Background
Despite substantial global progress in reducing child mortality, the annual deaths of more than 6 million children aged ≤15 years, 85% in under-5 years old, warrants intensified efforts, particularly in sub-Saharan Africa where the highest mortality ratios occur [
1]. More than half of child mortality is directly attributable to infectious diseases of bacterial, viral, parasitic, and fungal origin [
2,
3], with fever a key presenting symptom and often the main reason for seeking health care [
4].
In many tropical countries, malaria has long been a major cause of mortality in children, and typically presented with fever as a primary symptom [
5]. Improved access to diagnosis, particularly with the introduction of sensitive and specific rapid diagnostic tests (RDTs) [
6,
7], has allowed health workers to better manage malaria, as well as rule it out with a negative test. However, the diagnosis of the causes of non-malaria febrile illness has remained problematic in resource-constrained countries where laboratory facilities are limited or non-existent [
5]. In such settings, management guidelines rely heavily on clinical diagnosis even though fever aetiologies can be difficult to distinguish clinically [
3]. Empiric patient management can lead to diseases being undertreated, or treated with unnecessary drugs. Overuse or inappropriate use of antimicrobial agents is also recognised as a major driver of drug resistance, an ever-growing threat to global health [
8], which has led to several infections becoming harder to treat as drugs lose their effectiveness against pathogens [
9].
The challenge of managing febrile illnesses in the absence of adequate laboratory support demand systematic investigation to guide improvement of management approaches and strengthen disease control efforts at a local level. The World Health Organization (WHO) recognises the importance of studying fever aetiologies in various settings, age groups, and level of care [
3], but there have been relatively few such investigations in the countries most affected. Available studies from African countries have found that most children presenting with fever had acute respiratory or gastrointestinal infections which were mainly attributed to viral pathogens [
10,
11], and thus not amenable to antimicrobial treatment. On the other hand, urinary tract infections (UTIs) (2–41%) [
10‐
14] and bloodstream infections (1.3–6%) [
12‐
16] due to treatable pathogens were also documented.
Through a successful scale-up of malaria control interventions, Ethiopia has achieved remarkable reductions in disease burden, with declines in mortality and incidence of 96 and 89%, respectively, between 1990 and 2015 [
17]. The most recent national malaria indicator survey in children under 5 found a 2-week period prevalence of fever of 16%, but only 0.6% prevalence of malaria [
18], indicating the major role of non-malaria causes of fever. There have been recent investigations of bloodstream infections relating to
Salmonella disease [
19] and pneumonia [
20] in febrile children in Ethiopia. However, comprehensive data on the relative contribution of various pathogens to acute febrile illness in Ethiopian children are lacking. Therefore, we aimed to describe common aetiologies of fever in children attending a tertiary hospital in southern Ethiopia, a setting where malaria transmission has declined. We also evaluated the susceptibility of bacterial isolates to commonly prescribed antimicrobials.
Discussion
To our knowledge, our study is the first systematic investigation of common aetiologies of acute febrile illness among children in Ethiopia, and one of only a handful of such studies from Africa. The findings showed that proportions of children with malaria, bloodstream infections, and urinary tract infections were 3.2, 6.4 and 18.4%, respectively.
Malaria was uncommon (3.2%) among febrile children. This finding is consistent with the substantial malaria reductions recorded in Ethiopia [
18,
34], and associated with large-scale implementation of malaria control interventions, including the utilization of insecticide-treated mosquito nets, indoor residual spraying, and early diagnosis and treatment [
24]. A further contributor to the low prevalence of malaria may be effective management in lower level health care, leading to few cases appearing at the tertiary hospital. Our finding was similar to that reported from a study in Kenya (5.2%) [
35] although a higher (49.7%) result has been reported from a recent study in Burkina Faso [
13]. The more frequent detection of malaria in children aged 5 years and above was consistent with findings in Gabon [
36] and Tanzania [
37] which have both seen a decreased malaria burden and shift in risk towards children older than 5 years. Consistent to a report elsewhere [
35], clinical presentations other than a higher fever were not shown to be associated with malaria, reflecting that malaria can be difficult to diagnose clinically. A decline in malaria burden emphasizes the need for improving diagnostics to reliably rule out bacteraemia in febrile children and avoid inappropriate antimicrobial use.
Our study showed that 6.4% of febrile children had bloodstream infections. Similar results were found in investigations involving participants from referral hospitals in Tanzania (5.8%) [
15] and Burkina Faso (6%) [
13], and contrast with findings on bloodstream infection from lower level health facilities in Ethiopia (1.6%) [
38] and Tanzania (1.7–3.2%) [
12,
14]. Dominant blood culture isolates in the current study were
S. aureus and
Klebsiella species, while other studies that recruited participants from outpatient settings as well documented
Salmonella Typhi (0.7–0.9%) [
10,
12,
14], invasive non-typhoidal serovars of
Salmonella enterica (4.5%) [
13], and
S. pneumoniae (0.2–0.5%) [
12‐
14]. In Ethiopia, a low prevalence of salmonellosis (0.2%) in children was also reported recently during the Typhoid Fever Surveillance in Africa Program [
38]. While culture-based diagnosis is the gold standard for diagnosing bacteraemia, and allows for testing antimicrobial susceptibility, it is unlikely to be feasible on a routine basis in resource-constrained settings [
39]. The observed low proportion of blood cultures positive for a pathogen in febrile children attending outpatient department may point out blood culture testing services should be prioritised for patients with higher likelihood of bacteraemia including under-5 year old children with severe diseases.
The importance of UTI as cause of febrile illness among children is commonly overlooked in resource-constrained settings, due to non-specific symptoms in children and lack of availability of diagnostic tools. The proportion of urine culture positive cases in the current study (18.4%) was similar to that reported from a study in Tanzania (17.7%) [
14] although both lower (2–5.6%) [
11‐
13] and higher (41%) [
10] results have been reported in other African settings. Difference in composition of enrolled participants in terms of clinical characteristics and local risk factors may have played a role in the observed disparity of results. The predominance of
E. coli and
Klebsiella species as the detected uropathogens was consistent with findings from other research in Africa [
12,
14]. Untreated UTI can lead to serious renal disease [
40], so better approaches for UTI evaluation in febrile children are needed. As shown in other studies [
29,
41], we have found that UTI was more common in children aged under 3 years and those with longer duration of fever, emphasising the need for screening these groups with available tests such as urine dipstick and microscopy to ensure early management.
Among children with gastrointestinal symptoms, we detected
S. dysenteriae (1.8%) and
Salmonella Paratyphi A (1.8%) by stool culture.
S. flexneri (20%), and
Salmonella Typhi (1.9%) have been reported elsewhere [
10]. The proportion of rotavirus infection detected (25%) was virtually identical to the findings of a recent analysis focussing on prevalence of rotavirus infection in children under-five in Ethiopia [
42]. The occurrence of rotavirus infections in children aged under 3 years indicates the need to target this age group with rotavirus/adenovirus screening via RDT, to minimize antimicrobial over-prescription.
The burden of GAS in children has not been well investigated in Ethiopia, despite post-streptococcal immunological complications such as acute rheumatic fever, rheumatic heart disease, and glomerulonephritis being common [
43]. The observed proportion of GAS (15.8%) in the present study was similar to that found by culture in children aged 5–15 years with pharyngitis in southwest Ethiopia (11.3%) [
44]. Our finding underlines the importance of early diagnosis and prompt antimicrobial intervention in children with clinical indications to minimize long-term sequelae.
We found that the bacterial isolates were resistant to drugs such as ampicillin, trimethoprim-sulfamethoxazole, tetracycline, and amoxicillin and clavulanic acid, consistent with findings reported recently from Ethiopia [
45,
46] and elsewhere [
14]. Misuse and overuse of these drugs in relation to empiric treatment, prophylaxis, and self-medication may be contributing substantially to the development of resistance. In agreement with a recent report in the study area [
46], most isolates from urine were susceptible to nitrofurantoin and norfloxacin. The first line empiric treatment for UTI based on the national guideline is trimethoprim-sulfamethoxazole [
33] for which a high level of resistance by
E. coli and other uropathogens was observed in our study. Further, our findings indicate that fluoroquinolones which are currently reserved as second line options for treating UTI in Ethiopia present a viable alternative as first line therapies.
Our study had a number of limitations. We only recruited for this study during weekday working hours, which may have led to some form of selection bias. In addition, we were limited in the breadth of diagnostic tests and pathogens that we were able to test for. Specifically, investigations for zoonotic bacterial infections, arboviruses, and respiratory viruses were not included, but would have been useful to inform fever management guidelines. Another limitation is in regard to the extent of detection we could achieve with a single blood culture, and the absence of samples for some children. RDTs were used for the diagnosis of some infections despite being not the gold standard diagnostic, so cases might have been over- or under-detected. Antimicrobials taken prior to enrolment might have resulted in prevalence of bacterial infections being under-estimated. Finally, we did not include any testing of non-febrile controls, limiting our ability to interpret the role of detected pathogens in contributing to the fever episode. Despite these limitations, our study has the strength of being the first in Ethiopia to assess a wide range of pathogens including bacteria, parasites, viruses, and fungi, within the same cohort of children. The enrolment of study participants over a 10-month period minimized the risk of missing infections predominating in certain seasons. The inclusion of children who were managed as both outpatients and inpatients may help understand pathogens involving in various clinical conditions.
Acknowledgments
We would like to thank the study participants and their caregivers. We are grateful to study staff (Dr Bereketab T, Dr. Zelalem G, Dr. Abreham B, Sr Genet A, Sr Seble N, Sr Simegn T, Sr Tsion M, Mr. Enqusillassie M, Ms. Bereket T, Mrs. Netsanet N, Mrs. Elishaday A, Ms. Berhane M, Mr. Henok M, Ms. Seblewongel T, Mrs. Tihetina K, Mr. Mesfin W, Mr. Yidnekachew F) for their support with data collection. We extend our thanks to C. Escadafal for assistance with development of laboratory standard operating procedures. We would like to acknowledge Setema Ltd., Ethiopia and Biomerieux Company, France for donating part of blood culture bottles. Our acknowledgment goes to Hawassa University, College of Medicine and Health Sciences, Hawassa, Ethiopia, for allowing us to use the hospital and laboratory facilities and available resources required for this research work. Techalew Shimelis received a PhD scholarship (University International Postgraduate Award) administered by the University of New South Wales. John M Kaldor is supported by a Fellowship from the NHMRC.
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