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Validation of serum C-reactive protein for the diagnosis and monitoring of antibiotic therapy in neonatal sepsis.

Byline: Ejaz Ahmed, Abdur Rehman and Muhammad Asghar Ali

ABSTRACT

Objective: To evaluate the adequacy of serum C-reactive protein (CRP) in diagnosing neonatal sepsis and role of CRP in determining the duration of antibiotic treatment in neonatal sepsis.

Methods: In this validation study, we included 135 neonates with suspected diagnosis of sepsis within duration of nine months from September 2016 to May2017 in Children Hospital Multan. Blood samples were drawn from every neonate for culture sensitivity and measurement of serum C-reactive proteins. In all suspected neonates, empirical antibiotics e.g. Gentamycin or Ampicillin were started after taking blood samples. Serum CRP levels >5 mg/dl were marked as positive results. 2nd blood samples for measurement of serum CRP were taken after 72 hours of the first sample. There were two primary endpoints; one to determine the sensitivity and specificity of CRP against blood culture and second was to determine the negative predictive value of CRP in determining the duration of anti-biotic in neonates presenting with sepsis.

Results: Out of these 135 babies, 102 (75.5%) were confirmed to have sepsis using blood culture reports. CRP results were Positive in 85 (62.9%) neonates on first baseline measurement and were positive in 103 (76.29%) neonates after 72 hours of admission. The sensitivity of CRP in diagnosing sepsis was 98.03%, specificity was 91.0%, positive predictive value (PPV) was 97% and negative predictive value (NPV) was 93.7%. The mean duration of antibiotic treatment in CRP guided group was 5.03 days versus 7.02 days in standard treatment duration group (p-value 18 hours, history of fever in pre-natal or post-natal period. Neonates having birth weight 5 mg/dl were marked as positive results.15

Antibiotics if needed were changed after receiving culture sensitivity reports. The 2nd blood sample for measurement of serum CRP were taken after 72 hours of the first sample. Two consecutive positive CRP levels were confirmed as presence of neonatal sepsis. Moreover, two consecutive negative serums CRP were confirmed as absence of neonatal sepsis. Antibiotics were stopped in neonates having negative CRP results and we waited for culture reports of these neonates for further confirmation of septicemia. Blood cultures were followed for five days in CRP guided group and for seven days in standard treatment group and for positive result reports. In neonates, having two consecutive positive CRP levels. These neonates were divided into two groups using simple random sampling (Lottery method); in one group antibiotics were continued, blood samples were taken every day to measure serum levels of CRP, and the antibiotics were stopped as soon as the serum CRP became negative.

While in 2nd group, antibiotics were continued for seven days and on 7th days serum CRP were measured to determine positive or negative values. If CRP results were positive, then antibiotics were continued for more duration until the CRP results became negative.

After withdrawal of antibiotics, all these neonates were kept 48 hours (after stopping the anti-biotics therapy) in hospital to monitor any incidence of fever again within this period, if it happens then the plan was start the antibiotic course again.

There were two primary endpoints of this study, one was to determine the sensitivity and specificity of CRP against blood culture to determine the neonatal sepsis and secondary end-point was to determine the negative predictive value of CRP in determining the duration of antibiotics in neonates presenting with sepsis.

For measurement of sensitivity, and specificity we use 2x2 tables. Tables were made using SPSS v23. Mean duration of antibiotics in subgroups was compared using independent sample statistics. Frequencies were calculated for positive and negative serum CRP levels, blood culture reports and relapse rate.

RESULTS

The mean age of the neonates in this study was 6.7+-4.9 days. Out of 135 babies, 77 (57.1%) were male and 58 (42.9%) were female. Most of babies, 86 (63.8%) presented in first week of life, 40 (29.6%) in second week of life and remaining, 9 (6.6%) presented in within one month of life. Out of these 135 babies, 102 (75.5%) were confirmed to have sepsis using blood culture reports. CRP results were Positive in 85 (62.9%) neonates on first baseline measurement and were positive in 103 (76.29%) neonates after 72 hours of admission. The sensitivity of CRP in diagnosing sepsis was 98.03%, specificity was 91.0%, positive predictive value (PPV) was 97% and negative predictive value (NPV) was 93.7%. Most of the newborns were infected with gram negative organisms 75.5% versus only 24.5% with gram positive infections. Among grams negative organisms, E-coli, Klebsiella Pneumoniae, and Pseudomonas Species were the most common organisms.

Among gram positive organisms, Staphylococcus Aureus and Staphylococcus Epidermidis were most common causating agents of neonatal sepsis (Table-I).

Out of 103 neonates who had positive CRP levels on two consecutive readings, 55 neonates received CRP guided antibiotic therapy and the remaining 48 neonates received standard antibiotic duration treatment. In CRP guided group, there were 41 neonates in whom antibiotics were stopped in a$?5 days of therapy and 13 neonates the duration of antibiotics was 6-7 days and in one patient CRP was positive on 7th day and became negative on 9th day. In neonates receiving standard antibiotic treatment, CRP at 7th day was negative in all neonates except one, in whom antibiotics duration was eight days. The mean duration of antibiotic treatment in CRP guided group was 5.03 days versus 7.02 days in standard treatment duration group (p-value <0.001).

There was no relapse case of sepsis in any of the study neonates. The NPV of CRP in determining the duration of antibiotics was 100.0%.

Table-I: Etiological organisms of sepsis.

###Frequency

###Micro-organisms

###(%age)

###Escherichia Coli###25 (24.5%)

###Grams###Klebsiella Pneumoniae###23 (22.5%)

###Negative

###Pseudomonas Species###18 (17.6%)

###Organisms

###(N=77)###Acinetobacter###9 (8.8%)

###Enterobacter Cloacae###2 (1.9%)

###Staphylococcus Aureus###12 (11.8%)

###Gram

###Positive###Staphylococcus Epidermidis###7 (6.8%)

###Organisms###[alpha]-Hemolytic Streptococci###4 (3.9%)

###(N=25)

###Enterococcus Faecalis###2 (1.9%)

DISCUSSION

Neonatal sepsis is one of the commonest causes of morbidity and mortality in neonates. Mortality rate is very high if left untreated. Blood culture is the gold standard test for the diagnosis of neonatal sepsis. However, this test is time consuming and is not available in many hospitals of Pakistan so there is a need to look other easily and rapidly available methods for the diagnosis of neonatal sepsis. Among the various hematological factors studied for the early diagnosis of sepsis, CRP is one of them and is most widely studied.

As regards the primary end points of this study, we found 98.03% sensitivity and 91.0% specificity of CRP in confirming the diagnosis of sepsis in neonates after 72 hours of admission. These results are comparable to other conducted studies. Kumar et al.16 found 95.2% sensitivity and 85.3% specificity of CRP in neonates with proven sepsis. Nuntnarumit et al.17 found 100.0% sensitivity and 94.0% specificity of CRP in neonates with proven sepsis or those having local infections. Benitz et al.18 concluded that the sensitivity of CRP in diagnosing neonatal sepsis is increased with the passage of time. They found sensitivity of CRP only 40.0% in first 24 hours of sepsis and 90.0% after 24 hours of infection.

However some studies have found low sensitivity and specificity of CRP in diagnosing the neonatal sepsis. Hisamuddin et al.15 found only 76.92% sensitivity and 53.49% specificity of CRP after 72 hours of initial diagnosis in ruling out sepsis.

Saeed et al.19 also found similar results about CRP sensitivity and specificity. The reasons for these differences are not known.

Table-II: Sensitivity and Specificity of serum CRP against Blood Culture.

Sensitivity###98.03%

Specificity###91.0%

Positive Predictive Value###97.0%

Negative Predictive Value###93.7%

We also found 100% negative predictive value of CRP in determining the duration of antibiotics. In our study, there was no incidence of relapse in CRP-guided and standard treatment group and duration of antibiotics administration was also shorter 5.03 versus 7.02 days respectively. Siddaiah et al.20 also found similar results regarding reduction in the duration of antibiotics. These authors found NPV of CRP 100% in determining the duration of antibiotics. They concluded that antibiotics duration is reduced to five days in 54% CRP-guided neonates. These authors only included low birth weight (LBW) neonates in their study. Coggins et al.21 also conducted study in LBW neonates with sepsis and found significant in antibiotics duration using CRP guided therapy. Jaswal et al.14 and Ehl et al.22 found 100% and 99.0% NPVs of serum CRP levels in determining the duration of antibiotics.

Based on these results and other studies, we can conclude that serum CRP level is a reliable test in establishing the diagnosis of sepsis in neonates and it accurately monitors the duration of antibiotic therapy in these neonates and results in significant reduction in the treatment duration of neonatal sepsis.

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Publication:Pakistan Journal of Medical Sciences
Date:Dec 31, 2017
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