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Utility of the Rose Bengal Test as a Point-of-Care Test for Human Brucellosis in Endemic African Settings: A Systematic Review
review-article
Author(s):
Abel B. Ekiri
1
,
2 ,
Christopher Kilonzo
1 ,
Brian H. Bird
1 ,
Elizabeth VanWormer
1
,
3 ,
David J. Wolking
1 ,
Woutrina A. Smith
1 ,
Honorati Masanja
4 ,
Rudovick R. Kazwala
5 ,
Jonna A. K. Mazet
1
,
Publication date (Electronic):
16 September 2020
Journal:
Journal of Tropical Medicine
Publisher:
Hindawi
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Abstract
In endemic African areas, such as Tanzania, Brucella spp. cause human febrile illnesses, which often go unrecognized and misdiagnosed, resulting in delayed diagnosis, underdiagnosis, and underreporting. Although rapid and affordable point-of-care tests, such as the Rose Bengal test (RBT), are available, acceptance and adoption of these tests at the national level are hindered by a lack of local diagnostic performance data. To address this need, evidence on the diagnostic performance of RBT as a human brucellosis point-of-care test was reviewed. The review was initially focused on studies conducted in Tanzania but was later extended to worldwide because few relevant studies from Tanzania were identified. Databases including Web of Science, Embase, MEDLINE, and World Health Organization Global Index Medicus were searched for studies assessing the diagnostic performance of RBT (sensitivity and specificity) for detection of human brucellosis, in comparison to the reference standard culture. Sixteen eligible studies were identified and reviewed following screening. The diagnostic sensitivity (DSe) and specificity (DSp) of RBT compared to culture as the gold standard were 87.5% and 100%, respectively, in studies that used suitable “true positive” and “true negative” patient comparison groups and were considered to be of high scientific quality. Diagnostic DSe and DSp of RBT compared to culture in studies that also used suitable “true positive” and “true negative” patient comparison groups but were considered to be of moderate scientific quality varied from 92.5% to 100% and 94.3 to 99.9%, respectively. The good diagnostic performance of RBT combined with its simplicity, quickness, and affordability makes RBT an ideal (or close to) stand-alone point-of-care test for early clinical diagnosis and management of human brucellosis and nonmalarial fevers in small and understaffed health facilities and laboratories in endemic areas in Africa and elsewhere.
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Most cited references35
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Brucellosis: an overview.
M Corbel (1997)
Brucellosis remains a major zoonosis worldwide. Although many countries have eradicated Brucella abortus from cattle, in some areas Brucella melitensis has emerged as a cause of infection in this species as well as in sheep and goats. Despite vaccination campaigns with the Rev 1 strain, B. melitensis remains the principal cause of human brucellosis. Brucella suis is also emerging as an agent of infection in cattle, thus extending its opportunities to infect humans. The recent isolation of distinctive strains of Brucella from marine mammals has extended its ecologic range. Molecular genetic studies have demonstrated phylogenetic affiliation to Agrobacterium, Phyllobacterium, Ochrobactrum, and Rhizobium. Polymerase chain reaction and gene probe development may provide more effective typing methods. Pathogenicity is related to production of lipopolysaccharides containing a poly N-formyl perosamine O chain, CuZn superoxide dismutase, erythrlose phosphate dehydrogenase, stress-induced proteins related to intracellular survival, and adenine and guanine monophosphate inhibitors of phagocyte functions. Protective immunity is conferred by antibody to lipopolysaccharide and T-cell-mediated macrophage activation triggered by protein antigens. Diagnosis still centers on isolation of the organism and serologic test results, especially enzyme immunoassay, which is replacing other methods. Polymerase chain reaction is also under evaluation. Therapy is based on tetracyclines with or without rifampicin, aminoglycosides, or quinolones. No satisfactory vaccines against human brucellosis are available, although attenuated purE mutants appear promising.
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Etiology of Severe Non-malaria Febrile Illness in Northern Tanzania: A Prospective Cohort Study
John Crump, Anne Morrissey, William Nicholson … (2013)
Introduction Fever without a localized cause is one of the most common presenting complaints among persons seeking healthcare in many low- and middle-income countries [1], [2]. However, unlike the syndromes of pneumonia and diarrhea that feature in global disease burden estimates and have well coordinated programs integrating efforts across the range of responsible pathogens to avert morbidity and mortality, there has been a lack of a coordinated approach for febrile illness. While illness and death due to some specific infections causing fever, such as malaria [3] and increasingly bacterial sepsis are well quantified [4]–[6], others such as a range of zoonoses and viral infections are uncounted and consequently may be underappreciated. The various etiologies of febrile illnesses are difficult to distinguish from one another clinically [7], [8]. As clinical laboratory services are often limited in areas where febrile conditions are particularly common [9], [10], clinicians may have few diagnostic tools to establish an etiologic diagnosis. Therefore, clinical management is often driven by syndrome-based guidelines employing empiric treatment [11]–[13]. In the absence of systematically collected data on fever etiology, considerable mismatch between clinical diagnosis, clinical management, and actual etiology may occur resulting in poor patient outcomes [14]. It is increasingly recognized that malaria is over-diagnosed in many areas [14], [15]. To address this problem, the World Health Organization (WHO) malaria treatment guidelines moved away from clinical diagnosis of malaria to treatment based on the results of a malaria diagnostic test such as a blood smear or a malaria rapid diagnostic test. With more widespread availability of diagnostic tests to exclude malaria and apparent declines in malaria worldwide [3], clinicians in resource-limited areas are faced with a growing proportion of febrile patients who do not have malaria and few tools to guide subsequent management. We sought to describe comprehensively the causes of febrile illness in northern Tanzania among patients sufficiently ill to require hospitalization. Febrile patients admitted to two hospitals were evaluated for a wide range of infectious etiologies using conventional standard diagnostic techniques. Methods Ethics statement This study was approved by the Kilimanjaro Christian Medical Centre (KCMC) Research Ethics Committee, the Tanzania National Institutes for Medical Research National Research Ethics Coordinating Committee, and Institutional Review Boards of Duke University Medical Center and the CDC. All minors had written informed consent given from a parent or guardian and all adult participants provided their own written informed consent. Setting Moshi (population, >144 000) is the administrative center of the Kilimanjaro Region (population, >1.4 million) in northern Tanzania and is situated at an elevation of 890 m above mean sea level. The climate is characterized by a long rainy period (March–May) and a short rainy period (October–December) [16]. Malaria transmission intensity is low [17]. KCMC is a consultant referral hospital with 458 inpatient beds serving several regions in northern Tanzania, and Mawenzi Regional Hospital (MRH), with 300 beds, is the Kilimanjaro Regional hospital. Together KCMC and MRH serve as the main providers of hospital care in the Moshi area. In 2008, KCMC admitted 22,099 patients and MRH admitted 21,763 patients. Study design A study team that was independent of the hospital clinical team identified participants among infants and children admitted to KCMC from 17 September 2007 through 25 August 2008, and among adolescents and adult admitted to KCMC and MRH in Moshi, Tanzania, from 17 September 2007 through 31 August 2008. The methods of these studies have been described in detail elsewhere [7], [8]. In brief, all admitted patients were screened for eligibility by study team members as soon as possible after admission and no later than 24 hours after admission. Infants and children aged from ≥2 months to <13 years, with a history of fever in the past 48 h or an axillary temperature ≥37.5°C or a rectal temperature of ≥38.0°C, and adolescents and adults aged ≥13 years and with oral temperatures of ≥38.0°C were invited to participate in the study. Patients admitted with known malignancy, renal failure, hepatic failure, bone marrow aplasia, trauma or surgery were excluded. A standardized clinical history and physical examination were performed on consenting patients by a trained clinical officer who was a member of the study team and who worked in parallel with the hospital admitting team. Provisional diagnoses by the hospital clinical team made independently of the study team were recorded and coded using the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) codes. Following cleansing of the skin with isopropyl alcohol and povidone iodine, blood was drawn from adults and adolescents for aerobic blood culture (5 mL) and for mycobacterial blood culture (5 mL) and from pediatric patients for a single aerobic blood culture (4 ml). In addition, blood was drawn for complete blood count, examination for blood parasites, and HIV antibody testing. Acute serum, plasma, and whole blood were archived on all participants. For patients found to be HIV seropositive, CD4-positive T lymphocyte count (CD4 cell count) and serum cryptococcal antigen level were also measured. HIV-seronegative patients were screened for the presence of acute HIV infection by polymerase chain reaction (PCR) for HIV-1 RNA. Urine was collected as soon as possible after admission for detection of urine antimicrobial activity and for antigen detection. A discharge form was completed at the time of discharge from the hospital that captured whether the patient died in hospital, the in-hospital management, and the discharge diagnoses coded using ICD-10 codes. The results of study investigations done in Moshi were provided immediately to the hospital clinical team to inform patient management. The results of investigations done at reference laboratories were provided to the hospital clinical team as they became available. The hospital clinical team was responsible for all aspects of patient management, following clinical judgment and use of locally adapted and developed treatment guidelines. All participants were asked to return to a study clinic 4–6 weeks after enrollment to provide a convalescent serum sample. To promote high levels of follow up, the study team provided a follow up appointment card prior to hospital discharge, made reminder telephone calls to participants during the week prior to the appointment, reimbursed travel expenses of returning participants, and when necessary a field worker made home visits. Laboratory evaluations Laboratory evaluations were selected to reflect a range of infectious diseases that might occur in northern Tanzania. Priority was given to laboratory evaluations for infectious diseases that might require specific management. Malaria Thick and thin blood films stained with Giemsa were examined for blood parasites by oil immersion microscopy. Parasite density was determined by standard methods [18]. Bacteria and fungal bloodstream infections Blood culture bottles were assessed for volume adequacy comparing the weight before and after inoculation with blood. Adequate volume was defined as the recommended volume ±20%. BacT/ALERT standard aerobic and mycobacterial bottles were loaded into the BacT/ALERT 3D Microbial Detection system (BioMérieux), where they were incubated for 5 and 42 days, respectively. Standard methods were used for identifying bloodstream isolates [7], [8]. Serum antigen testing Cryptococcal antigen level was measured using the Latex Cryptococcal Antigen Detection System assay (Immuno-Mycologics). Urine antigen testing Urine was tested for all participants for Legionella pneumophila serogroup 1 antigen using the Binax NOW Legionella urinary antigen test, and for adolescents and adults using the Sreptococcus pneumoniae using the Binax NOW S. pneumoniae antigen test (Binax). Urine was tested for Histoplasma capsulatum antigen using the MVista H. capsulatum quantitative antigen enzyme immunoassay (Miravista Diagnostics) [19], [20]. Leptospirosis Leptospirosis laboratory diagnosis was made using the standard microscopic agglutination test (MAT) performed at the CDC. Live leptospiral cell suspensions representing 20 serovars and 17 serogroups described elsewhere [21] were incubated with serially diluted serum specimens. Resulting agglutination titers were read using darkfield microscopy. The reported titer was the highest dilution of serum that agglutinated at least 50% of the cells for each serovar tested [22]. Confirmed leptospirosis was defined as a ≥4-fold rise in the agglutination titer between acute and convalescent serum samples [23]. Brucellosis Brucellosis serology was performed using the standard microagglutination test (MAT) performed at the CDC. Standardized Brucella abortus strain 1119-3 killed antigen (National Veterinary Services Laboratory, Ames, IA) was used for MAT at a 1∶25 working dilution described elsewhere [24]. Results were read on a Scienceware Plate Reader (Bel-Art Products, Wayne, NJ). Minor modifications were made to the CDC's standard MAT, including the use of U-bottom plates, incubation at 26°C, and discontinued use of staining techniques [25]. Confirmed brucellosis was defined as a ≥4-fold rise in the agglutination titer between acute and convalescent serum samples. Q fever Convalescent-phase serum samples were screened using C. burnetii immunoglobulin (Ig) G enzyme-linked immunosorbent assay (ELISA) against Phase II antigen (Inverness Medical Innovations). For samples that were either positive or equivocal by ELISA, paired serum samples were tested by indirect immunofluorescence antibody (IFA) IgG assay to C. burnetii (Nine Mile strain) Phase I and Phase II antigens. A fourfold or greater increase in IFA reciprocal titer to Phase II antigen defined acute Q fever [26]. Spotted fever group and typhus group rickettsioses Serum samples were tested for SFGR and TGR by IgG IFA to R. conorii (Moroccan strain) and to R. typhi (Wilmington strain), respectively. Among paired serum samples, a fourfold or greater increase in IFA titer to R. conorii and R. typhi defined acute SFGR and TGR infections, respectively [26]. Arboviruses RNA was extracted from serum samples using the QIAamp Viral RNA Mini kit (QIAGEN, Hilden, Germany). Reverse transcription was performed using Invitrogen Superscript III First Strand Synthesis System (Life Technologies, Carlsbad, CA). Real-time PCRs for flavivirus, DENV, and CHIKV were carried out with the LightCycler 480 SYBR Green I Master kit (Roche Diagnostics, Penzberg, Germany) in a total reaction volume of 20 µL containing 2 µL of cDNA using primers published elsewhere [27]–[29]. Confirmed acute CHIKV, DENV, and flavivirus infections were defined as a positive PCR result for CHIKV, DENV, and flavivirus viral RNA, respectively [30]. HIV HIV-1 antibody testing was done on whole blood using both the Capillus HIV-1/HIV-2 (Trinity Biotech) and Determine HIV-1/HIV-2 (Abbott Laboratories) rapid HIV antibody tests. The Capillus test was replaced with the SD Bioline HIV-1/HIV-2 test (version 3.0; Standard Diagnostics) on 4 March 2008 after a change in Tanzania Ministry of Health HIV testing guidelines. If rapid tests were discordant, the sample was tested using enzyme-linked immunosorbent assay (ELISA; Vironostika Uni-Form II plus O Ab; bioMe'rieux). If the ELISA was negative, no further testing was done. If the ELISA was positive, a Western blot (Genetic Systems HIV-1 Western blot kit; Bio-Rad) was done to confirm the result [31]. HIV-1 RNA PCR was done using the Abbott m2000 system RealTime HIV-1 assay (Abbott Laboratories) [32], [33]. Statistic analysis Data were entered using the Cardiff Teleform system (Cardiff Inc., Vista, Ca., USA) into an Access database (Microsoft Corp, Va., USA). When a diagnostic test was not applied to the whole cohort due lack of availability of an acute or convalescent sample, the proportion of confirmed cases in the tested group was extrapolated to the untested group by assuming that prevalence was the same in the tested group as in the untested group. Statistical analyses were performed with SAS version 9.1 software (SAS Inc, Cary, NC). Results Participant characteristics Figure 1 summarizes participant screening, enrollment, and diagnostic testing. Of 870 febrile admissions to two hospitals in northern Tanzania enrolled in the study 484 (55.6%) were female. Of participants, 467 (53.7%) were infants and children with a median (range) age of 2 years (2 months - 13 years); the remainder adolescents and adults with a median (range) age of 38 (14–96) years. Fifty seven (12.2%) infants and children were HIV-infected compared with 157 (39.0%) adolescents and adults. Among infants and children 34 (7.3%) of 464 with hospital outcome data died; 2 (5.9%) of those who died had invasive infections. Among adolescents and adults, 41 (10.3%) of 398 with hospital outcome data died; 11 (26.8%) of those who died had invasive infections. In hospital deaths could not be attributed to etiologies requiring serologic diagnosis due to the requirement for testing a convalescent serum sample. 10.1371/journal.pntd.0002324.g001 Figure 1 Study flow diagram. KCMC: Kilimanjaro Christian Medical Centre; MRH: Mawenzi Regional Hospital; MAT: microagglutination test; IFA: immunoflouresence assay; NAAT: nucleic acid amplification test. Proportions of febrile admissions attributed to specific etiologies Table 1 shows the number of patients with acute and convalescent samples available for testing for each etiologic agent or group of etiologic agents. Not all tests could be applied to all participants because of limited volumes of sample for some participants, and by the lack of availability of convalescent serum for participants who died before the follow up visit or who did not return. The number of confirmed cases in each group is also shown. The proportion of febrile admissions attributed to each etiology is calculated. A complete sample set was available for 243–467 (52.0–100.0%) infants and children and for 207–403 (51.4–100.0%) adolescents and adults. 10.1371/journal.pntd.0002324.t001 Table 1 Calculation of the proportion of hospitalized infants and children, and adolescents and adults, with specific etiologies of febrile illness, northern Tanzania, 2007–8. Etiology Infants and children Adults and adolescents All n confirmed cases n tested (%) n confirmed cases n tested (%) n confirmed cases n tested (%) Bloodstream infections Bacterial 16 467 (3.4) 69 403 (17.1) 85 870 (9.8) Mycobacterial 0 467 (0.0) 14 403 (3.5) 14 870 (1.6) Fungal 4 467 (0.9) 21 403 (5.2) 25 870 (2.9) Malaria 6 467 (1.3) 8 403 (2.0) 14 870 (1.6) Subtotal 26 467 (5.6) 112 403 (27.8) 138 870 (15.9) Bacterial zoonoses Brucellosis 5 246 (2.0) 11 207 (5.3) 16 453 (3.5) Leptospirosis 19 246 (7.7) 21 207 (10.1) 40 453 (8.8) Q fever 7 268 (2.6) 17 215 (7.9) 24 482 (5.0) Spotted fever group rickettsioses 18 243 (7.4) 18 207 (8.7) 36 450 (8.0) Typhus group rickettsioses 0 243 (0.0) 2 207 (1.0) 2 450 (0.4) Subtotal 49 243 (20.2) 69 207 (33.3) 118 450 (26.2) Arboviruses Chikungunya 34 332 (10.2) 21 368 (5.7) 55 700 (7.9) Flaviviruses 0 332 (0.0) 0 368 (0.0) 0 700 (0.0) Subtotal 34 332 (10.2) 21 368 (5.7) 55 700 (7.9) No diagnosis (64.0) (33.2) (50.1) Due to changing denominators for individual diagnostic tests, the proportion with no diagnosis is calculated as the proportion without a positive result from any test. Bloodstream infections are those diagnosed predominantly by blood culture, including organisms such as Salmonella enterica, Streptococcus pneumoniae, Cryptococcus neoformans, and Mycobacterium tuberculosis. Bacterial zoonoses, including brucellosis, leptospirosis, Q fever, and rickettsioses were diagnosed predominantly by serology, based on a 4-fold or greater rise in antibody titer between an acute and convalescent sample. Etiology of fever among infants and children Of 467 infants and children enrolled, malaria was the clinical diagnosis for 282 (60.4%), but was the actual cause of fever in 6 (1.3%). Bacterial and fungal bloodstream infections described in detail elsewhere [8] accounted for 16 (3.4%) and 4 (0.9%) febrile admissions, respectively, and were underrepresented on admission differential diagnoses. Bacterial zoonoses were identified among 49 (20.2%) of febrile admissions; 5 (2.0%) had brucellosis, 19 (7.7%) leptospirosis, 7 (2.6%) had Q fever, 18 (7.4%) had spotted fever group rickettsioses, and none had typhus group rickettsioses. In addition, 34 (10.2%) of participants had a confirmed acute arbovirus infection, all due to chikungunya (Table 1). No patient had a bacterial zoonoses or an arbovirus infection included in the admission differential diagnosis. Etiology of fever among adolescents and adults Of 403 adolescents and adults enrolled, malaria was the clinical diagnosis for 254 (63.0%), but was the actual cause of fever in 8 (2.0%). Bacterial, mycobacterial, and fungal bloodstream infections described in detail elsewhere [7] accounted for 69 (17.1%), 14 (3.5%), and 21 (5.2%) febrile admissions, respectively, and were underrepresented on admission differential diagnoses. Bacterial zoonoses were identified among 69 (33.3%) of febrile admissions; 11 (5.3%) had brucellosis, 21 (10.1%) leptospirosis, 17 (7.9%) had Q fever, 18 (8.7%) had spotted fever group rickettsioses, and 2 (1.0%) had typhus group rickettsioses. In addition, 21 (5.7%) of participants had a confirmed acute arbovirus infection, all due to chikungunya (Table 1). No patient had a bacterial zoonosis or an arbovirus infection included in the admission differential diagnosis. Etiology of fever overall Among all 870 participants, malaria was the clinical diagnosis for 528 (60.7%), but was the actual cause of fever in 14 (1.6%). By contrast, bacterial, mycobacterial, and fungal bloodstream infections accounted for 85 (9.8%), 14 (1.6%), and 25 (2.9%) febrile admissions, respectively, and were underrepresented on admission differential diagnoses. Bacterial zoonoses were identified among 118 (26.2%) of febrile admissions; 16 (13.6%) had brucellosis, 40 (33.9%) leptospirosis, 24 (20.3%) had Q fever, 36 (30.5%) had spotted fever group rickettsioses, and 2 (1.8%) had typhus group rickettsioses. In addition, 55 (7.9%) of participants had a confirmed acute arbovirus infection, all due to chikungunya (Table 1). No patient had a bacterial zoonoses or an arbovirus infection included in the admission differential diagnosis. The proportional etiology of febrile illness among study participants after extrapolating to the untested group is summarized in Figure 2. 10.1371/journal.pntd.0002324.g002 Figure 2 Laboratory confirmed causes of febrile illness among infants and children (panel A) and adolescents and adults (panel B) hospitalized in northern Tanzania, 2007–8*. *In instances that diagnostic test results were not available for all participants, the proportion positive from Table 1 was applied to the whole study population. Pie graphs do not account for concurrent infections. A complete listing of specific bacterial, mycobacterial, and fungal bloodstream infections is available elsewhere [7], [8]. Discussion We demonstrate among hospitalized febrile patients in northern Tanzania that malaria is uncommon and over-diagnosed, while invasive bacterial, mycobacterial, and fungal infections are underappreciated. At the same time, the bacterial zoonoses leptospirosis, Q fever, and spotted fever rickettsioses, and to a lesser extent brucellosis, and the arbovirus infection chikungunya are common yet unrecognized causes of fever. Our findings point to important mismatches between clinical diagnosis and management with actual diagnoses that have major implications for patient care, disease control and prevention, and for judicious use of antimalarial medications. While the problem of malaria over-diagnosis has been appreciated for some time [14], [15], studies that comprehensively describe the causes of severe non-malaria fever requiring hospital admission beyond bloodstream infections have been lacking. The over-diagnosis of malaria results in inappropriate use of antimalarial medications and may be associated with higher case fatality rates among patients treated for malaria who do not have the infection [14], [15], [34]. While the underlying causes of the over-diagnosis of malaria are complex [35], the lack of epidemiologic information about the importance of alternative infections and guidance on their management is likely to play a role. Our findings confirm the potential benefits of making reliable malaria diagnostic tests available at healthcare facilities and using the results as the basis for prescription of antimalarial medications [36]. When adopted, such an approach to malaria treatment would support the judicious use of antimalarials and would define the population of patients with nonmalaria fever. We found that the bacterial zoonoses, leptospirosis, Q fever, and spotted fever group rickettsioses, and to a lesser extent brucellosis, are major causes of febrile illness among patients sufficiently unwell to require hospitalization. That a group of neglected bacterial zoonoses are of major clinical and public health importance in sub-Saharan Africa is a new and paradigm-changing finding. For clinical practice, with the exception of leptospirosis that may be effectively treated with commonly prescribed antibacterials, patients with brucellosis, Q fever, and the rickettsioses are likely to leave hospital without specific treatment. In northern Tanzania where many rely on livestock for their health and economic wellbeing, Leptospira, Brucella, and Coxiella spp. also indirectly affect human health through their impact on animal fertility, growth, and survival. The control and prevention of the neglected bacterial zoonoses is likely to involve interventions that require the collaboration of human health experts with the animal and environmental health disciplines, an approach that is underdeveloped in many parts of the world. Clinical guidelines for management of febrile patients in low resource areas focus on the identification and treatment of malaria and bacterial sepsis [11]–[13]. Our findings suggest that there is a need to identify and incorporate guidance on when to use a tetracycline for treatment of Q fever or rickettsial infection and when to consider treatment for brucellosis. We have previously demonstrated that features of the clinical history and physical examination do not perform well for identifying fever etiology [7], [8], [21], [26], [30]. Therefore, improvements to treatment algorithms for febrile patients are likely to require the development and incorporation of reliable diagnostic tests that provide timely diagnostic information to clinicians [37]. Unfortunately, many rapid diagnostic tests for infections related to fever management other than malaria and HIV suffer from poor performance characteristics [38], [39]. Lack of coordination among groups working on the various etiologies of febrile illness in low-resource areas has meant that sentinel studies that could provide much more comprehensive information on a wide range of responsible organisms instead have focused on only one or a small handful of etiologies. For example, a clinical trial evaluating the impact of pneumococcal conjugate vaccine on rates of Streptococcus pneumoniae bacteremia in a community has the potential to identify and report all bloodstream infections. Similarly, a study designed to estimate the incidence of typhoid fever to inform vaccine policy could collect acute serum along with the blood culture and, with subsequent collection of convalescent serum, would have the ability to estimate the incidence of leptospirosis and a range of other etiologic agents using conventional serologic methods [40]. However, resources for research have tended to be targeted to specific pathogens and researchers have struggled to leverage additional resources to address a broader range of organisms. Sentinel site studies seeking to understand the infectious causes of febrile illness in low-resource settings have utilized blood culture to highlight the importance of invasive bacterial and fungal infections [4], [41]. Expanding laboratory evaluations to include serologic and molecular approaches to diagnosing infections requiring specific antimicrobial management such as the bacterial zoonoses brucellosis, leptospirosis, Q fever, and the rickettsioses adds considerable value [40]. Detection of infections of public health importance such as those caused by the arboviruses dengue, Rift Valley fever, and yellow fever can inform national control programs. Since considerable etiologic overlap exists between the syndromes of fever, acute respiratory tract infection, and diarrhea [42], [43], addressing these simultaneously in integrated sentinel studies would inform enhancements in empiric treatment guidelines and improvements in the accuracy of syndrome-based disease burden estimates. Our study had a number of limitations. While we examined a wide range of etiologies of fever, a large proportion of patients were undiagnosed suggesting that we failed to identify potentially important infections. The undiagnosed group is being investigated further using pathogen discovery approaches. Some of the diagnostic tests used in our study are less than 100% sensitive and specific and we did not test for every known pathogen. As a consequence, we probably underestimated the prevalence of some infections while misclassifying others that were falsely positive. Because a number of our diagnostic tests relied on the demonstration of a four-fold rise in antibody titer between the acute and convalescent serum sample, not all enrolled patients returned for collection of convalescent serum to have diagnoses confirmed. It follows that calculation and comparison of case fatality rate was not possible since those who died before the convalescent visit could not be confirmed cases. Incomplete diagnostic information meant that we had to extrapolate prevalence from the tested population to the untested population, potentially introducing bias. Similarly, instances of apparent infection with multiple agents were not accounted for in presentation of pie graphs. Inclusion of a well control group would have allowed the calculation of attributable fractions for individual pathogens, something that should be considered for future febrile illness research, especially in areas where malaria is endemic. Since considerable geographic variation in fever etiology is known to occur, the generalizability of our findings is uncertain. What is needed to support an integrated approach to the syndrome of fever in resource-limited areas? First, fever should be recognized alongside pneumonia and diarrhea as a major clinical syndrome of public health importance. Achieving this is likely to require leadership from international institutions of public health and reappraisal of the way that the febrile illnesses are approached in burden of disease estimates. This could include estimating total morbidity and mortality from the syndrome of fever as a first step before attributing the associated illnesses and deaths to specific etiologies, much as is done for the other major syndromes [44], [45]. Second, efforts are needed to bring together the diverse groups and disciplines currently working on the febrile illnesses to quantify the morbidity and mortality attributable to each major etiologic agent. Such integration could be facilitated by support for research efforts that study the syndrome of fever comprehensively as well as its etiologies individually, an approach that has been modeled by studies addressing the syndromes of pediatric pneumonia and diarrhea in developing countries [46], [47]. Third, improved diagnostic services are urgently needed to establish disease burden estimates and patient management for the febrile illnesses in resource-limited areas [10]. Conventional diagnostic tests for some infections, such as leptospirosis, are complex. For example, the collection of both acute and convalescent serum samples may be required, and testing services may be available at only a few national or supra-national reference laboratories. Assays relying on convalescent samples cannot be used to estimate case fatality rates [21], [26]. Conversely, simple, rapid tests applied to acute samples may have poor performance characteristics [38]. Finally, clinical studies, including clinical trials, are needed to test and improve clinical management algorithms for febrile patients. The goal should be to target antimicrobial therapy to those who need it and to avoid inappropriate use among patients who will not benefit. In this way, patient outcomes can be improved, health resources can be conserved, and disease prevention and control efforts for febrile conditions can be rationally resourced. Supporting Information Text S1 STROBE checklist. (DOC) Click here for additional data file.
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Clinical Manifestations of Human Brucellosis: A Systematic Review and Meta-Analysis
Anna S Dean, Lisa Crump, Helena Greter … (2012)
Introduction Brucellosis is one of the most common zoonotic infections globally [1]. This bacterial disease causes not only a severely debilitating and disabling illness, but it also has major economic ramifications due to time lost by patients from normal daily activities [2] and losses in animal production [3]. In a review of 76 diseases and syndromes of animals, brucellosis lies within the top ten in terms of impact on impoverished people [4]. A brucellosis disability weighting of 0.2 has been previously proposed for Disability-Adjusted Life Years (DALY) calculation, based on the pain and impaired productivity known to result from infection [3]. However, a more informed estimate is needed for an accurate assessment of disease burden. In 1992, the World Bank commissioned the original Global Burden of Disease (GBD) study, providing a comprehensive assessment of 107 diseases and injuries and 10 risk factors in eight major regions [5]. This review did not include any neglected tropical zoonoses. Such diseases often do not attract the interest of health researchers or sufficient resources for adequate control, yet they continue to impact significantly on human health and wellbeing, livestock productivity, and local and national economies [6]. There is a need for more accurate data relating to the burden of neglected zoonoses to facilitate more effective implementation of disease control interventions. In 2009, the Foodborne Disease Burden Epidemiology Reference Group (FERG) of the World Health Organization (WHO) commissioned a series of systematic reviews on the burden of neglected zoonotic diseases, with the aim of incorporating the findings into the overall global burden of disease assessments. This report presents a systematic review of scientific literature published between 1990–June 2010 relating to morbidity from human brucellosis infection. The objectives of this review were to assess the frequency and severity of the clinical manifestations of brucellosis, the duration of disease, the associated disabilities and important risk factors, with a view to estimating an appropriate disability weight for calculation of the brucellosis DALY. A systematic review of scientific literature investigating the incidence and prevalence of brucellosis globally is the subject of a companion paper [7]. Methods Searching Thirty three databases were searched for relevant articles using the search terms of (brucellosis OR malta fever OR brucella melitensis OR brucella abortus) AND (symptom* OR sequelae* OR morbidity OR mortality OR transmission mode OR foodborne), with a publication limitation of 1990–30 June, 2010. The search term was adapted to the predominate language of the database. If a database did not allow the combining of Boolean operators, (18 of 33 databases), ‘brucellosis’ was used as the sole term. Reference Manager bibliographic software was used to manage citations. Duplicate entries were identified by considering the author, the year of publication, the title of the article, and the volume, issue and page numbers of the source. In questionable cases, the abstract texts were compared. Selection The articles were sorted by a team of four reviewers with a combined fluency in English, German, French, and Spanish. Articles in other languages were noted for future translation, pending resources. All reports were classified into one of two categories, based on their abstracts: Category 1: Relevant – articles related to human brucellosis related to brucellosis infection in populations (i.e. disease frequency) or cases of human brucellosis (i.e. disease morbidity); Category 2: Irrelevant - articles related to non-human brucellosis; articles addressing topics not related to the current review, such as genetics, laboratory diagnostic tests, experimental laboratory animal studies. The abstracts of studies belonging to Category 1 and meeting the following criteria for disease morbidity studies were retained: published between 1990 and 30 June 2010, at least 10 study subjects, clinical symptoms/syndromes described, and some information relating to diagnostic tests provided. Articles relating to disease frequency and meeting the following criteria were also retained: published between 1990 and 30 June 2010, at least 100 study subjects drawn from the general population, prevalence or incidence data included, and some information relating to diagnostic tests provided. The assessment and classification of frequency articles will be the subject of a companion paper and will not be considered further here. Articles for which the necessary data for classification could not be obtained were identified for possible future assessment, according to availability of resources. In general, non peer-reviewed or review articles, conference proceedings and book chapters were excluded. Validity Assessment After applying the aforementioned screening steps, the full text of each selected article was retrieved for detailed analysis. Each article was reviewed by two or three reviewers, and classification discrepancies were resolved by discussion. Using a pre-designed Access database, articles were coded according to the following parameters: 1) Study type Studies were classified as a prospective case series, a retrospective case series, a case-control study, or of another type. 2) Study population The populations studied were grouped according to age category – children only (<15 years), adults only (≥15 years), or including both children and adults. Additionally, they were coded according to whether the study population represented the general population of brucellosis cases in the age category, or only a specific sub-group. 3) Diagnostic methods Studies were classified according to their use of microbial culture to diagnose brucellosis patients. In order for studies to be included in the review, they had to not only mention culture in their methods but to also present laboratory results. 4) Overall study quality Studies were given an overall quality grade of 1, 2, or 3. Quality 1 studies provided data drawn from general brucellosis cases, of which 75% or more were diagnosed by culture, and had well described study design and methods. Quality 2 studies also presented data from general brucellosis cases, utilised culture as a method and presented relevant laboratory results. However, unlike for Quality 1 studies, the majority of cases did not have to be diagnosed by positive culture in order to be included as Quality 2. Quality 3 studies were either drawn from only a specific sub-group of brucellosis cases such that general conclusions could not be drawn, did not use culture as a diagnostic method or failed to present culture results, or had poorly described study design and methods such that the quality of the data could not be assured. Data Extraction Based on brucellosis literature [8] a comprehensive list of clinical manifestations associated with brucellosis cases was developed: General: documented fever, sweats, chills, fatigue, headache, malaise, weight loss, nausea/vomiting Abdominal: abdominal pain, splenomegaly, hepatomegaly, hepatitis Musculoskeletal: arthralgia, arthritis, myalgia, back pain, spondylitis, sacroiliitis Specific organ involvement: epididymo-orchitis, abortion, endocarditis, respiratory and neurological signs, cutaneous changes Numbers of subjects with each symptom/syndrome were recorded for each study, as well as the number of male and female patients. For the sex-related outcomes of epididymo-orchitis and abortion, the study population was considered to be only the male and pregnant female sub-groups of the study population respectively. Information relating to duration of disease prior to treatment and exposure to potential risk factors were also recorded wherever provided. Data Analysis To calculate the proportion of patients by sex, numbers of male and female patients were aggregated across all studies as well as within each age category. 95% confidence intervals were calculated using the normal approximation to the binomial. Where appropriate data were available from two or more studies, pooled proportions of patients with each clinical manifestation were estimated using generalized linear mixed models. Pooled estimates with 95% confidence intervals were calculated both within age categories and overall across all studies, using a Freeman-Tukey double arscine transformation. Homogeneity across studies was assessed using a Cochrane's Q test and total variability due to between-study variation was reflected in the I2 index. The meta-analysis was performed with R statistical software [9] using the meta package [10]. Additionally, in order to assess the impact of study design, the same analysis was conducted according to study type category. The pooled estimates for proportions of patients with each clinical manifestation were compared with the disability weights used in the GBD 2004 study [11]. A disability weight for brucellosis was then proposed. Median proportions of patients with exposure to particular risk factors were calculated. Data relating to duration of illness and diagnostic delay were recorded. In order to assess the duration of untreated illness, an additional, non-systematic search for data prior to the availability of appropriate antibiotics was undertaken by manually searching library records. Results Searching Table 1 lists the databases searched and the number of hits obtained for each. A total of 28,824 studies were identified, of which 59% were duplicates, leaving 11,000 original reports. 10.1371/journal.pntd.0001929.t001 Table 1 Databases searched and number of hits. Database Website Hits Global databases Medline http://www.ncbi.nlm.nih.gov/sites/pubmed 6176 ISI Web of Science http://isiwebofknowledge.com 3458 EMBASE http://www.embase.com 4980 Popline http://www.popline.org 55 CAB http://www.cabdirect.org 3424 ProMed http://www.promedmail.org 666 The Cochrane Library http://www.thecochranelibrary.com 100 BIOLINE http://www.bioline.org.br 37 WHOLIS http://www.bireme.br 76 Regional WHO databases African Index Medicus http://indexmedicus.afro.who.int 14 Index Medicus for the Eastern Mediterranean Region http://www.emro.who.int/whalecom0/Library/Databases/wxis.exe/Library/Databases/iah/ 526 Western Pacific Region Index Medicus http://www.wprim.org/ 96 Index Medicus for the South-East Asia Region http://imsear.hellis.org/ 247 Afro Library http://afrolib.afro.who.int/ 2 Other regional databases Health Information Locator http://www.bireme.br 7 Institute of Tropical Medicine, Antwerp, Belgium http://lib.itg.be:8000/webspirs/start.ws 122 King's Fund Information & Library Service http://www.kingsfund.org.uk/library/ 0 African Journals Online http://ajol.info/ 71 LILACS http://www.bireme.br 538 MedCarib http://www.bireme.br 9 REPIDISCA http://www.bireme.br 29 PAHO http://www.bireme.br 157 IBECS http://www.bireme.br 148 CUIDEN http://www.index-f.com/ 17 Indian Medlars Center IndMed http://indmed.nic.in/ 84 KoreaMed http://www.koreamed.org/SearchBasic.php 89 Japan Science and Technology Information Aggregator http://www.jstage.jst.go.jp/search/?typej=on&typep=on&typer=on&search=1 137 Health Research and Development Information Network http://www.herdin.ph/ 0 Panteleimon http://www.panteleimon.org/maine.php3 6 l'Ecole Nationale de la Santé Publique http://test.bdsp.ehesp.fr/Base/ 191 La Bibliotàgue de Santé Tropicale http://www.santetropicale.com/resume/catalogue.asp 0 System for Information on Grey Literature in Europe http://opensigle.inist.fr 474 Swiss Tropical and Public Health Institute, Human and Animal Health Unit, electronic departmental reference library 6906 Flow of Included Studies Figure 1 shows a flow diagram of the process for the selection of articles included in the review. In total, 289 frequency and morbidity studies were selected, for which full text was available for 153. However, 14 of these were in languages in which the team was not competent (Croatian (6), Turkish (4), Korean (2), Persian (1), Mandarin (1)), leaving 96 morbidity studies for quality assessment. Some articles contained both frequency and morbidity data and were thus counted in both categories. 10.1371/journal.pntd.0001929.g001 Figure 1 Flow of selected studies. *Some morbidity studies were also classified as frequency studies. Of the 96 morbidity studies for quality assessment, five were classified as Quality 1 and 52 as Quality 2. Thirty-nine were excluded from further analysis as Quality 3, one of which was due to duplication of data from another larger study. Two pairs of Quality 2 studies were based on the same data [12]–[15]. These studies were included because each provided some unique information; however, the duplicated data were only included once in the meta-analysis. Except for two articles in Spanish and one in French, all Quality 1 and 2 studies were in English. Study Characteristics The median number of study subjects was 143 (IQR: 85-283), ranging from 20-1028. Studies from high income countries such as Germany, France, and USA were generally situated at the lower end of the range (less than 60 subjects), although larger studies were reported from Spain, including one study of over 900 subjects. Of the 57 studies selected, 24 were from Turkey. The next most represented country was Saudi Arabia, with 8 studies, followed by Spain with 4 and Greece with 4. One or two studies each came from Cuba, France, Germany, Israel, India, Iran, Jordan, Kuwait, Tunisia, USA, Uzbekistan and Yemen. The geographic distribution of the selected studies is shown in Figure 2. 10.1371/journal.pntd.0001929.g002 Figure 2 Geographical distribution of selected studies. In terms of study type, 37 were classified as retrospective case series with data retrieved from medical records, and 19 as prospective case series. One study was a case-control. Seventeen studies provided detailed information about cases with specific syndromes, e.g. neurological brucellosis [16]–[19], epididymoorchitis [20]–[23], osteoarticular complications [13], [14], [24], [25], spondylitis [26], [27], pulmonary brucellosis [28], pancytopaenia [29], and pregnant women [30]. As these studies also provided some information about proportions of general brucellosis cases with specific symptoms/syndromes, they were included in the review. Twenty-three studies included both children and adult participants [12]–[15], [18], [20], [24], [30]–[44]. Twelve studies investigated only children [29], [45]–[55], with an upper age limit ranging from 13 years to 18 years. Of the 19 studies with an adult population of 15 years or older [16], [17], [21]–[23], [25]–[27], [56]–[67], five consisted of only male participants [21]–[23], [64], [65]. Three studies did not clearly state the age category [19], [28], [68] and were analysed as if containing data for both adults and children. Data Analysis In studies consisting of only children, 64% patients (95% CI: 60–68%) were male. The proportion of male patients in adult studies was significantly lower, at 56% (95% CI: 55–58%). In studies including both children and adult patients, 48% were male (95% CI: 46–51%). Overall, 55% patients (95% CI: 54–56%) across all studies were male. Table 2 shows the pooled proportions of patients estimated by the random-effects model, according to clinical manifestations by age category. Forest plots are provided as Supplementary Information. An analysis by study type did not show any significant changes or trends. 10.1371/journal.pntd.0001929.t002 Table 2 Meta-analysis of clinical manifestations of brucellosis by age category. Manifestation Age Category All studies Children Adults All Ages General n % (95% CI) n % (95% CI) n % (95% CI) n % (95% CI) Fever 7 82 (69; 91) 10 73 (59; 85) 9 79 (49; 97) 26 78 (66; 87) Sweats 8 23 (11; 37) 14 55 (35; 74) 12 73 (60; 85) 34 54 (42; 66) Chills 4 18 (9; 29) 5 47 (34; 60) 7 60 (34; 83) 16 45 (30; 61) Fatigue 2 19 (13; 23) 2 33 (13; 100) 5 51 (27; 75) 9 39 (16; 65) Headache 6 9 (5; 15) 11 34 (19; 50) 11 52 (32; 72) 28 35 (24; 46) Malaise 2 24 (16; 34) 6 81 (71; 89) 8 74 (48; 93) 16 71 (57; 83) Nausea/vomiting 0 - 5 16 (5; 31) 6 26 (15; 38) 11 26 (15; 38) Weight loss 3 13(8;18) 4 31 (15; 50) 7 29 (15; 47) 14 26 (17; 36) Abdominal Abdominal pain 3 14 (1; 38) 4 9 (1; 22) 9 26 (13; 41) 16 19 (11; 29) Splenomegaly 9 31 (19; 43) 13 24 (18; 31) 14 25 (17; 34) 36 26 (21; 31) Hepatomegaly 10 27 (15; 41) 13 22 (16; 26) 14 22 (15; 29) 37 23 (19; 27) Hepatitis 1 1 (0; 5)* 2 8 (1; 38) 4 3 (1; 6) 7 4 (1; 9) Musculoskeletal Arthralgia 9 71 (56; 84) 12 65 (49; 79) 16 62 (52; 70) 37 65 (58; 72) Arthritis 7 41 (18; 65) 5 13 (3; 28) 14 25 (17; 34) 26 26 (19; 34) Myalgia 2 18 (11; 26) 5 56 (38; 75) 8 49 (36; 63) 15 47 (38; 57) Back pain 1 10 (3; 21)* 11 49 (31; 67) 11 45 (31; 60) 23 45 (34; 56) Sacroiliitis 4 6 (3; 10) 3 32 (20; 46) 9 14 (7; 22) 16 15 (9; 22) Spondylitis 1 18 (1; 28)* 6 12 (7, 19) 9 11 (6; 18) 16 12 (8; 17) Specific organs Epididymo-orchitis 1 10 (1; 32)* 10 10 (7; 15) 10 9 (6; 13) 21 10 (7; 13) Endocarditis 2 3 (1; 6) 6 2 (1; 3) 7 1 (1; 2) 15 2 (1; 2) Neurological 5 2 (1; 4) 11 5 (3; 7) 10 4 (2; 6) 26 4 (3; 5) Respiratory 3 5 (1; 14) 5 2 (1; 5) 11 9 (4; 14) 19 6 (3; 9) Cutaneous 6 5 (2; 10) 4 4 (1; 11) 7 8 (4; 14) 17 6 (4; 9) * One study only, with a binomial 95% confidence interval. Pooled proportions of patients with each manifestation are presented as percentages with 95% confidence intervals. The numbers of studies (n) contributing to each estimate are given. Documented fever was common, with an estimated 78% of patients affected across the three age categories. Estimates of the proportions of patients with self-reported symptoms of sweats, chills, fatigue, headache, and malaise, were significantly lower in children, ranging from 9–24% depending on symptom, compared to 33–81% for adults. Weight loss in children, at 13%, was also lower than the 31% reported in adults. Abdominal-related manifestations of pain, splenomegaly and hepatomegaly were fairly uniformly distributed across age categories, with overall estimated proportions of 19%, 26% and 23%, respectively. The number of studies reporting the presence of hepatitis was small, totalling only seven, with an estimated 4% patients affected overall. Arthralgia was common, affecting 65% patients overall, whereas arthritis affected only 26% patients. In adult patients, 56% and 49% suffered from myalgia and back pain, respectively. Only two studies reported myalgia and back pain in children. Overall, spondylitis and sacroiliitis were detected in 12–36% adults. In relation to reproductive problems, only one study reported abortion rates as a proportion of pregnant female participants, which was 46% [30]. Overall, 10% male patients had epididymo-orchitis. For more severe outcomes, endocarditis was reported in an overall 1% patients, and neurological manifestations in 4%. Neurological outcomes reported included motor deficits, cranial nerve deficits, sciatica, confusion and/or psychological disturbances, meningitis and seizures. 6% of patients suffered from respiratory manifestations, including cough, bronchopneumonia, pleural adhesion and pleural adhesion. Cutaneous changes were reported in 6% patients. As most studies were case series without a control group, an evaluation of the importance of risk factors was not possible. However, median proportions were calculated from 27 studies which provided some exposure history. Median proportions of brucellosis cases with exposure to a potential risk factor were 64% (IQR: 34–78%) for consumption of unpasteurised dairy products, 42% (IQR: 23–59%) for contact with livestock, and 6% (IQR: 3–19%) for occupational exposure, including veterinarians, butchers, and abattoir workers. From fifteen studies, the median proportion of cases with a history of brucellosis in a family member was 20% (IQR: 17–46%). Only six studies included in the systematic review provided data regarding duration of illness prior to diagnosis and treatment [32], [41], [52], [55], [57], [62]. The age of the patient and the nature of the illness were influential factors. One study reported a longer duration of illness in adults compared to children under 15 years, averaging 8 weeks versus 4 weeks, respectively [41]. In another study, the average duration of illness prior to diagnosis and treatment was 40 days, but cases with osteoarticular disease generally experienced longer periods of illness, extending to 6 months [62]. The GBD 2004 study estimated the disability weights for low back pain due to chronic intervertebral disc disease and osteoarthritis of the knee to be 0.121 (range 0.103–0.125) and 0.129 (range 0.118–0.147), respectively [11]. Given the high proportion of patients in our systematic review with joint, back, or muscular pain, a disability weight of at least 0.150 is proposed as a minimum estimate for localised, chronic brucellosis. Generalised, non-specific clinical manifestations were also common. Acute, non-localised brucellosis could be approximated by an episode of malaria, estimated to be 0.191 (range 0.172–0.211) by the GBD 2004 study [11]. Discussion The clinical picture of brucellosis presented in this systematic review is consistent with other literature [69]. Although a large amount of data are available regarding clinical manifestations of brucellosis, its geographical distribution is limited. No high quality studies were identified from Sub-Saharan Africa, Central and South America or South-East Asia. This could potentially reflect either a lower disease burden or a poorer brucellosis surveillance system. The proportion of male patients was greater than female patients amongst both children and adults. Although this difference was only small in adults, it was more pronounced in children. Possible explanations could be a greater risk of exposure amongst boys, with household responsibilities such as shepherding of livestock being preferentially delegated to boys, or gender-related differences in accessing to health care. Given the high proportion of brucellosis cases with fever, brucellosis should be considered as a differential diagnosis for fevers of unknown origin. In malaria-endemic countries, fever patients are often diagnosed and treated for malaria based solely on clinical findings [70]. Improved diagnostic capacity would reduce the diagnostic delay and facilitate prompt and appropriate treatment. These health service inadequacies are compounded by socioeconomic factors, with brucellosis affecting poor, marginalised communities who often do not have the means to seek treatment. Although studies included in this systematic review did not investigate health-seeking behaviour, a study from rural Tanzania revealed that 1 in 5 patients did not present to a health centre for assessment until more than one year after the onset of illness. Once at the health centre, nearly half (45%) were not diagnosed with brucellosis at their first visit [71]. In children, particularly, under-diagnosis of brucellosis is likely. The lower proportions of reported general symptoms such as sweats, chills, fatigue, and headache in study populations consisting only of children in this systematic review could reflect difficulty in obtaining accurate case histories from this group. One in 10 men experienced epididymo-orchitis, the most common genitourinary complication of brucellosis infection. This can have serious repercussions such as abscessation and infertility. Although other severe outcomes were less common, 4 neurological cases and 1 endocarditis case per 100 brucellosis patients were reported, which is substantial. Arthralgia, myalgia, and back pain were common manifestations. The relative lower proportions of patients with sacroiliitis and spondylitis compared to those reporting back pain might reflect limitations in diagnostic capacity. Chronic pain has been shown to severely affect the quality of sufferers' social and working lives [72]. As the majority of the brucellosis disease burden is in less developed countries, where livelihoods are often reliant on physical activities, the impact of musculoskeletal pain and impaired function in these settings may be even more serious. One study reported that patients with osteoarticular disease experienced a greater diagnostic delay than other cases [62], reflecting the chronic debilitation that can result from brucellosis infection. Indeed, in an endemic area of Russia prior to the availability of effective antibiotic therapies approximately 40% of 1,000 brucellosis cases followed over a 20 year period continued to suffer from clinical manifestations two years after disease onset. In this study, cited by Wund in 1966, approximately 90% of cases had self-cured after 6 years. [73]. Given the complexity of the clinical manifestations of brucellosis, summarising its impact into a single disability weight risks being too reductionist. However, a disability weight is required for an assessment of the global burden of disease which is, in turn, essential for engagement of policy-makers and funding bodies. Using the disability classes formerly used by the GBD 2004 study [74], a disability weight of 0.2 has been previously proposed based on Mongolian patient data [3]. This estimate fell between Class 1 (0.096), which referred to a limited ability to perform at least one activity in the one of the following areas: recreation, education, procreation or occupation; and Class 2 (0.22), referring to a limited ability to perform most activities in one of the aforementioned areas. Based on this systematic review and meta-analysis, better informed estimates of disability weights are proposed: at least 0.150 for chronic, localised brucellosis and 0.190 for acute brucellosis. However, as this is the first informed estimate of a brucellosis disability weight, there is a need for further debate amongst brucellosis experts and a consensus to be reached. Research Agenda Morbidity could vary geographically according to epidemiological setting. Well designed epidemiological studies from regions under-represented in this review would greatly contribute to an overall assessment of the global disease burden. A surveillance system amongst fever patients in malaria-endemic countries could be particularly informative. Additionally, risk factors for disease should be investigated through case-control studies. This would provide invaluable information to guide disease control interventions and policy. Limitations Studies for which a title or abstract was not published in a language using the Latin alphabet, such as those published only in Chinese characters or Arabic script, may not have been identified during the original database search. Of the foreign language studies that were identified, those published in languages in which the team was not competent were excluded from the analysis. It is possible that some of these studies contained data that could have contributed to this global assessment of brucellosis morbidity. Additionally, although studies in English were independently reviewed by three team members, this was not always possible for studies reviewed in other languages (German, French, Spanish). There were likely some differences between the case definitions and diagnostic capacity of different studies. For neurological and respiratory syndromes, many studies provided only an overall aggregated estimate without details of the different disease forms. A respiratory case could potentially vary from a patient with only a cough to severe bronchopneumonia, or a neurological case from altered behaviour and confusion to nerve deficits, meningitis or seizures. All patients were positive by culture in only 3 studies. Given the complexity of brucellosis serology interpretation, it is possible that some patients in other studies were misdiagnosed as cases of active brucellosis. The studies provide data from brucellosis patients presenting to health centres. It is possible that cases that do not present to health centres are less severe. The results of this review may, therefore, be biased towards more severe cases. As with the estimation of other disability weights, the proposed brucellosis disability weight estimate assumes that a given clinical manifestation will result in the same disability in all settings, which is unlikely [75]. Conclusion This systematic review adds to the understanding of the global burden of brucellosis, one of the most common and important zoonotic diseases worldwide. Brucellosis is shown to have a severe, debilitating, and often chronic impact on its sufferers. Significant delays in appropriate diagnosis and treatment are the result of both health system inadequacies and socioeconomic factors. Well designed epidemiological studies from those regions identified to be lacking in data would allow a better understanding of the clinical manifestations of disease and exposure risks and provide further evidence for policy-makers. Based on the findings of this systematic review and the disability weights from the 2004 Global Burden of Disease Study, a disability weight of 0.150 is proposed as the first informed estimate for chronic, localised brucellosis and 0.190 for acute brucellosis. As this is the first informed estimate of a disability weight for brucellosis, there is a need for further debate amongst brucellosis experts and a consensus to be reached. Supporting Information Checklist S1 PRISMA checklist. (DOC) Click here for additional data file. Figure S1 Forest plot for fever. (TIFF) Click here for additional data file. Figure S2 Forest plot for sweats. (TIFF) Click here for additional data file. Figure S3 Forest plot for chills. (TIFF) Click here for additional data file. Figure S4 Forest plot for fatigue. (TIFF) Click here for additional data file. Figure S5 Forest plot for headache. (TIFF) Click here for additional data file. Figure S6 Forest plot for malaise. (TIFF) Click here for additional data file. Figure S7 Forest plot for nausea/vomiting. (TIFF) Click here for additional data file. Figure S8 Forest plot for weight loss. (TIFF) Click here for additional data file. Figure S9 Forest plot for abdominal pain. (TIFF) Click here for additional data file. Figure S10 Forest plot for splenomegaly. (TIFF) Click here for additional data file. Figure S11 Forest plot for hepatomegaly. (TIFF) Click here for additional data file. Figure S12 Forest plot for hepatitis. (TIFF) Click here for additional data file. Figure S13 Forest plot for arthralgia. (TIFF) Click here for additional data file. Figure S14 Forest plot for arthritis. (TIFF) Click here for additional data file. Figure S15 Forest plot for myalgia. (TIFF) Click here for additional data file. Figure S16 Forest plot for back pain. (TIFF) Click here for additional data file. Figure S17 Forest plot for sacroiliitis. (TIFF) Click here for additional data file. Figure S18 Forest plot for spondylitis. (TIFF) Click here for additional data file. Figure S19 Forest plot for epididymo-orchitis. (TIFF) Click here for additional data file. Figure S20 Forest plot for endocarditis. (TIFF) Click here for additional data file. Figure S21 Forest plot for neurological sequelae. (TIFF) Click here for additional data file. Figure S22 Forest plot for respiratory sequelae. (TIFF) Click here for additional data file. Figure S23 Forest plot for cutaneous sequelae. (TIFF) Click here for additional data file.
Author and article information
Contributors
Jonna A. K. Mazet:
ORCID: https://orcid.org/0000-0002-8712-5951
Journal
Journal ID (nlm-ta): J Trop Med
Journal ID (iso-abbrev): J Trop Med
Journal ID (publisher-id): JTM
Title:
Journal of Tropical Medicine
Publisher:
Hindawi
ISSN
(Print):
1687-9686
ISSN
(Electronic):
1687-9694
Publication date Collection: 2020
Publication date
(Electronic):
16
September
2020
Volume: 2020
Electronic Location Identifier: 6586182
Affiliations
1One Health Institute and Karen C. Drayer Wildlife Health Center, School of Veterinary
Medicine, University of California, Davis, CA 95616, USA
Author notes
Author information
Jonna A. K. Mazet
https://orcid.org/0000-0002-8712-5951
Article
DOI: 10.1155/2020/6586182
PMC ID: 7519193
PubMed ID: 33014074
SO-VID: 3ad56d3f-ba89-4ccd-a4e3-b515dff897a3
Copyright © Copyright © 2020 Abel B. Ekiri et al.
License:
This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
History
Date
received
: 6
November
2019
Date
revision received
: 26
April
2020
Date
accepted
: 10
August
2020
Categories
Subject:
Review Article
ScienceOpen disciplines: Infectious disease & Microbiology
Data availability:
ScienceOpen disciplines: Infectious disease & Microbiology