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 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 7  |  Issue : 1  |  Page : 1-6

Pediatric brucellosis: A short review


Department of Clinical Pharmacy, Faculty of Pharmacy, Jazan University, Jizan, KSA

Date of Web Publication16-Apr-2018

Correspondence Address:
Santhosh Joseph Menachery
Pharmacy Practice Research Unit, Department of Clinical Pharmacy, Faculty of Pharmacy, Jazan University, Jizan 45142
KSA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjhs.sjhs_47_17

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  Abstract 


Brucellosis is a zoonotic disease caused by Gram-negative coccobacilli (Brucella) which is commonly spread by ingestion of animal milk or its products or inhalation of infectious aerosols. Modernization of milk and meat processing has reduced the incidence of brucellosis significantly in most developed nations. Literature search was carried out in the search engines using medical subject headings terms. Articles published in English between 1990 and 2016 were included in the review. Articles that describe the pediatric brucellosis particularly in the Middle East region were evaluated while preparing this short review. The disease is currently endemic in several African countries. As a result of mass migrations from endemic regions, the disease is reemerging in several nonendemic countries, and the global prevalence of the disease is likely to see an upward trend in the coming years. The disease has a wide spectrum of clinical symptoms and signs and could result in complications with significant morbidity. Pediatric brucellosis has major influence of the health of young children and is often underdiagnosed. This review details the overall prevalence of the disease in the community, the microbiological and clinical profile, diagnostic methods, and appropriate treatment strategies. The review findings highlight the need to implement strategies for early identification and treatment reemerging zoonotic infection to curb its complications and associated morbidity and mortality.

Keywords: Brucella abortus, Brucella melitensis, Brucella, brucellosis, zoonoses


How to cite this article:
Al Barraq AA, Makeen HA, Menachery SJ. Pediatric brucellosis: A short review. Saudi J Health Sci 2018;7:1-6

How to cite this URL:
Al Barraq AA, Makeen HA, Menachery SJ. Pediatric brucellosis: A short review. Saudi J Health Sci [serial online] 2018 [cited 2018 Aug 16];7:1-6. Available from: http://www.saudijhealthsci.org/text.asp?2018/7/1/1/230230




  Introduction Top


Zoonotic infections are common globally, and the ancient zoonotic infection  Brucellosis More Details, caused by the bacteria  Brucella More Details, is one of the most prevalent zoonoses worldwide.[1] It is known across the world by several names;  Mediterranean fever More Details,  Malta fever More Details, gastric remittent fever, and undulant fever. The disease is associated with high morbidity in man and in animals. It is now considered as a significant public health problem in the community including children, imperative reason for economic loss in most developing countries, and the global burden of human brucellosis remains huge.[2] The rising prevalence of brucellosis has been attributed to increased international tourism and mass immigration from endemic countries. It may also be due to possible use of Brucella as a biologic weapon.[3],[4] It is important for health-care professionals to be knowledgeable regarding the common manifestations, laboratory studies essential for the recognition of the disease, and the appropriate management of this reemerging zoonosis in human. This disease is often not considered under differential diagnosis in children during the assessment of pediatric pyrexia of unknown/unexplained origin, and few cases are confirmed by specific diagnostic methods. This short review focuses on the epidemiology, microbiological aspects, clinical manifestations, and the management of brucellosis in children.

The purpose of this article is to provide a short review regarding brucellosis in children with a particular emphasis on the Middle East region. Published articles that describe the pediatric brucellosis particularly in the Middle East region were evaluated while preparing this short review.


  Methods Top


Literature search was carried out in the search engines such as MEDLINE, Proquest, and Google Scholar databases, using medical subject headings (MeSH) terms. The MeSH terms included brucellosis, Brucella, Brucella melitensis, Brucella abortus, zoonoses, treatment, epidemiology, bioterrorism, microbiology, and laboratory methods. The MeSH terms were used in combination with names of countries in the Middle East to retrieve relevant articles. Articles published in English language between 1990 and 2016 were included in the review. The information extracted from retrieved published full-text articles on brucellosis included the epidemiology, microbiology modes of transmission, pathogenicity, clinical manifestation, diagnostic and laboratory methods, treatment, prevention, and bioterrorism. The results of the analysis have been presented in tables and text under headings mentioned.

Epidemiology

Brucellosis is considered to be endemic in several African countries with nearly 500,000 cases reported annually across the globe;[5] however, there has been significant drop in number of reported cases in a few countries (United States) following adoption of policies of mandatory milk pasteurization, infected animal slaughter and its safe disposal, and aggressive animal vaccination drives.[3] Although cases of human brucellosis have dropped down significantly in many developed countries, it continues to be an important public health problem in developing countries, particularly in the Mediterranean region, Middle East, and West Asian countries.[6] Among the Middle Eastern region, countries such as Saudi Arabia, Syria, and Iran have reported higher prevalence of brucellosis.[7] Previous reports from Saudi Arabia showed an overall seroprevalence rate of 15% among the general population and 10% among the pediatric population (children aged 0–14 years).[8] Another study from Iran reported that 4.3% of pediatric population affected with brucellosis in endemic areas were asymptomatic and many of these children may have been symptomatic for short duration.[9] The prevalence of pediatric brucellosis in endemic regions is reported to be from 11% to 56%.[10] The higher rate of brucellosis in the Middle Eastern region is probably related to import of farm animals from endemic areas and increased awareness of the disease.[11]

Organisms involved

Brucella organisms are small fastidious intracellular Gram-negative coccobacilli which are nonmotile and nonspore forming.[12] Among the bacterial genus Brucella, about eight species have been identified based on phenotype, antigenic variation, and infection prevalence in different animal hosts. Of these eight species, four are known to be associated with human brucellosis with moderate to significant pathogenicity. B. melitensis which is associated with sheep infection, B. abortus with cattle infection, Brucella suis with pigs, and Brucella canis with dogs are known to cause human brucellosis.[13],[14] The Brucella species tend to concentrate in the reproductive organs of these host animals and are associated with abortions and sterility in the infected animals. These organisms are shed in large amounts in the animal's urine, milk, placental fluid, and other fluids. The Brucella species, the common animal host, and the degree of human pathogenicity have been listed in [Table 1].
Table 1: Brucella bacterial species, animal host, pathogenicity in humans, and route of inoculation

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Modes of transmission and pathogenicity

The different modes of transmission of the organism to humans include ingestion of unpasteurized or raw milk and milk products (especially soft cheese, butter, and cream prepared from unpasteurized milk). The other modes of transmission in humans include consumption of infected food products, direct contact with an infected animal or their products (among shepherds, farmers, and veterinarians), inhalation of aerosols (by workers in abattoirs and microbiology laboratories), and rarely in laboratories when dealing with infected blood and other infected fluid cultures.[17],[18]

The prime mode of disease acquisition among children in school age group, especially boys, is through contact with animals. The children in Shepherd families in endemic region are at higher risk due to consumption of young cheese from unpasteurized milk, family history of brucellosis infection, the living conditions of the children, and husbandry activities of the family members.[10]

After gaining entry into the human bloodstream, the organism invades both phagocytic as well as nonphagocytic cells and survives in the intracellular milieu avoiding the body's immune system by developing mechanisms to avoid or suppress bactericidal responses. It has been reported that the lipopolysaccharide coat (smooth in B. melitensis, B. abortus, and B. suis; rough in B. canis) is one of the important factors involved in intracellular survival.[16] It can involve any or every organ; kidney, liver, spleen, breast tissue, joints, central nervous system, heart, joints, genitourinary system, pulmonary system, and skin. Cell-mediated immunity is primarily involved in the recovery phase. However, the immunity to reinfection is provided by serum immunoglobulin (Ig). IgM levels rise in the early phase of infection and it is followed by rise in the IgG titers. A chronic or relapsed infection is indicated by a persistently elevated IgG titer or subsequent rises in IgG.

Clinical manifestation

Human brucellosis is a systemic infection with a wide-ranging clinical spectrum and severity, from asymptomatic disease presentation to severe and/or fatal illness. This nonspecific clinical profile observed in human brucellosis is due to variable pathogenicity of different strains. It is often difficult to differentiate clinically from a number of other infections, especially the infections caused by tubercle bacilli and typhoid bacilli, and the infective endocarditis. The incubation period is usually 1–4 weeks; infrequently, it may be as long as several months.[19] It commonly presents as a multisystem disease involving many organs and tissues.[20]

Among children, it could present either as acute or subacute presentation (febrile illness and a variety of manifestations) lasting from 2 to 4 weeks.[15],[21]Brucella infection among pediatric age group is generally more benign compared to the adult population with respect to the response to treatment and the likelihood and severity of complications.[15],[22]

B. melitensis is known to cause more serious infection than B. abortus; infection caused by B. abortus causes milder disease with either mild symptoms or focal lesions. Infection with B. melitensis is usually associated with a high bacterial load, short incubation period, and significant observable symptoms.[23],[24] About three-quarters of the patients with brucellosis report with symptoms by the 2nd week of the infection. Human infections by B. suis can be as severe as B. melitensis. B. canis is infrequently associated with human disease and usually milder disease.

Patients with brucellosis usually present with fever (80%–100%) and its constitutional symptoms such as anorexia, fatigue, weakness, malaise, and weight loss (>90% of cases). Joint involvement (55%–80% cases) is also very common in brucellosis with symptoms of arthralgia, low back pain, spine, and joint pain. Predominant gastrointestinal symptoms are dyspepsia (50% cases) and constipation, but diarrhea and vomiting may also occur in some children. In addition, patients can present with neuropsychiatric symptoms (headache, depression, and fatigue), genitourinary infections, neurologic symptoms (weakness, dizziness, unsteadiness of gait, and urinary retention), and respiratory tract symptoms such as cough and dyspnea.

In children, the most common presenting signs include fever, arthritis, hepatomegaly, splenomegaly, and neck stiffness. The bone marrow and spleen are commonly involved; thus, hematological complications of brucellosis are common due to the pathogen's tropism to these two organs.[25] Monoarthritis is more frequent than polyarthritis in children, with hip and knee joints being the most commonly involved joints.[26] Sometimes, children can present with features of Brucella osteomyelitis, neurobrucellosis, hydrocephalus, pseudotumor cerebri, Guillain–Barre syndrome, cranial nerve palsy, and cerebral venous sinus thrombosis.[27],[28] Brucellosis in children may also present in many rare forms such as endocarditis, myocarditis, pericarditis, nephritis, episcleritis, chorioretinitis, uveitis, cholecystitis, ataxia, peritonitis, central and peripheral neuritis, acute flaccid paralysis, demyelination, depression, electrocardiographic changes, brain abscess, jaundice, leukemoid reaction, systolic murmur, epistaxis, and parotitis.[29],[30],[31],[32]


  Diagnosis Top


The human brucellosis lacks pathognomonic symptoms and laboratory tests that are critical for its diagnosis.

Presumptive diagnosis

Presumptive diagnosis can be made by serological tests based on detection of antibodies produced against lipopolysaccharide and those based on antibody production against other bacterial antigens such as Rose Bengal test (RBT), standard agglutination test (SAT), complement fixation test, enzyme-linked immunosorbent assay (ELISA), and milk ring test. RBT, a rapid slide-type agglutination assay, is a simple screening test for human brucellosis, and as per the WHO guidelines, the test value needs to be confirmed by other confirmatory tests. The disadvantages with RBT are the low sensitivity in long chronic cases and relatively low specificity in endemic areas.[33] The SAT is one of the commonly used diagnostic tests for brucellosis; titers above 1:160 are considered diagnostic in conjunction with a characteristic clinical presentation.[34] The SAT detects antibodies to the smooth lipopolysaccharide. Antibodies reacting against smooth lipopolysaccharide can also be detected by other tests, such as ELISA. The sensitivity of ELISA is reported to be lower than SAT in patients with Brucella bacteremia, and studies recommend against the use of nonagglutination tests such as ELISA for confirmation of Brucella infection.[35],[36]

Confirmatory diagnosis

Mononuclear phagocytic cells are the primary sites where the Brucella species live and even multiply. This is one of the prime reasons for the prolonged and relapsing clinical course of the disease and also the challenges associated with its diagnosis and treatment.[17],[26] Isolation of the Brucella organisms from blood, bone marrow, or tissue samples is the most definitive method of confirming the brucellosis infection, but this method is complicated and time consuming. The sensitivity of the blood culture varies from 15% to 70% depending on various laboratory associated factors.[26],[37] Bone marrow cultures are the gold standard diagnostic tests for absolute diagnosis of brucellosis, due to the fact that these organisms reside in the reticuloendothelial system in relatively large concentration. Bacterial elimination from the bone marrow ensures complete microbial eradication from the body system. The only disadvantage associated with collecting bone marrow for culture is the invasive, painful technique involved. Previous studies among Turkish children have reported that although positive blood culture is the standard for diagnosis, it is not necessary for the diagnosis of brucellosis in situ ations with positive exposure history, supporting clinical manifestations, and positive serologic tests.[38]

In addition, a quick and reliable substitute for diagnosing acute brucellosis is offered by the dipstick tests that are currently available.[39] Polymerase chain reaction assays that are both sensitive and specific are being tried out using a variety of gene sequences as targets for rapid diagnosis of brucellosis in humans.[40] However, all the diagnostic test results must be interpreted considering the epidemiologic and clinical findings.

Management

The management includes supportive care in addition to antimicrobial therapy. The general principles applied in the antimicrobial therapy of brucellosis include; the antimicrobial therapy should be with combination regimens, the selected antimicrobial should be active intracellularly and in acidic media, and the duration of the antimicrobial therapy should depend on the organ involved in the disease.[41]

Multidrug combination antimicrobial regimens are the primary therapy in brucellosis management considering the high relapse rates and treatment failures with a single antimicrobial treatment approach. The antimicrobials that display clinical activity with low relapse rates are doxycycline, rifampicin, trimethoprim–sulfamethoxazole (TMP/SMZ), streptomycin, gentamicin, and ciprofloxacin.[42],[43]

A combination of rifampicin and TMP/SMZ is administered for 6 weeks for children younger than 8 years of age; the relapse rate is reported to be 5% or lower with this regimen.[44],[45] For children older than 8 years of age, the combination of doxycycline and rifampicin is recommended. The doxycycline-based combination with rifampicin has reported the highest success rate and should be used only in children above 8 years to avoid the adverse effects on the teeth in younger children.[41],[46],[47] The detailed treatment and prophylaxis guidelines for brucellosis in children are listed in [Table 2].
Table 2: Common antimicrobials used in the management of pediatric brucellosis

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In serious infections, such as neurobrucellosis, three to five antimicrobials are required to be used for a longer period, usually extending for 3–12 months.[41],[46],[47] The combinations preferred are doxycycline-streptomycin-rifampin or doxycycline − TMP-SMZ − rifampin regimen with short course of adjunct corticosteroid therapy to control the inflammation. In cases of endocarditis, requiring aggressive therapy, aminoglycoside therapy in combination with doxycycline, rifampin, and TMP-SMZ for 2-4 weeks followed by two-three antimicrobial combination without aminoglycosides for another 8–12 weeks, is administered. Ciprofloxacin may be considered as an alternative option for the combination in selected cases with serious infections.[46] Chronic brucellosis is managed with triple antimicrobial therapy. The potential side effects of these drug combinations include ototoxicity and nephrotoxicity of the aminoglycoside-containing regimens which need further investigation.

Relapse after initial treatment with duration of at least 4 weeks in childhood brucellosis has been reported to range between 0% and 32% of the patients, and this usually occurs in the 1st year after treatment.[10],[19],[29],[38],[48] Relapse is confirmed in patients with symptoms by performing serology and blood culture.[49]

Prevention

Children and adults can be protected against foodborne infection with Brucella by ensuring pasteurization of milk, avoiding raw milk products, and thorough cooking of meat from susceptible animals. Avoidance of other risk factors such as contact with infected animals and their products, creating awareness among animal owners about the prevalence of this infection among animals and promoting regular veterinary visits for their animals and ensuring regular screening of animals, and adoption of vaccination schedules can reduce the prevalence to a great extent. Live attenuated vaccine of B. abortus and B. melitensis provides protection only for animals. Among health-care professionals handling brucellosis cases, appropriate precautions such as mask, gloves, and eye protection should be used while undertaking procedures or handling body fluids. Specimens from the patient should be handled in the laboratory under biosafety level III conditions.


  Brucella And Bioterrorism Top


Brucella species can be part of potential bioterrorism as it is highly infectious through aerosol route and is readily spread through the mucous membranes of the conjunctivae, nasal passages, oropharynx, and respiratory tract. A small inoculum (10–100 microorganisms) is sufficient to induce the disease in humans. The resulting disease may present with the various manifestations known to occur with Brucella species. A deliberate outbreak can have serious consequences to humanity, animal livestock, and the environment. Several researches have concentrated on appropriate sampling of Brucella spp. from environment including finding ways for its early detection and development of new drugs and vaccines to tackle this biological weapon.[42],[50]


  Conclusion Top


This study reviewed the epidemiology, microbiological aspects, clinical manifestations, and the management of brucellosis in children. As the disease is reemerging across the world, it is important for health-care providers to adopt suitable strategies for early identification and prompt management of this zoonotic infection to prevent its complications and associated morbidity and mortality. It is also important for the community to also be educated and aware of this disease.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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