Presepsin as diagnostic marker for bacterial infection in young infants with fever of unknown origin

Fever is the most frequent presenting symptom of young infants (i.e. under 3
months of age) visiting the emergency department. The vast majority of these
infants will suffer from a viral infection. However in a small proportion of
patients, the fever will be caused by a bacterial infection, warranting
antibiotic treatment. Current diagnostic strategies to distinguish between
these two causes of fever are insufficiently accurate and/or too
time-consuming. Therefore young infants are frequently submitted to the
hospital and superfluously treated with antibiotics. This diagnostic and
treatment strategy is based on the current national Dutch guideline *Koorts in
de tweede lijn bij kinderen van 0-16 jaar*, leading to high amount of invasive
diagnostic and therapeutic procedures. A recent retrospective study of this
guideline showed a rate of intravenous antibiotics in 41% of the infants <1
month of age and 30% in infants between 1 and 3 months of age, whilst only 15%
of them suffered from a bacterial infection (Klarenbeek et al - accepted in The
Pediatrics Infectious Disease Journal).
Regular infection parameters such as C-reactive protein (CRP) and procalcitonin
(PCT) have to be synthesized by the body, leading to a peak time of 24-48 and
12-24 hours respectively. Furthermore, sensitivity and specificity to detect
bacterial infections in febrile infants vary between 69-79% for CRP and 69-83%
for PCT.
Culture of the specific pathogen remains the golden standard to confirm severe
bacterial infections such as sepsis, meningitis and urinary tract infection.
However, the culture result is not available at time of presentation and
treatment initiation. Furthermore, cultures are prone for false-negative
results.
In summary, the lack of timely and accurate diagnostic strategies can either
lead to significant morbidity and mortality when missing a bacterial infection,
or lead to severe overtreatment of infants with fever with hospital admissions
and antibiotic therapy.

Infants under 3 months of age have to rely mostly on their innate immune
system, as the adaptive immune system has not matured yet. Recently, a direct
product of the innate immune system, presepsin or soluble CD14 subtype
(sCD14-ST), has been introduced as biomarker for sepsis. CD14 is a cell-surface
protein on the monocytes and macrophages, which binds to bacterial
lippolysacharides. After this recognition and binding, CD14 is either
extracellularly or after internalization to the cell proteolysed into smaller
fragments. One of these smaller fragments is sCD14-ST or presepsin and is
thought to be detectable in the early stages of a bacterial infection. It is
possible to evaluate presepsin with a point-of-care assay, allowing a bedside
evaluation.
In neonates, presepsin has been extensively studied for the prediction of
early- and late-onset sepsis. Presepsin proves to be rapid-responding and
accurate in the diagnosis of sepsis in neonates (sensitivity and specificity
varying between 81-100%).
A recent systematic review on sepsis in children and adolescents showed a
higher diagnostic accuracy of presepsin as compared to CRP and PCT. However,
the value of this meta-analysis is limited as it included four small and very
heterogenic studies. To date, no studies investigating presepsin in young
infants with fever of unknown origin have been published. Therefore this study
aims to evaluate the role of presepsin in the diagnosis of bacterial infections
in young infants with fever of unknown origin.

This study aims to evaluate the role of presepsin in the diagnosis of bacterial
infections in young infants with fever of unknown origin.

Prospective observational

The burden and risks associated with participation are considered to be
negligible. An additional 0,5mL blood will be drawn during the puncture
required for standard care. No additional punctures will be performed for study
purposes.