Non-typhoidal Salmonella co-infect and complsicate <i>Plasmodium falciparum</i> malaria in children under-five: A prospective cohort study on clinical presentation and outcome in Kisantu district hospital, DR Congo

Introduction
Non-typhoidal Salmonella (NTS) bloodstream infections complicate Plasmodium falciparum (Pf) malaria infections in children under-five, but bacterial co-infections are often missed due to absence of microbiological diagnosis. We compared signs/symptoms and outcome of NTS bloodstream infection, severe Pf malaria and NTS-Pf malaria co-infections.

Methods
In an area with high, stable Pf malaria transmission (Kongo Central, DR Congo), children (>28 days- <5 years) admitted to hospital with severe febrile illness were enrolled during 18 months (NCT04473768/NCT04850677). Data (in-hospital and 1-month post-discharge) were prospectively collected.

Results
NTS bloodstream infections and severe Pf malaria were diagnosed in 12% (331/2682) and 52% (1389/2682) of enrolled children, respectively. NTS-Pf co-infections occurred in 10% (264/2682) of enrolled children, i.e., Pf malaria co-infected 80% (264/330) of NTS bloodstream infections and NTS co-infected 6% (78/1389) of severe Pf malaria. In children with recent Pf malaria (i.e., HRP2-antigen persistence with negative microscopy), NTS occurred in 32% (173/545), making recent malaria a major risk factor for NTS (OR=5.85, p < 0.001). Compared to severe Pf malaria, age under-two (OR=2.19), > 3 days of fever (OR=3.28) and acute malnutrition (OR=2.20-3.48) were risk factors for NTS (p < 0.001) and NTS cases more often had hypoglycemia, grunting, hepato-/splenomegaly, jaundice or altered consciousness, but overall clinical presentation was not discriminative. In-hospital NTS case fatality was high (24% versus 3% in severe Pf malaria), occurred within 2 days of admission in 64% of deaths, and was preceded by general danger/sepsis signs. NTS cases had slower fever resolution, more frequent in-hospital fever recurrence, longer hospital stays, and more post-discharge deaths (n = 4) than severe Pf malaria cases.

Conclusion
NTS and Pf malaria frequently co-infected children under-five. Severe Pf malaria and NTS bloodstream infections could not be distinguished clinically, but fatality rates were higher in NTS. Low thresholds for empirical NTS antibiotics and early danger sign recognition triggering sepsis care might improve outcome.