Non-typhoidal Salmonella infections unmask the challenges in pediatric febrile illness care in DR Congo

Non-typhoidal Salmonella (NTS) frequently cause, often fatal, bloodstream infections in children in sub-Saharan Africa. In this region, circulating NTS serotypes have genetically evolved towards more invasive and human-adapted phenotypes. Furthermore, sub-Saharan African children are susceptible to invasive NTS infections due to comorbidities impairing their immune system (Plasmodium falciparum (Pf) malaria, anemia, malnutrition, HIV). The general aim of this PhD project was to understand the (seasonal) epidemiology of NTS bloodstream infections in children in DR Congo and to identify challenges in and potential solutions for their diagnosis and (pre)hospital management. This PhD research demonstrated that NTS causes approximately three-quarters of bloodstream infections in children under-five admitted to Kisantu district hospital in DR Congo. Most NTS were serotype Typhimurium, Typhimurium variant Copenhagen or Enteritidis, and were extensively drug resistance due to concurrent ampicillin, cotrimoxazole, chloramphenicol, third generation cephalosporin and fluoroquinolone or azithromycin resistance. Bloodstream infections by NTS mainly occurred during the rainy season which can be explained by increased host-susceptibility (more Pf malaria infections during rainy season). There was however also a direct association between rainfall and NTS, independent of host susceptibility, which suggests environmental contribution to NTS transmission. A quarter of children with NTS bloodstream infections died and this was often preceded by general signs of sepsis. In-hospital death mostly occurred during the first 2 days of admission and was associated with hospital admission >3 days after fever onset. This late hospital presentation was observed in half of children with NTS bloodstream infection. Delaying factors predisposing to death were consulting traditional, private and/or multiple providers, rural residence, prehospital intravenous therapy, and prehospital overnight stays. Handheld diagnostic devices can help to recognize (pre-)sepsis signs and improve referral and triage. However, difficulties with device selection, procurement and shipment, adoption and maintenance were observed for a tympanic thermometer, multimodal oximeter with automated respiratory rate measurement, hemoglobinometer and glucometer. These included poor guidance for device selection, poor availability and affordability, poor performance and user-friendliness, and poor robustness and client-centeredness of post-sale (technical) support services. Most children with NTS bloodstream infection were co-infected with Pf malaria and presented without pathognomonic clinical signs and symptoms. Therefore, a clinical prediction model was developed for clinicians in settings where NTS are often resistant to standard-of-care empirical antibiotics. This model can be used to decide to modify a child's empirical antibiotic treatment based on the predicted NTS risk. Despite the rapidly emerging antimicrobial resistance in invasive NTS infections, antibiotic treatment recommendations for invasive NTS infections are extrapolated from enteric fever or based on expert consensus. In this PhD, the first (observational) data of third generation cephalosporins, fluoroquinolones and azithromycin efficacy to treat NTS bloodstream infections in children under-five in sub-Saharan Africa were generated. Therefore, epidemiological cut-offs to interpret in vitro azithromycin susceptibility in invasive NTS infections were first determined. Next, it was documented that survival was better in children with NTS bloodstream infection who received susceptibility-matched third generation cephalosporins, ciprofloxacin or azithromycin compared to children who received only susceptibility-mismatched antibiotics. Finally, it was described how poor antibiotic products (no age-appropriate formulations, poor quality & access), processes (delayed prescription/administration, missed doses), and practices (inaccurate doses, (bio)safety risks) must be addressed to improve pediatric antibiotic treatment. In conclusion, this PhD thesis reports the high burden of NTS bloodstream infections in children under-five in DR Congo. Challenges and potential solutions to facilitate their diagnostic and therapeutic management were identified and many of these challenges and solutions can be generalized to other causes of severe febrile illness in children under-five in sub-Saharan Africa.