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Dengue and chikungunya among outpatients with acute undifferentiated fever in Kinshasa, Democratic Republic of Congo: A cross-sectional study
research-article
Author(s):
Sam Proesmans
1
,
* ,
Freddy Katshongo
2 ,
John Milambu
3 ,
Blaise Fungula
3 ,
Hypolite Muhindo Mavoko
1
,
4 ,
Steve Ahuka-Mundeke
4
,
5 ,
Raquel Inocêncio da Luz
6 ,
Marjan Van Esbroeck
6 ,
Kevin K. Ariën
1
,
6 ,
Lieselotte Cnops
6 ,
Birgit De Smet
6 ,
Pascal Lutumba
4
,
5 ,
Jean-Pierre Van geertruyden
1 ,
Veerle Vanlerberghe
6
Publication date (Electronic):
5 September 2019
Journal:
PLoS Neglected Tropical Diseases
Publisher:
Public Library of Science
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Abstract
Background
Pathogens causing acute fever, with the exception of malaria, remain largely unidentified in sub-Saharan Africa, given the local unavailability of diagnostic tests and the broad differential diagnosis.
Methodology
We conducted a cross-sectional study including outpatient acute undifferentiated fever in both children and adults, between November 2015 and June 2016 in Kinshasa, Democratic Republic of Congo. Serological and molecular diagnostic tests for selected arboviral infections were performed on blood, including PCR, NS1-RDT, ELISA and IFA for acute, and ELISA and IFA for past infections.
Results
Investigation among 342 patients, aged 2 to 68 years (mean age of 21 years), with acute undifferentiated fever (having no clear focus of infection) revealed 19 (8.1%) acute dengue–caused by DENV-1 and/or DENV-2 –and 2 (0.9%) acute chikungunya infections. Furthermore, 30.2% and 26.4% of participants had been infected in the past with dengue and chikungunya, respectively. We found no evidence of acute Zika nor yellow fever virus infections. 45.3% of patients tested positive on malaria Rapid Diagnostic Test, 87.7% received antimalarial treatment and 64.3% received antibacterial treatment.
Discussion
Chikungunya outbreaks have been reported in the study area in the past, so the high seroprevalence is not surprising. However, scarce evidence exists on dengue transmission in Kinshasa and based on our data, circulation is more important than previously reported. Furthermore, our study shows that the prescription of antibiotics, both antibacterial and antimalarial drugs, is rampant. Studies like this one, elucidating the causes of acute fever, may lead to a more considerate and rigorous use of antibiotics. This will not only stem the ever-increasing problem of antimicrobial resistance, but will–ultimately and hopefully–improve the clinical care of outpatients in low-resource settings.
Author summary
Malaria remains one of the most important causes of fever in sub-Saharan Africa. However, its share is declining, since the diagnosis and treatment of malaria have improved significantly over the years. Hence leading to an increase in the number of patients presenting with non-malarial fever. Often, obvious clinical signs and symptoms like cough or diarrhea are absent, probing the question: “What causes the fever?” Previous studies have shown that the burden of arboviral infections–like dengue and chikungunya–in sub-Saharan Africa is underestimated, which is why we screened for four common arboviral infections in patients presenting with ‘undifferentiated fever’ at an outpatient clinic in suburban Kinshasa, Democratic Republic of Congo. Among the patients tested, we found that one in ten presented with an acute arboviral infection and that almost one in three patients had been infected in the past. These findings suggest that clinicians should think about arboviral infections more often, thereby refraining from the prescription of antibiotics, a practice increasingly problematic given the global rise of antimicrobial resistance.
Related collections
Most cited references44
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A new world malaria map: Plasmodium falciparum endemicity in 2010
Peter W. Gething, Anand P Patil, David Smith … (2012)
Background Transmission intensity affects almost all aspects of malaria epidemiology and the impact of malaria on human populations. Maps of transmission intensity are necessary to identify populations at different levels of risk and to evaluate objectively options for disease control. To remain relevant operationally, such maps must be updated frequently. Following the first global effort to map Plasmodium falciparum malaria endemicity in 2007, this paper describes the generation of a new world map for the year 2010. This analysis is extended to provide the first global estimates of two other metrics of transmission intensity for P. falciparum that underpin contemporary questions in malaria control: the entomological inoculation rate (PfEIR) and the basic reproductive number (PfR). Methods Annual parasite incidence data for 13,449 administrative units in 43 endemic countries were sourced to define the spatial limits of P. falciparum transmission in 2010 and 22,212 P. falciparum parasite rate (PfPR) surveys were used in a model-based geostatistical (MBG) prediction to create a continuous contemporary surface of malaria endemicity within these limits. A suite of transmission models were developed that link PfPR to PfEIR and PfR and these were fitted to field data. These models were combined with the PfPR map to create new global predictions of PfEIR and PfR. All output maps included measured uncertainty. Results An estimated 1.13 and 1.44 billion people worldwide were at risk of unstable and stable P. falciparum malaria, respectively. The majority of the endemic world was predicted with a median PfEIR of less than one and a median PfR c of less than two. Values of either metric exceeding 10 were almost exclusive to Africa. The uncertainty described in both PfEIR and PfR was substantial in regions of intense transmission. Conclusions The year 2010 has a particular significance as an evaluation milestone for malaria global health policy. The maps presented here contribute to a rational basis for control and elimination decisions and can serve as a baseline assessment as the global health community looks ahead to the next series of milestones targeted at 2015.
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Antimicrobial Resistance.
Hilary Marston, Dennis Dixon, Jane Knisely … (2016)
The development of antibiotics is considered among the most important advances of modern science. Antibiotics have saved millions of lives. However, antimicrobial resistance (AMR) threatens this progress and presents significant risks to human health.
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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.
Author and article information
Contributors
Sam Proesmans:
ORCID: http://orcid.org/0000-0002-1246-5118
Role: ConceptualizationRole: InvestigationRole: Writing – original draftRole: Writing
– review & editing
Freddy Katshongo: Role: InvestigationRole: Resources
John Milambu: Role: InvestigationRole: Resources
Blaise Fungula: Role: InvestigationRole: Resources
Hypolite Muhindo Mavoko: Role: Validation
Steve Ahuka-Mundeke: Role: Investigation
Raquel Inocêncio da Luz: Role: Investigation
Marjan Van Esbroeck:
ORCID: http://orcid.org/0000-0002-7294-6319
Role: InvestigationRole: Writing – review & editing
Kevin K. Ariën: Role: InvestigationRole: Writing – review & editing
Lieselotte Cnops: Role: Investigation
Birgit De Smet: Role: InvestigationRole: Writing – review & editing
Pascal Lutumba: Role: Writing – review & editing
Jean-Pierre Van geertruyden: Role: Funding acquisitionRole: Writing – review & editing
Veerle Vanlerberghe:
ORCID: http://orcid.org/0000-0002-6531-0793
Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole:
MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole:
Writing – original draftRole: Writing – review & editing
Stuart D. Blacksell: Role: Editor
Journal
Journal ID (nlm-ta): PLoS Negl Trop Dis
Journal ID (iso-abbrev): PLoS Negl Trop Dis
Journal ID (publisher-id): plos
Journal ID (pmc): plosntds
Title:
PLoS Neglected Tropical Diseases
Publisher:
Public Library of Science
(San Francisco, CA USA
)
ISSN
(Print):
1935-2727
ISSN
(Electronic):
1935-2735
Publication date
(Electronic):
5
September
2019
Publication date Collection:
September
2019
Volume: 13
Issue: 9
Electronic Location Identifier: e0007047
Affiliations
Author notes
* E-mail:
sam.proesmans@
123456gmail.com
Author information
Sam Proesmans
http://orcid.org/0000-0002-1246-5118
Marjan Van Esbroeck
http://orcid.org/0000-0002-7294-6319
Veerle Vanlerberghe
http://orcid.org/0000-0002-6531-0793
Article
Publisher ID: PNTD-D-18-01834DOI: 10.1371/journal.pntd.0007047
PMC ID: 6748445
PubMed ID: 31487279
SO-VID: e98ebd21-cb63-41e5-ba75-3d0ab909164e
Copyright © © 2019 Proesmans et al
License:
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
History
Date
received
: 28
November
2018
Date
accepted
: 6
August
2019
Page count
Figures: 2,
Tables: 3,
Pages: 16
Funding
Funded by: Framework agreement between the Institute of Tropical Medicine and the Belgian development
cooperation
Award Recipient
:
ORCID: http://orcid.org/0000-0002-6531-0793
Veerle Vanlerberghe
Funded by: Vlaamse Interuniversitaire Raad - Universitaire Ontwikkelingssamenwerking
Award ID: ZRDC2014MP083
Award Recipient
:
Jean-Pierre Van geertruyden
This study was co-funded by the framework agreement between the Institute of Tropical
Medicine and the Belgian development cooperation (
https://www.itg.be/E/cooperation) to VV and Vlaamse Interuniversitaire Raad - Universitaire Ontwikkelingssamenwerking
(
https://www.vliruos.be/en) (VLIR-UOS, Grant reference ZRDC2014MP083) to JPVG. The funders had no role in study
design, data collection and analysis, decision to publish, or preparation of the manuscript.
Categories
Subject:
Research Article
Subject:
Medicine and Health Sciences
Subject:
Tropical Diseases
Subject:
Neglected Tropical Diseases
Subject:
Chikungunya Infection
Subject:
Medicine and Health Sciences
Subject:
Infectious Diseases
Subject:
Viral Diseases
Subject:
Chikungunya Infection
Subject:
Medicine and Health Sciences
Subject:
Diagnostic Medicine
Subject:
Signs and Symptoms
Subject:
Fevers
Subject:
Medicine and Health Sciences
Subject:
Pathology and Laboratory Medicine
Subject:
Signs and Symptoms
Subject:
Fevers
Subject:
Medicine and Health Sciences
Subject:
Infectious Diseases
Subject:
Viral Diseases
Subject:
Arboviral Infections
Subject:
Research and Analysis Methods
Subject:
Immunologic Techniques
Subject:
Immunoassays
Subject:
Enzyme-Linked Immunoassays
Subject:
Medicine and Health Sciences
Subject:
Parasitic Diseases
Subject:
Malaria
Subject:
Medicine and Health Sciences
Subject:
Tropical Diseases
Subject:
Malaria
Subject:
Biology and life sciences
Subject:
Organisms
Subject:
Viruses
Subject:
RNA viruses
Subject:
Togaviruses
Subject:
Alphaviruses
Subject:
Chikungunya Virus
Subject:
Biology and Life Sciences
Subject:
Microbiology
Subject:
Medical Microbiology
Subject:
Microbial Pathogens
Subject:
Viral Pathogens
Subject:
Togaviruses
Subject:
Alphaviruses
Subject:
Chikungunya Virus
Subject:
Medicine and Health Sciences
Subject:
Pathology and Laboratory Medicine
Subject:
Pathogens
Subject:
Microbial Pathogens
Subject:
Viral Pathogens
Subject:
Togaviruses
Subject:
Alphaviruses
Subject:
Chikungunya Virus
Subject:
Biology and Life Sciences
Subject:
Organisms
Subject:
Viruses
Subject:
Viral Pathogens
Subject:
Togaviruses
Subject:
Alphaviruses
Subject:
Chikungunya Virus
Subject:
Biology and life sciences
Subject:
Organisms
Subject:
Viruses
Subject:
RNA viruses
Subject:
Flaviviruses
Subject:
Dengue Virus
Subject:
Biology and Life Sciences
Subject:
Microbiology
Subject:
Medical Microbiology
Subject:
Microbial Pathogens
Subject:
Viral Pathogens
Subject:
Flaviviruses
Subject:
Dengue Virus
Subject:
Medicine and Health Sciences
Subject:
Pathology and Laboratory Medicine
Subject:
Pathogens
Subject:
Microbial Pathogens
Subject:
Viral Pathogens
Subject:
Flaviviruses
Subject:
Dengue Virus
Subject:
Biology and Life Sciences
Subject:
Organisms
Subject:
Viruses
Subject:
Viral Pathogens
Subject:
Flaviviruses
Subject:
Dengue Virus
Subject:
Biology and Life Sciences
Subject:
Physiology
Subject:
Immune Physiology
Subject:
Antibodies
Subject:
Medicine and Health Sciences
Subject:
Physiology
Subject:
Immune Physiology
Subject:
Antibodies
Subject:
Biology and Life Sciences
Subject:
Immunology
Subject:
Immune System Proteins
Subject:
Antibodies
Subject:
Medicine and Health Sciences
Subject:
Immunology
Subject:
Immune System Proteins
Subject:
Antibodies
Subject:
Biology and Life Sciences
Subject:
Biochemistry
Subject:
Proteins
Subject:
Immune System Proteins
Subject:
Antibodies
Custom metadata
PLOS Publication Stage vor-update-to-uncorrected-proof
Publication Update 2019-09-17
Data Availability All relevant data are within the manuscript and its Supporting Information files.
ScienceOpen disciplines: Infectious disease & Microbiology
Data availability:
ScienceOpen disciplines: Infectious disease & Microbiology