DISCUSSION
In this prospective, case-control study we compared the clinical
characteristics and laboratory parameters, including 10 serum
proinflammatory cytokines, in SCD children with fever of different
etiologies and asymptomatic steady-state controls. We found that IL-6
was a very good biomarker for the diagnosis of SBI in these patients,
with similar NPV to other biomarkers and better PPV. To our knowledge,
this is the first study describing IL-6 as a marker of SBI in febrile
SCD children.
Most of the children included in this study had been diagnosed with SCD
by newborn screening, had a complete vaccination status and were
receiving penicillin prophylaxis. In the group of SCD patients with
fever, we found a low proportion of confirmed SBI (5.1%), similarly to
other studies performed in high-income
countries1,3–5. However, in more than a half of the
cases (52.6%) a virus was detected by multiplex-PCR from respiratory
samples, as it has been observed in recent pediatric
studies16,17. In the remaining 42.8% of cases an
infectious etiology was not confirmed. The only statistically
significant differences among the baseline characteristics of study
subgroups were a higher percentage of patients with CVC and on
hypertransfusional regimen in the group of SBI, suggesting a poorer
clinical baseline condition of these patients and also highlighting the
presence of long-term CVC as a predisposing factor for
bacteremia6.
Despite the low proportion of confirmed SBI in this cohort, almost all
patients received at least one dose of antibiotic (96.2%), in agreement
to current guidelines18–20. This high use of
antibiotics emphasizes the importance of defining laboratory parameters
that could early discriminate the etiology of fever in these patients,
in order to optimize the antimicrobial prescription. Children with SBI
presented more frequently with hemodynamic instability and had higher
inflammatory parameters (neutrophils, CRP and procalcitonin) than the
rest of the patients, similarly to what was described in other
studies1,5–9. We also found that children with SBI
had significantly higher IL-6 levels when compared with those with VI,
NPI and controls, with the highest value observed in the only patient
with confirmed pneumococcal pneumonia. The optimal cut-off value of IL-6
for the diagnosis of SBI was 125 pg/ml, with a very high PPV
(significantly better than other biomarkers) and NPV applying to
different PR. In a setting with a PR of SBI of 5% in children with SCD
(average PR in high-income countries1,4,5), the PPV
would be 100% and NPV 98.7%. Therefore, we consider that IL-6 could be
a very useful marker for the diagnosis of SCD patients with confirmed
SBI.
IL-6 is an important factor in systemic and local immune response. It
can be secreted by almost all stromal cells and cells of the immune
system at an early stage of inflammation (with rapid elevation in 1-3
hours), and further promote the synthesis and release of CRP by the
liver 21,22. IL-6 has been previously described as a
marker of different types of SBI (alone or in combination with other
biomarkers)23,24, such as early-onset neonatal
sepsis25,26, sepsis and septic
shock21,23,27, bacteremia in patients with febrile
neutropenia28,29 or pneumococcal
pneumonia30–33. The early elevation of IL-6 that
occurs in the presence of SBI is an important advantage of this cytokine
over other biomarkers.
In SCD patients, it has previously been described that IL-6 and other
proinflammatory cytokines are elevated in asymptomatic steady-state
patients when compared to healthy individuals10–13.
However, in our study all controls (steady-state SCD patients) had
undetectable levels of IL-6. A possible explanation for this could be
that almost all children included in this study were receiving vitamin D
supplements. According to the study performed by Adegoke et al.,
children with SCD had a maintained vitamin D deficiency with a high
level of proinflammatory cytokines (IL-6, IL-8 and IL-18), which
normalizes after vitamin D supplementation34. Other
previous studies also found higher levels of IL-6 in patients with
VOC14,15, a finding that we did not observe in our
study.
The strengths of this study were its prospective design, the homogeneity
of the patients and that it was carried out in a reference center for
patients with SCD in Spain; therefore, this cohort may be quite
representative of the pediatric population with SCD in high-income
countries. However, it has also several limitations. Most importantly,
the sample size was relatively small, with few cases of confirmed
bacterial infection, and the categorization in several study groups
might have decreased the statistical power. Blood samples were collected
regardless the previous duration of fever and serial samples were not
collected, so it was not possible to evaluate the trend over time of the
different biomarkers during the febrile episode. Finally, only confirmed
SBI were included in the study to avoid bias in the analysis, but maybe
some not-confirmed bacterial infections (e. g. pneumonia) were included
in the NPI group.
Conclusion
In this prospective study, we found that IL-6 (with an optimal cut-off
of 125 pg/ml) was a good marker of SBI with a high PPV and NPV.
Therefore, given its rapid elevation, IL-6 may be useful (alone or in
combination with other biomarkers) to early discriminate SCD children at
risk of SBI, in order to guide their management. In settings with a low
PR of SBI, its use could help to reduce unnecessary antibiotic
treatments and hospital admissions. These findings should be confirmed
in larger cohorts and multicenter studies.