الفهرس 
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Abstract
Neonatal sepsis is a disease of infants who are younger than one month of age, clinically ill, and have positive blood cultures. Two patterns of disease, early onset (first week of life) and late onset (after the first week) bacterial infection occur during the first month of life.
Neonatal sepsis is a major health problem throughout the world. The diagnosis of sepsis is challenging due to the non-specific nature of clinical presentation (such as respiratory distress syndrome like symptoms: tachypnea, temperature instability, feeding difficulties), the variety of other neonatal disorders with the differential diagnostic work up and lack of sensitivity and specificity of available diagnostic procedures.
The current gold standard for confirming the diagnosis of neonatal sepsis is isolation of the causal microorganism by blood culture, however, blood culture results are not available until 24-48 hours after starting the culture, and they are often negative in cases of pneumonia and meningitis, or even in fatal generalized bacterial infection. Accordingly, a diagnosis of suspected sepsis has to be based on clinical symptoms together with biochemical parameters.
Considering the high mortality and serious morbidity associated with NS, a diagnostic marker with high diagnostic sensitivity and specificity would be a valuable tool for therapeutic decision-making, thus avoiding the unnecessary use of antibiotics, in those patients without infection but in whom sepsis is suspected on a clinical basis.
The aim of this work was to evaluate the validity of IL-6 in early diagnosis of neonatal sepsis or the use of combination of diagnostic markers, CRP and IL-6.
The study included 60 newborns that were admitted to NICU from January 2017 to June 2017 and were divided into two groups according to:
-30 patients with NS obtained from clinical signs and symptoms, blood culture results, and positive CRP (group I).
-30 apparently healthy newborns with negative CRP results as control (group II).
This study included any patient presented at NICU, any age group not more than one month age, and any sex.
-Exclusion was done to newborns with age ˃ 30 days or on antibiotics treatment before admission.
-consent to be enrolled in our study, was obtained from parents of baby after explaining the steps, the aim of study, and its benefits.
All neonates were subjected to history taking, clinical examination, and laboratory investigations including: CBC, blood culture and sensitivity testing, CRP, and IL-6.
The results of the study revealed the following data:
Age of patients in group I ranged from 1-15 days with a mean value of 4.57±3.64, and in group II ranged from 1-27 days with a mean value of 6.43±6.34.
group I included 20 male (66.7%) and 10 female (33.3). group II included 17 male (56.7%), and 13 female (43.3%).
Regarding CBC results, red blood cells (RBC) count, there was no statistically significant difference in NS group as compared to control group (p. value ˃ 0.05), However, for white blood cells (WBC) count, there was high statistical significant difference in NS group as compared to control group (p. value ˂ 0.05), with platelets count, there was no statistically significant difference in NS group as compared to control group (p. value ˃ 0.05). The abnormal TLC sensitivity, specificity, PPV, and NPV were 54.62%, 83.87%, 77.27, and 68.42% respectively. Also the sensitivity of abnormal platelets counts (thrombocytopenia) was 13.8% with specificity of 100%, PPV of 100%, and NPV of 54.5%. The diagnostic accuracy of TLC was 61.25% and that of platelets was 56.9%. So abnormal TLC and platelets counts as individual tests were not significant in the diagnosis of NS and this may be due to differences in blood sampling time, severity of infections, the age of neonate, and the reduced sensitivity of these tests in the first week of life.
Regarding blood culture, the study showed that the most causative organism of neonatal sepsis in NICU was klebsiella spp. followed by CONS. The study showed that isolated bacteria are highly susceptible to the usual antibiotics used in the NICU as vancomycin and amoxyclav for gram positive organisms and ciprofloxacin for gram negative.
Regarding CRP results with cut-off value 6mg/dl, the sensitivity was 93.1%, the specificity was 90.32%, the patient had 93.3% probability of not having NS, 90% probability of having NS, and diagnostic accuracy of 91.71%.
Regarding IL-6 results with cut-off value 50pg/ml, the sensitivity was 100%, the specificity was 90.32%, positive predictive value of 90.63%, negative predictive value, and the diagnostic accuracy was 95.16.
We conclude in this study that IL-6 level is higher in NS patients than controls, so we can use it as a good diagnostic marker for neonatal sepsis.
The combined accuracy use of CRP & IL-6 showed sensitivity of 100%, specificity of 90.32%, the patient had 100% probability of not having NS, and the patient had 90 % probability of having NS at cut-off value of CRP ≥ 6 mg/dl and IL-6 at >50 pg/ml. so clinically the measurement of IL-6 in combination with CRP in the first 48 hours of presumed septic episodes have been shown to yield better diagnostic accuracy (95.16%) than either marker alone.
Small sample size, lack of clear reference values for IL-6 and lack of homogeneity in the study group. Thus, there remains a need for a cohort study to confirm the diagnostic accuracy of IL-6 & CRP in an early stage.
Conclusion
Early diagnosis of neonatal sepsis is very difficult when it is based only on clinical signs. The clinical profile is neither uniform nor specific and could mislead the health care professionals. Keeping in mind the mortality caused by neonatal sepsis, empirical treatment should not be delayed but again this can result in unnecessary and prolonged exposure to antibiotics in this early age group. Cost effective and rapid diagnostic tool is the only way to tackle this issue.
This study validated the diagnostic capability of IL-6 and assessed the combination of CRP and IL-6 as a panel for the early diagnosis of NS. These findings suggest that the combination of these markers could enhance the sensitivity in the diagnosis of NS and may provide a new diagnostic strategy for NS patients.
The most common isolated microorganism was Klebsiella Pneumonie followed by Staph Aureus and E.Coli. Also cases show high sensitivity to vancomycin while high resistance to penicillin. The study of antibiotic sensitivity to avoid the emerging of broad spectrum antibiotic resistance with implementation of infection control measures can result in decreased microbial resistance. So the ergency of need for early diagnosis of NS is mandatory to avoid this serious problem.
Hematological parameters are poor screening tools for neonatal sepsis; however they may have a definite role as prognostic indicators.
CRP is a simple, cost effective, and rapid tool in the diagnosis of NS so it is an ideal diagnostic marker but its lower sensitivity than IL-6 makes it as late and specific marker.
CRP appears to be a good screening tool for sepsis; however the evolution of sepsis is poorly correlated with changes in serum CRP level. There is a need to combine CRP with other markers like IL-6 as early sensitive marker in newer septic screens to aid early diagnosis of neonatal sepsis as CRP is a late specific marker.
IL-6 is a highly sensitive, independent, and useful biomarker of NS. It correlates with the severity of sepsis with cut-off value 50 pg ̸ ml.
Hence, it can be concluded that IL-6 concentration increases to significant level in the patient having bacterial septicemia. IL-6 has maximum sensitivity (100%) as well as specificity (90.32%) in comparison to C - reactive protein with sensitivity (93.1%) and specificity (90.32%). Therefore, IL-6 level can be used as an early sensitive diagnostic marker for neonatal sepsis.
Study demonstrated that serum IL-6 levels were comparable to those of CRP in NS group of patients, so serum IL-6 may serve as a good diagnostic biomarker for the early diagnosis of NS especially in high risk patients, IL-6 alone or in combination with CRP significantly improve the diagnostic accuracy of NS with a sensitivity, specificity, and accuracy higher than that of CRP alone.
The studied biomarkers (CRP, IL-6) could be used to confirm or exclude neonatal sepsis and their combined use, together with other hematological markers (CBC and blood culture) in addition to clinical suspicion is important.
The lack of automation for test results in many institutions, and the costs involved in manual immunoassay have hindered the acceptance of cytokines in general as diagnostic markers for identifying neonatal sepsis.
Recommendations
from the finding of the present study, we recommended the followings:
_ The use of CRP and IL-6 combination for early diagnosis of NS especially in risky neonates is to start treatment soon to decrease complications and death.
_ Further studies examining large coharts of patients with NS are needed to confirm the clinical relevance of serum IL-6 in patients with NS.
̶ Further studies examining large coharts of patients with both EOS and LOS are needed to detect the diagnostic accuracy of IL-6 in both EOS and LOS.
_ Long term follow up studies should be performed to study the prognostic value of IL-6 and the survival rate in patients who showed increased levels of IL-6.
_ Further studies should be carried out targeting IL-6 levels in NS after starting treatment as follow up.
_ Cytokine levels in urine are virtually unexplored, and have the advantage that urine is constantly produced and can be collected without pain or risk of anaemia. So cytokines in urine are therefore suitable for daily screening, and studies evaluating the utility of this monitoring method should be of widespread interest.