rural Thailand, and, for 1 child, no epidemiologic history was recorded. The duration of symptoms before diagnosis varied from <1 week for 10 patients, 1 to 4 weeks for 5 patients, and 1 to 3 months for 5 patients.

Symptoms varied, although fever was the most common initial complaint, present in 16 (80%) of 20 patients. A history of chills was present in 5 patients, and other constitutional symptoms included weight loss, fatigue, diffuse aching pain, and lack of energy in 1 patient each. Two patients reported prominent sweating. Musculoskeletal pain, most commonly arthralgia, was noted in 15 (75%) patients; 5 of these patients had histories of multifocal or migratory pain, 6 patients had abdominal pain, and 3 patients had headaches. An 8-year-old child presented with symptoms of depression and was reported to be "withdrawn, sad [and] weepy." "She cries often [and] only lays around."

Common signs of brucellosis included 10 patients with arthritis on initial presentation, 8 of whom had monoarticular disease. Two children had 2 affected joints. Of the 5 patients who relapsed, 3 developed monoarticular arthritis, 2 of whom had not previously had articular disease. Including cases of relapse, the distribution of joint disease is seen in Table 2. Two patients had osteomyelitis: 1 patient had osteomyelitis of the distal fibular metaphysis, and another had osteomyelitis of the distal femur in association with arthritis of the knee. Five patients had hepatosplenomegaly, whereas 3 patients had liver enlargement only. Three patients had a skin rash. Epididymoorchitis was noted in 1 adolescent, on relapse.


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  		TABLE 2 Location of Arthritis in Patients With Brucellosis

 
Of the 18 positive blood cultures, time until positivity was available for 16 and is shown in Fig 1. A complete blood count was available for all but 1 patient. Total white blood cell count on presentation ranged from 2900 to 106000/mm3, with a median of 5300/mm3. Twelve patients were anemic for their age, with hemoglobin values ranging from 8.9 to 11.6 g/dL. Three patients had platelet counts of <150000/mm3, whereas 5 patients had platelet counts between 150000/mm3 and 159000/mm3. Two patients were pancytopenic, defined as a low total white blood cell count and hemoglobin for age, and a platelet count of <150000/mm3. Initial erythrocyte sedimentation rates and C-reactive protein values were available for 16 and 14 patients, respectively, and encompassed a broad range of values (Figs 2 and 3).


Figure 1
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  		FIGURE 1 Incubation time to positive cultures in 16 cases of Brucellosis. Time until first notification of a positive blood culture. Bars represent the number of cultures that returned positive within the particular time frame.

 

Figure 2
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  		FIGURE 2 Initial ESR in 17 cases of brucellosis. (ESR measurements on presentation.) Bars represent the number of patients with an ESR in the given ranges.

 

Figure 3
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  		FIGURE 3 Initial CRP in 14 cases of Brucellosis. CRP levels on presentation. Bars represent number of patients with CRP levels in the given ranges.

 
In 19 of 20 cases, treatment regimens consisted of rifampin for 3 to 6 weeks in combination with doxycycline or of trimethoprim-sulfamethoxazole (TMP-SMX) for children who were younger than 8 years, for 4 to 6 weeks. Gentamicin was also given intravenously or intramuscularly for 3 to 14 days as initial treatment for 17 of 20 patients. Sixteen of these patients received 3 drugs concurrently as initial treatment. One patient received 2 weeks of gentamicin in combination with 6 weeks of doxycycline.

Five patients experienced relapse (Table 1), and 3 had late treatment failure. Patient 1 was treated with 14 days of intravenous gentamicin, in combination with 6 weeks of doxycycline and rifampin and 4 weeks of ciprofloxacin (started after the gentamicin). His initial treatment plan involved 7 days of intravenous gentamicin; however, this was extended to 14 days because of persistently positive blood cultures at the end of the first week of therapy. One month after completion of his 6-week course of therapy, he returned to the emergency department with scrotal swelling and received a diagnosis of epididymoorchitis. A previous history of brucellosis was not documented in the emergency department chart. He was discharged with a prescription for doxycycline and then was subsequently lost to follow-up. Patient 2 was initially treated with a 4-week course of oral TMP-SMX and rifampin at a different medical center in Dallas. She experienced relapse 2 months later with fever and subsequently had a positive blood culture for B melitensis. Patient 8 presented with fever and arthritis of the knee and was given intravenous gentamicin for 7 days in combination with TMP-SMX and rifampin. He improved but presented 2 weeks later, in the midst of therapy, with fever, arthritis of his hip, and a markedly elevated SAT (>1:1280). Patient 10 was initially treated with intravenous gentamicin for 7 days, in combination with TMP-SMX and rifampin; however, he was noncompliant with therapy at home. He experience relapse 5 months later with fever, osteoarthritis of his knee and distal femur, and an elevated serum agglutination test (1:320). Patient 11 had previously been treated in Mexico with an unknown regimen and presented 2 to 3 months afterward with fever, abdominal pain, headache, and sore throat. Patient 13 was treated with intravenous gentamicin for 7 days, in combination with 6 weeks of TMP-SMX and rifampin, and experienced relapse 9 months later with fever and a positive blood culture for B melitensis. Patient 16 initially presented with osteomyelitis of his distal fibula and was treated with intravenous gentamicin for 5 days, in combination with 6 weeks of TMP-SMX and rifampin. He presented 2 weeks later, during therapy, with left knee swelling. Patient 19 also experienced treatment failure, not relapse. He had previously been treated for brucellosis in Mexico (serum agglutination test 1:640), with 10 days of TMP-SMX and tetracycline. One month later, he presented with persistent knee pain without a symptom-free interval and received a diagnosis of "chronic brucellosis" after a blood culture returned positive for B melitensis.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Brucellosis is a clinically enigmatic disease. Insidious onset, undulating symptoms, and protean manifestations often make the diagnosis difficult. This may be further compounded in nonendemic areas such as the United States, where control of the disease in animals has resulted in a rate of ~100 reported new diagnoses per year.6,7 Brucellosis is a zoonotic disease, and epidemiologic clues typically come from a history of animal exposure or ingestion of unpasteurized milk products; however, a shifting epidemiology of this disease in the United States in the past 50 years has resulted in a transition to the latter being a much more prominent risk factor for disease. Once a disease of white men with occupational exposure to livestock, brucellosis now predominantly affects the Hispanic population.1,5 This is the first study to extend firmly this observation to children. A clear finding is the strong epidemiologic link either to travel to Mexico or to homemade cheese products brought from Mexico.

B melitensis was cultured in 90% of the patients in this study, and the logical reservoir of disease is in Mexico. Despite a recent decline in reported human cases, caprine and bovine brucellosis remain widespread in Mexico, particularly in regions that border the United States.8 In addition, with the exception of a reported outbreak in South Texas in 1999, B melitensis has been eradicated from animals in the United States since the early 1970s.9

The experience at this center reflects Texas's status as a state bordering an endemic area. Although this may not be applicable to all parts of the United States, continued high rates of Mexican immigration may represent an unappreciated risk factor for disease in states where brucellosis is not common. Unfortunately, substantive information regarding childhood brucellosis outside of California and Texas is lacking. Air travel to other endemic areas must also be considered and has been demonstrated to be a source of disease in children.10 Patient 9 had a history of travel to rural Thailand and a SAT of 1:160, a value that may be regarded as a borderline titer. Although this presents a measure of diagnostic uncertainty, brucellosis has been reported to be present in Thailand,11 and in many parts of Asia, animal disease remains difficult to control.1 New and old pathogens have made notable appearances in the United States in recent years, and brucellosis remains but a short trip away.

In cases of brucellosis acquired from travel, the duration of time between travel and onset of symptoms may allow for the elaboration of potential incubation periods without the potential confounding of reexposure that is typically present in endemic areas. The majority of patients developed symptoms within 1 to 6 weeks of travel to Mexico, which is typical for brucellosis. Longer incubation periods have been documented in the literature, and patients 4, 5, and 6 (siblings) reportedly developed symptoms up to 1 year after traveling to Mexico. The retrospective nature of this study precludes definitive conclusions, because with this family, there may have been other exposures to unpasteurized cheese after the travel occurred and the exact travel dates were not documented.

The symptoms and signs of brucellosis in this review are consistent with other large series reported from children in endemic areas. Fever, present in up to 90% of patients, is the most common symptom of brucellosis.12–14 Constitutional symptoms of malaise, fatigue, sweating, and chills are typically common, as are headache and abdominal pain. An illustration of the severity and/or variability in the manifestations of disease is seen in the child who presented with prominent symptoms of depression. This can be a common complaint in adults,15 but the frequency of this symptom in children is unknown. Neuropsychiatric symptoms typically improve with treatment.16 As a historical note, it is likely that neuropsychiatric symptoms contributed to the association of brucellosis with the now outdated term neurasthenia.17

Focal disease is common and most frequently localizes to the musculoskeletal system. Musculoskeletal pain was present in 75% of the children in this series, and arthritis was found on presentation in 50%, consistent with ranges published in previous reports (Table 3). Brucellar arthritis is monoarticular in at least two thirds of patients and involves the large, weight-bearing joints of the lower extremities. In children, hips and knees are affected most frequently, followed by the sacroiliac joint, ankle, and upper extremity joints.18–20 Osteomyelitis is rare in childhood brucellosis,14 in contrast to adults, in whom spondylitis is 1 of the most common manifestations of osteoarticular disease.


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  		TABLE 3 Osteoarticular Complications of Brucellosis in Children

 
The diagnosis of brucellosis is made definitively by culture of the organism from blood or bone marrow culture. Blood cultures returned positive in 90% of the cases in this series. The literature typically reports similar or lower rates; however, the data are difficult to compare globally because of differences in blood culture systems and technological advances over the years.21 Most cultures in this series required 72 to 96 hours of incubation for initial growth to be detected. In several instances, slow growth of Gram-negative coccobacilli was initially regarded as a contaminant because brucellosis was not entertained as a diagnostic possibility. This error is likely in nonendemic areas, where the suspicion of brucellosis remains low.22 One culture returned positive at ~136 hours (5.7 days). The BacT/Alert automated culture system was in use at this time, and cultures were not routinely kept for >5 calendar days; however, it remained common practice to call the laboratory in cases of suspected brucellosis to ask that the cultures be held for a longer period. No information was available as to whether this occurred or was necessary in this instance. Recent reports supported the ability of automated blood culture systems to reduce culture times of Brucella species to a period of days, rather than weeks,21,23 yet in the absence of larger studies with well-defined sensitivity results, there is likely not enough evidence to support a 5-day cutoff for holding blood cultures with an automated system in cases of suspected brucellosis.

Laboratory findings may assist in raising the suspicion of brucellosis. In our cases, the initial white blood cell count never exceeded 10 600/mm3, and anemia and decreased platelet counts were common. In conjunction with the common finding of hepatosplenomegaly, this is consistent with the predilection of Brucella species for the reticuloendothelial system.24 Pancytopenia, with the appropriate epidemiologic history, should raise the suspicion of brucellosis.25,26 The erythrocyte sedimentation rates and C-reactive protein levels were generally not helpful, because many values were normal or near normal. In the setting of suspected infectious arthritis, brucellosis may be a diagnostic consideration when elevated serum markers of inflammation are paradoxically absent.

Although treatment regimens for adults are well established, studies of children have had conflicting results. The historical standard for adult regimens consists of a tetracycline, most commonly doxycycline, for 6 weeks, in combination with an aminoglycoside, traditionally streptomycin, for the first 2 weeks. The World Health Organization recommends doxycycline and rifampin for 6 weeks as an alternative, a convenient oral regimen.27 This may be somewhat less effective than doxycycline plus streptomycin.28,29 Gentamicin for 7 days seems to be an acceptable substitute for streptomycin.30,31 For children who are younger than 8 years, TMP-SMX is used to avoid the dental staining associated with the use of tetracyclines.

Three large studies of children have examined the use of TMP-SMX for childhood brucellosis.13,32,33 Monotherapy with TMP-SMX is not as effective as combination therapy,32 but results with combination therapy, most commonly TMP-SMX and rifampin, have had mixed results. The largest study, a prospective trial of 1100 children, demonstrated impressive success with the use of short-term (3 weeks) combination therapy of TMP-SMX plus streptomycin, gentamicin, or rifampin.32 These findings have not been replicated, and others have called for a minimum of 6 weeks of therapy.13,33,34 Some have proposed even longer durations of therapy in adults.35

Average relapse rates of brucellosis are ~10%.36 Five (25%) patients in our series relapsed, yet this may underestimate the true incidence of relapse because many patients were lost to follow-up or were followed for only 2 to 3 months. Patient 1 did not have laboratory confirmation of relapse; however, his presentation of epididymoorchitis is a classic finding, described more than 100 years ago to occur "more commonly during relapses after apparent convalescence has been established."37 Comparison of initial treatment regimens was impossible because they were highly variable, they were unknown (patient 11), or noncompliance was a factor (patient 10). Patient 2 was treated at an outside facility with 4 weeks of TMP-SMX and rifampin. Patient 13 received 7 days of intravenous gentamicin plus 6 weeks of TMP-SMX and rifampin. Patient 1 received the most aggressive regimen, consisting of 6 weeks of 3-drug therapy: doxycycline, rifampin, and 2 weeks of intravenous gentamicin, followed by 4 weeks of ciprofloxacin. One difficulty in endemic areas, where brucellosis is typically studied, is distinguishing reinfection from relapse. All patients in our study who experienced relapse had no history of reexposure to unpasteurized milk products or travel to Mexico. In light of this, it is interesting that 2 children experienced relapse at 5 and 9 months after completion of therapy. This is within the realm of what has been reported for brucellosis and speaks to the extended duration of follow-up that is required for these patients.38

Three patients experienced failure of initial therapy, not frequently discussed in the literature. One child was treated in Mexico with an inappropriate regimen, 10 days of tetracycline and TMP-SMX. The other 2 children received intravenous gentamicin for 5 to 7 days, in conjunction with a planned course of 6 weeks of TMP-SMX and rifampin. They seemed to respond to a repeat course of intravenous gentamicin and a re-initiation of 6 weeks of oral therapy. Small numbers of patients, variable presentations, different treatment regimens, and poor follow-up combine to make any retrospective analysis of treatment regimens difficult.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Childhood brucellosis in the United States is associated with the ingestion of unpasteurized milk products from Mexico and/or travel to the region. In the appropriate epidemiologic context, brucellosis should be considered particularly when systemic signs of inflammation and arthritis are present. Patients should have extended periods of follow-up, because >50 years after the first successful treatment of brucellosis with streptomycin and tetracyclines, the optimal therapy eludes us still.


   ACKNOWLEDGMENTS
 
I thank Charles M. Ginsburg, MD, and John D. Nelson, MD, for thoughtful comments and guidance.


   FOOTNOTES
 
Accepted Oct 8, 2007.

Address correspondence to Mark W. Shen, MD, UTMB Pediatrics, Austin, 4900 Mueller Blvd, Austin, TX 78723-3079. E-mail: mshen{at}seton.org

The author has indicated he has no financial relationships relevant to this article to disclose.

This work was performed while the author was at Department of Pediatrics, University of Texas Southwestern Medical School, Dallas, Texas.


What's Known on This Subject

Brucellosis is now an uncommon disease in the United States as a result of the control of disease in animals.

 

What This Study Adds

Childhood brucellosis is now almost exclusively an imported disease, typically from exposure to unpasteurized milk products from Mexico.

 


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics




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