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Use of the Serum Bacterial Antigen Test for the Detection of Group B Streptococcal Neonatal Sepsis
Newborn & Infant Nursing Reviews 15 (2015) 28–32
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Use of the Serum Bacterial Antigen Test for the Detection of Group B Streptococcal Neonatal Sepsis Mitchell Goldstein a,b,⁎, Linda Yang a,b, Gilbert Martin a,b, Mita Shah b, Sue Bloom b, Clark Ochikubo b, Perpetua Lawas-Alejo b, Bruce Sindel b, Gilbert Furman b a b
Loma Linda University Children’s Hospital, Loma Linda, CA Citrus Valley Medical Center, Queen of the Valley Campus, West Covina, CA
a r t i c l e
i n f o
Keywords: GBS antigen screening Neonate Blood culture Group B Streptococcus
a b s t r a c t The Revised Guidelines from the Centers for Disease Control for the Prevention of Perinatal Group B Streptococcal Disease were presented in the Morbidity and Mortality Weekly Report. An algorithm for evaluation of Group B Streptococcal sepsis (GBS) included CBC and differential, blood culture, possible chest x-ray, and lumbar puncture when signs of sepsis were present. The serum bacterial antigen was not mentioned in the recommendations although its clinical use for GBS evaluation has continued. We sought to determine if routine use of Group B Streptococcal Serum Antigen screening was indicated. According to hospital practice, serum bacterial antigens were drawn along with blood cultures in evaluation of sepsis for patients up to 2 months of age. Use of serum bacterial antigen testing using the BD Directigen Combo test was analyzed retrospectively over a five year period. Predictive value, sensitivity, and specificity of the analysis were studied relative to presence of a positive blood culture result. Over a five year period (2001–2005), 3336 serum bacterial antigens were performed. During that time, there were 23 positives (0.69%) for GBS. There were 3313 negatives (99%). There were 11 cases where the bacterial antigen predicted the Group B neonatal sepsis. There were 12 cases where the bacterial antigen test was positive for GBS; however, the blood cultures had no growth. In two cases, the antigen test was positive for GBS with a positive blood culture for a different bacterium: one blood culture grew Bacillus species; and the other, coagulase negative Staphylococcus. During 2005, the NICU had no positive blood cultures for GBS, and there were only two other cases hospital-wide where the bacterial antigen test predicted a positive blood culture for GBS. Although sensitivity, specificity, and negative predictive value were 99%–100%, the positive predictive value was 48% with a disease prevalence of 0.33%. Continued evaluation of Group B Streptococcal Antigen would not result in an identifiable risk reduction and is not justifiable for routine screening. © 2015 Elsevier Inc. All rights reserved.
Despite the great accomplishments since the institution of effective prophylaxis, GBS remains the number one cause of infant morbidity and mortality in the United States.1–6 Revised Guidelines for the Prevention of Perinatal Group B Streptococcal (GBS) Disease were published in the Morbidity and Mortality Weekly Report (MMWR) on November 19, 2010. 7 These 2010 guidelines were developed using an evidence-based approach in collaboration with a number of different professional associations including the American Academy of Family Physicians (AAFP), the American Academy of Pediatrics (AAP), the American College of Nurse-Midwives (ACNM), the American College of Obstetricians and Gynecologists (ACOG), and the American Society for Microbiology (ASM). An algorithm for evaluation of Group B Streptococcal sepsis (GBS) was presented. This evaluation included a CBC with differential, blood culture, possible chest x-ray, and lumbar puncture when signs
of sepsis were present. These changes were subsequently incorporated into the Red Book recommendations.7–9 In our practice, the testing for Group B Streptococcal bacterial antigen was not intended to be used as a substitute for bacterial culture in the diagnosis of group B streptococcal septicemia and/or meningitis.10 A positive or negative group B streptococcal result only reflected whether or not there is group B streptococcal antigen present at sufficient concentration in the sample measured and is not diagnostic for group B streptococcal disease. 11,12 Although the serum bacterial antigen was not specifically mentioned in the recommendations for the evaluation of newborn sepsis, its clinical use for GBS evaluation has continued in a number of venues. 8 Very little information is available regarding the use of serum bacterial antigens in determination of neonatal sepsis.
Objective ⁎ Corresponding author at: Pediatrics, Division of Neonatology, Loma Linda University Children's Hospital, Loma Linda, CA. E-mail address: [email protected] (M. Goldstein). http://dx.doi.org/10.1053/j.nainr.2015.01.009 1527-3369/© 2015 Elsevier Inc. All rights reserved.
We sought to determine if routine use of Group B Streptococcal Serum Antigen screening was indicated in the evaluation of neonatal sepsis.
M. Goldstein et al. / Newborn & Infant Nursing Reviews 15 (2015) 28–32
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Materials and Methods According to hospital practice, serum bacterial antigens were drawn along with blood cultures in evaluation of sepsis for patients up to 2 months of age. The Directigen™ Meningitis Combo Test is a presumptive latex agglutination test for the direct qualitative detection of antigens to H. influenzae type b, S. pneumoniae, N. meningitidis groups A, B, C, Y or W135 and Escherichia coli K1 in cerebrospinal fluid (CSF), serum or urine (see Fig.1). Rabbit polyclonal, purified antisera are used for H. influenzae type b, S. pneumoniae, Group B Streptococcus, N. meningitidis Groups C, W135, A and Y. Mouse monoclonal antibody is used for N. meningitidis Group B and E. coli K1. 3,13 The test can also be used for the direct qualitative detection of antigens to group B Streptococcus in CSF and serum. In addition to qualitative detection, the test kit provides confirmation and serogrouping capabilities from suspected colonies of H. influenzae type b, S. pneumoniae, group B Streptococcus, and N. meningitidis groups A/Y, B or C/W135.13 Visible agglutination occurs when a sample containing any of these bacterial antigens reacts with its respective antibody-coated latex beads. Specimens were tested as soon as possible; however, if the sample was not or could not be tested immediately, it was stored at 2–8 °C (for up to 48 h), or at −20 °C according to the specification provided by the manufacturer. Specimen preparation (Serum) was performed as follows. Serum specimens of at least 0.6 mL were diluted 1:1 with Directigen Specimen Buffer and mixed uniformly. Specimens were then heated for 5 min at 100 °C (e.g., water bath or heat block) and allowed to cool to room temperature before use. Using a wooden applicator stick, a protein “clot” that formed was dispersed, and then “vortexed” vigorously (approximately 5 s). The sample was then centrifuged at a minimum of 1400 ×g for 15 min. The supernatant fluid was then drawn off as serum must be separated from whole blood prior to testing or storage. 13 The use of serum bacterial antigen testing using the BD Directigen Meningitis Combo test was analyzed retrospectively over a five year period. Predictive value, sensitivity, and specificity of the analysis were studied relative to presence of a positive blood culture result. Study Oversight The study was approved for human subjects by the Institutional Review Board at Queen of the Valley Campus, Citrus Valley Review Board and conducted in accordance with the California Experimental Subjects Bill of Rights, applicable regional and local regulations, the Declaration of Helsinki, and the study protocol. 14 Use of the test kit was standard of care during the study period. BD provided neither the analysis test kit for use in the study, nor funding for technician time. Study-specific procedures and lab analysis were performed prior to its consideration as a research protocol. The study was approved as a retrospective chart review after the fact. The investigators and participating institution agreed to maintain the confidentiality of the data. All the authors had access to the data, assume responsibility for the integrity and completeness of the reported data, and vouch for the fidelity of this report to the study protocol. Statistics Data were analyzed using StatSoft, Inc. (2014), STATISTICA (data analysis software system), version 12.5. www.statsoft.com. Results Over a five year period (2001–2005), 3336 serum bacterial antigens were performed. During that time, there were 23 positives (0.69%) for GBS. There were 3313 negatives (99%). There were 11 cases where the bacterial antigen predicted the Group B neonatal sepsis. There were 12 cases where the bacterial antigen test was positive for GBS; however in all of these cases, the blood cultures had no growth. In two cases, the antigen test was positive for GBS with a positive blood culture for a different bacterium: one blood culture grew Bacillus species; and the other,
Fig. 1. Directigen Test Kit
coagulase negative Staphylococcus. During the last year of study, the Neonatal Intensive Care Unit had no positive blood cultures for GBS. In that year, there were only two other cases of GBS sepsis hospital-wide where the bacterial antigen test predicted a positive blood culture for GBS. Although sensitivity, specificity, and negative predictive value were 99%–100%, the positive predictive value was 48% with a disease prevalence of 0.33% as in Table 1. Discussion In 2010, an estimated 393,000 infection-related neonatal deaths occurred worldwide. 15 Group B Streptococcus is considered the leading cause of neonatal infectious morbidity although Escherichia coli K1 is also a major bacterial pathogen in the newborn. 2,16,17 Strains of group B streptococci and E. coli K1 frequently colonize in the vagina and/or rectum and may be associated with maternal septicemia and neonatal septicemia, pneumonia and meningitis. 18,19 Despite the presence of multiple bacterial antigen testing provided by the test kit, there were no bacterial antigen studies that were positive for E. coli or any other bacterial antigen covered by the test kit during the study period. These latex agglutination tests are not intended as a substitute for bacterial culture.12,20 Confirmatory diagnosis of bacterial sepsis or meningitis is only possible with appropriate culture procedures. Samples with low levels of antigen, as in early in sepsis, may yield false negative results.21–25 Samples with a very high antigen concentration may exhibit prozone effects or Hook effects producing inappropriately negative results.26 Although not extensively studied, prozone phenomena have only been observed in specimens seeded with extremely high antigen levels, and not in clinical specimens. If too many antibodies are present that can bind to the antigen, then the antigenic sites are completely coated by antibodies, and few or no antibodies that directed toward the pathogen can bind more than one antigenic site. No agglutination occurs because there are too few bridging reactions with the substrate. Without agglutination, the test is interpreted as negative — a false negative. The zone of relatively high antibody concentrations within which no reaction occurs is called the prozon.12,26 A positive or negative result is a presumptive result for group B streptococcal antigen only. Infection must still be confirmed by culture. 11,12,27 The only infant specimens recommended for the direct qualitative detection of group B streptococcal antigen are serum and cerebrospinal fluid. Testing infant urine for direct qualitative detection of group B streptococcal antigen is not recommended by the manufacturer. The lack of sufficient urine concentration may be important in this consideration. 24 Although this is in clinical use, currently there are
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Table 1 Results.
insufficient performance data supporting the use of this test on infant urine as a reliable predictor of group B streptococcal disease. 25,28–30 Changes in the management of perinatal colonization have reduced the incidence of vertically acquired neonatal GBS sepsis.5,31–33 In the latest care pathways, where appropriate pretreatment has been provided and there are minimal risk factors, no further work up is indicated.34,35 Most early onset sepsis secondary to GBS, despite appropriate prophylaxis, occurs within the first 24 h of life.36,37 Management strategies with appropriate follow-up may allow for early discharge but an adequate follow up program is a predicate for this process. Nonetheless, failure to follow a guideline adequately, results in an increase in the risk.38–43 Although there were no identified issues with the performance of the test or incompleteness in the sampling procedure in this study (i.e., all positive neonatal blood cultures for GBS had an accompanying positive antigen screen), prevalence in this population has been significantly reduced from what has been previously described in the literature. Further work has focused on varied novel modes of more rapidly identifying the presence or absence of a potential bacterial pathogen. The use of laboratory data including total WBC, differential and CRP has been enhanced by the acceptance of various newer studies that can give additional information beyond the “basic” sepsis evaluation. Procalcitonin as well as other indicators of acute phase reaction can help more readily identify those babies at risk. 3 Physical examination is of paramount importance although other non-invasive measures of perfusion may be very beneficial in identifying those babies at risk secondary to known maternal chorioamnionitis.44 As various strategies in the developed world have developed to provide more regimented evaluation, the incidence of GBS sepsis has dropped precipitously. 34,45,46 However, GBS sepsis remains the leading cause of neonatal morbidity secondary to sepsis.46–48 Prophylaxis with Penicillin, Ampicillin, or other antibiotics capable of reducing GBS colonization in mom is an important consideration in this process. Although the data strongly support the continuation of the practice, there are several reports of increased resistance and a shift to other pathogenic bacteria. 2,17,49,50 In certain countries, the lack of antibiotic stewardship has created a number of “superbugs” (e.g., Acinetobacter and Klebsiella). 31,51 At some point in the future, the continued use of prophylaxis may be subject to question, not from the perspective of increased resistance of GBS, but out of concern that large scale administration of Ampicillin or Penicillin will drive selection of perinatal infection towards more resistant bacteria.52–56 Guidelines have helped manage the risk. However, discrepancies between American Academy of Pediatrics (AAP), American College of Obstetrics and Gynecology (ACOG), and Centers for Disease Control
(CDC) guidance have resulted in provider confusion. 8,57–61 Various cost models have attempted to demonstrate a more reasonable way to manage the risk. 62–64 GBS positive mothers may not face risks of increased transmission if they have high levels of GBS antibody, deliver by Cesarean section with intact membranes, or have native or induced low levels of colonization.8,48,65–72 Although more research is necessary, other modes of prophylaxis including vaginal washes and oral administration of antibiotics may ultimately have important implications for reducing the risk especially in third world countries. 72–74 Conclusions The potential consequences of GBS colonization cannot be underestimated; however, ongoing intervention in management and prophylaxis in the perinatal period appears to have produced a significant reduction in the utility of antigen testing. Continued use of Group B Streptococcal Antigen for evaluating neonatal blood serum will not result in an identifiable risk reduction and is not justifiable for routine screening.24,29 Disclosures Presenters have documented that they have nothing to disclose. References 1. Vergnano S, Embleton N, Collinson A, Menson E, Russell AB, Heath P. Missed opportunities for preventing group B Streptococcus infection. Arch Dis Child Fetal Neonatal Ed. 2010;95(1):F72-3, http://dx.doi.org/10.1136/adc.2009.160333. 2. Stoll BJ, Hansen NI, Sanchez PJ, et al. Early onset neonatal sepsis: the burden of group B Streptococcal and E. coli disease continues. Pediatrics. 2011;127(5): 817-26, http://dx.doi.org/10.1542/peds.2010-2217. 3. Simonsen KA, Anderson-Berry AL, Delair SF, Davies HD. Early-onset neonatal sepsis. Clin Microbiol Rev. 2014;27:21-47, http://dx.doi.org/10.1128/CMR.00031-13. 4. Shane AL, Stoll BJ. Neonatal sepsis: progress towards improved outcomes. J Infect. 2014;68:S24-32, http://dx.doi.org/10.1016/j.jinf.2013.09.011. 5. Narava S, Rajaram G, Ramadevi A, Prakash GV, Mackenzie S. Prevention of perinatal group B streptococcal infections: a review with an Indian perspective. Indian J Med Microbiol. 2014;32:6-12, http://dx.doi.org/10.4103/0255-0857.124286. 6. Matsubara K, Hoshina K, Suzuki Y. Early-onset and late-onset group B streptococcal disease in Japan: a nationwide surveillance study, 2004–2010. Int J Infect Dis. 2013;17:e379-84, http://dx.doi.org/10.1016/j.ijid.2012.11.027. 7. Verani JR, McGee L, Schrag SJ, Division of Bacterial Diseases NCfI, Respiratory Diseases CfDC, Prevention. Prevention of perinatal group B streptococcal disease–revised guidelines from CDC, 2010. MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports / Centers for Disease Control. 2010;59(RR-10):1-36. 8. Committee on Infectious, D.. Policy statement—recommendations for the prevention of perinatal group B streptococcal (GBS) disease. Pediatrics. 2011;128: 611-6, http://dx.doi.org/10.1542/peds.2011-1466.
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71. Persaud RR, Azad MB, Chari RS, et al. Perinatal antibiotic exposure of neonates in Canada and associated risk factors: a population-based study. J Matern Fetal Neonatal Med. 2014;1–6, http://dx.doi.org/10.3109/14767058.2014.947578. 72. Christensen KK, Dykes AK, Christensen P. Reduced colonization of newborns with group B streptococci following washing of the birth canal with chlorhexidine. J Perinat Med. 1985;13:239-43. 73. Baecher L, Grobman W. Prenatal antibiotic treatment does not decrease group B Streptococcus colonization at delivery. Int J Gynaecol Obstet. 2008;101: 125-8, http://dx.doi.org/10.1016/j.ijgo.2007.10.012. 74. Cohain JS. GBS, pregnancy and garlic: be a part of the solution. Midwifery Today Int Midwife. 2004:24-5.
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Newborn & Infant Nursing Reviews journal homepage: www.nainr.com
Use of the Serum Bacterial Antigen Test for the Detection of Group B Streptococcal Neonatal Sepsis Mitchell Goldstein a,b,⁎, Linda Yang a,b, Gilbert Martin a,b, Mita Shah b, Sue Bloom b, Clark Ochikubo b, Perpetua Lawas-Alejo b, Bruce Sindel b, Gilbert Furman b a b
Loma Linda University Children’s Hospital, Loma Linda, CA Citrus Valley Medical Center, Queen of the Valley Campus, West Covina, CA
a r t i c l e
i n f o
Keywords: GBS antigen screening Neonate Blood culture Group B Streptococcus
a b s t r a c t The Revised Guidelines from the Centers for Disease Control for the Prevention of Perinatal Group B Streptococcal Disease were presented in the Morbidity and Mortality Weekly Report. An algorithm for evaluation of Group B Streptococcal sepsis (GBS) included CBC and differential, blood culture, possible chest x-ray, and lumbar puncture when signs of sepsis were present. The serum bacterial antigen was not mentioned in the recommendations although its clinical use for GBS evaluation has continued. We sought to determine if routine use of Group B Streptococcal Serum Antigen screening was indicated. According to hospital practice, serum bacterial antigens were drawn along with blood cultures in evaluation of sepsis for patients up to 2 months of age. Use of serum bacterial antigen testing using the BD Directigen Combo test was analyzed retrospectively over a five year period. Predictive value, sensitivity, and specificity of the analysis were studied relative to presence of a positive blood culture result. Over a five year period (2001–2005), 3336 serum bacterial antigens were performed. During that time, there were 23 positives (0.69%) for GBS. There were 3313 negatives (99%). There were 11 cases where the bacterial antigen predicted the Group B neonatal sepsis. There were 12 cases where the bacterial antigen test was positive for GBS; however, the blood cultures had no growth. In two cases, the antigen test was positive for GBS with a positive blood culture for a different bacterium: one blood culture grew Bacillus species; and the other, coagulase negative Staphylococcus. During 2005, the NICU had no positive blood cultures for GBS, and there were only two other cases hospital-wide where the bacterial antigen test predicted a positive blood culture for GBS. Although sensitivity, specificity, and negative predictive value were 99%–100%, the positive predictive value was 48% with a disease prevalence of 0.33%. Continued evaluation of Group B Streptococcal Antigen would not result in an identifiable risk reduction and is not justifiable for routine screening. © 2015 Elsevier Inc. All rights reserved.
Despite the great accomplishments since the institution of effective prophylaxis, GBS remains the number one cause of infant morbidity and mortality in the United States.1–6 Revised Guidelines for the Prevention of Perinatal Group B Streptococcal (GBS) Disease were published in the Morbidity and Mortality Weekly Report (MMWR) on November 19, 2010. 7 These 2010 guidelines were developed using an evidence-based approach in collaboration with a number of different professional associations including the American Academy of Family Physicians (AAFP), the American Academy of Pediatrics (AAP), the American College of Nurse-Midwives (ACNM), the American College of Obstetricians and Gynecologists (ACOG), and the American Society for Microbiology (ASM). An algorithm for evaluation of Group B Streptococcal sepsis (GBS) was presented. This evaluation included a CBC with differential, blood culture, possible chest x-ray, and lumbar puncture when signs
of sepsis were present. These changes were subsequently incorporated into the Red Book recommendations.7–9 In our practice, the testing for Group B Streptococcal bacterial antigen was not intended to be used as a substitute for bacterial culture in the diagnosis of group B streptococcal septicemia and/or meningitis.10 A positive or negative group B streptococcal result only reflected whether or not there is group B streptococcal antigen present at sufficient concentration in the sample measured and is not diagnostic for group B streptococcal disease. 11,12 Although the serum bacterial antigen was not specifically mentioned in the recommendations for the evaluation of newborn sepsis, its clinical use for GBS evaluation has continued in a number of venues. 8 Very little information is available regarding the use of serum bacterial antigens in determination of neonatal sepsis.
Objective ⁎ Corresponding author at: Pediatrics, Division of Neonatology, Loma Linda University Children's Hospital, Loma Linda, CA. E-mail address: [email protected] (M. Goldstein). http://dx.doi.org/10.1053/j.nainr.2015.01.009 1527-3369/© 2015 Elsevier Inc. All rights reserved.
We sought to determine if routine use of Group B Streptococcal Serum Antigen screening was indicated in the evaluation of neonatal sepsis.
M. Goldstein et al. / Newborn & Infant Nursing Reviews 15 (2015) 28–32
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Materials and Methods According to hospital practice, serum bacterial antigens were drawn along with blood cultures in evaluation of sepsis for patients up to 2 months of age. The Directigen™ Meningitis Combo Test is a presumptive latex agglutination test for the direct qualitative detection of antigens to H. influenzae type b, S. pneumoniae, N. meningitidis groups A, B, C, Y or W135 and Escherichia coli K1 in cerebrospinal fluid (CSF), serum or urine (see Fig.1). Rabbit polyclonal, purified antisera are used for H. influenzae type b, S. pneumoniae, Group B Streptococcus, N. meningitidis Groups C, W135, A and Y. Mouse monoclonal antibody is used for N. meningitidis Group B and E. coli K1. 3,13 The test can also be used for the direct qualitative detection of antigens to group B Streptococcus in CSF and serum. In addition to qualitative detection, the test kit provides confirmation and serogrouping capabilities from suspected colonies of H. influenzae type b, S. pneumoniae, group B Streptococcus, and N. meningitidis groups A/Y, B or C/W135.13 Visible agglutination occurs when a sample containing any of these bacterial antigens reacts with its respective antibody-coated latex beads. Specimens were tested as soon as possible; however, if the sample was not or could not be tested immediately, it was stored at 2–8 °C (for up to 48 h), or at −20 °C according to the specification provided by the manufacturer. Specimen preparation (Serum) was performed as follows. Serum specimens of at least 0.6 mL were diluted 1:1 with Directigen Specimen Buffer and mixed uniformly. Specimens were then heated for 5 min at 100 °C (e.g., water bath or heat block) and allowed to cool to room temperature before use. Using a wooden applicator stick, a protein “clot” that formed was dispersed, and then “vortexed” vigorously (approximately 5 s). The sample was then centrifuged at a minimum of 1400 ×g for 15 min. The supernatant fluid was then drawn off as serum must be separated from whole blood prior to testing or storage. 13 The use of serum bacterial antigen testing using the BD Directigen Meningitis Combo test was analyzed retrospectively over a five year period. Predictive value, sensitivity, and specificity of the analysis were studied relative to presence of a positive blood culture result. Study Oversight The study was approved for human subjects by the Institutional Review Board at Queen of the Valley Campus, Citrus Valley Review Board and conducted in accordance with the California Experimental Subjects Bill of Rights, applicable regional and local regulations, the Declaration of Helsinki, and the study protocol. 14 Use of the test kit was standard of care during the study period. BD provided neither the analysis test kit for use in the study, nor funding for technician time. Study-specific procedures and lab analysis were performed prior to its consideration as a research protocol. The study was approved as a retrospective chart review after the fact. The investigators and participating institution agreed to maintain the confidentiality of the data. All the authors had access to the data, assume responsibility for the integrity and completeness of the reported data, and vouch for the fidelity of this report to the study protocol. Statistics Data were analyzed using StatSoft, Inc. (2014), STATISTICA (data analysis software system), version 12.5. www.statsoft.com. Results Over a five year period (2001–2005), 3336 serum bacterial antigens were performed. During that time, there were 23 positives (0.69%) for GBS. There were 3313 negatives (99%). There were 11 cases where the bacterial antigen predicted the Group B neonatal sepsis. There were 12 cases where the bacterial antigen test was positive for GBS; however in all of these cases, the blood cultures had no growth. In two cases, the antigen test was positive for GBS with a positive blood culture for a different bacterium: one blood culture grew Bacillus species; and the other,
Fig. 1. Directigen Test Kit
coagulase negative Staphylococcus. During the last year of study, the Neonatal Intensive Care Unit had no positive blood cultures for GBS. In that year, there were only two other cases of GBS sepsis hospital-wide where the bacterial antigen test predicted a positive blood culture for GBS. Although sensitivity, specificity, and negative predictive value were 99%–100%, the positive predictive value was 48% with a disease prevalence of 0.33% as in Table 1. Discussion In 2010, an estimated 393,000 infection-related neonatal deaths occurred worldwide. 15 Group B Streptococcus is considered the leading cause of neonatal infectious morbidity although Escherichia coli K1 is also a major bacterial pathogen in the newborn. 2,16,17 Strains of group B streptococci and E. coli K1 frequently colonize in the vagina and/or rectum and may be associated with maternal septicemia and neonatal septicemia, pneumonia and meningitis. 18,19 Despite the presence of multiple bacterial antigen testing provided by the test kit, there were no bacterial antigen studies that were positive for E. coli or any other bacterial antigen covered by the test kit during the study period. These latex agglutination tests are not intended as a substitute for bacterial culture.12,20 Confirmatory diagnosis of bacterial sepsis or meningitis is only possible with appropriate culture procedures. Samples with low levels of antigen, as in early in sepsis, may yield false negative results.21–25 Samples with a very high antigen concentration may exhibit prozone effects or Hook effects producing inappropriately negative results.26 Although not extensively studied, prozone phenomena have only been observed in specimens seeded with extremely high antigen levels, and not in clinical specimens. If too many antibodies are present that can bind to the antigen, then the antigenic sites are completely coated by antibodies, and few or no antibodies that directed toward the pathogen can bind more than one antigenic site. No agglutination occurs because there are too few bridging reactions with the substrate. Without agglutination, the test is interpreted as negative — a false negative. The zone of relatively high antibody concentrations within which no reaction occurs is called the prozon.12,26 A positive or negative result is a presumptive result for group B streptococcal antigen only. Infection must still be confirmed by culture. 11,12,27 The only infant specimens recommended for the direct qualitative detection of group B streptococcal antigen are serum and cerebrospinal fluid. Testing infant urine for direct qualitative detection of group B streptococcal antigen is not recommended by the manufacturer. The lack of sufficient urine concentration may be important in this consideration. 24 Although this is in clinical use, currently there are
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Table 1 Results.
insufficient performance data supporting the use of this test on infant urine as a reliable predictor of group B streptococcal disease. 25,28–30 Changes in the management of perinatal colonization have reduced the incidence of vertically acquired neonatal GBS sepsis.5,31–33 In the latest care pathways, where appropriate pretreatment has been provided and there are minimal risk factors, no further work up is indicated.34,35 Most early onset sepsis secondary to GBS, despite appropriate prophylaxis, occurs within the first 24 h of life.36,37 Management strategies with appropriate follow-up may allow for early discharge but an adequate follow up program is a predicate for this process. Nonetheless, failure to follow a guideline adequately, results in an increase in the risk.38–43 Although there were no identified issues with the performance of the test or incompleteness in the sampling procedure in this study (i.e., all positive neonatal blood cultures for GBS had an accompanying positive antigen screen), prevalence in this population has been significantly reduced from what has been previously described in the literature. Further work has focused on varied novel modes of more rapidly identifying the presence or absence of a potential bacterial pathogen. The use of laboratory data including total WBC, differential and CRP has been enhanced by the acceptance of various newer studies that can give additional information beyond the “basic” sepsis evaluation. Procalcitonin as well as other indicators of acute phase reaction can help more readily identify those babies at risk. 3 Physical examination is of paramount importance although other non-invasive measures of perfusion may be very beneficial in identifying those babies at risk secondary to known maternal chorioamnionitis.44 As various strategies in the developed world have developed to provide more regimented evaluation, the incidence of GBS sepsis has dropped precipitously. 34,45,46 However, GBS sepsis remains the leading cause of neonatal morbidity secondary to sepsis.46–48 Prophylaxis with Penicillin, Ampicillin, or other antibiotics capable of reducing GBS colonization in mom is an important consideration in this process. Although the data strongly support the continuation of the practice, there are several reports of increased resistance and a shift to other pathogenic bacteria. 2,17,49,50 In certain countries, the lack of antibiotic stewardship has created a number of “superbugs” (e.g., Acinetobacter and Klebsiella). 31,51 At some point in the future, the continued use of prophylaxis may be subject to question, not from the perspective of increased resistance of GBS, but out of concern that large scale administration of Ampicillin or Penicillin will drive selection of perinatal infection towards more resistant bacteria.52–56 Guidelines have helped manage the risk. However, discrepancies between American Academy of Pediatrics (AAP), American College of Obstetrics and Gynecology (ACOG), and Centers for Disease Control
(CDC) guidance have resulted in provider confusion. 8,57–61 Various cost models have attempted to demonstrate a more reasonable way to manage the risk. 62–64 GBS positive mothers may not face risks of increased transmission if they have high levels of GBS antibody, deliver by Cesarean section with intact membranes, or have native or induced low levels of colonization.8,48,65–72 Although more research is necessary, other modes of prophylaxis including vaginal washes and oral administration of antibiotics may ultimately have important implications for reducing the risk especially in third world countries. 72–74 Conclusions The potential consequences of GBS colonization cannot be underestimated; however, ongoing intervention in management and prophylaxis in the perinatal period appears to have produced a significant reduction in the utility of antigen testing. Continued use of Group B Streptococcal Antigen for evaluating neonatal blood serum will not result in an identifiable risk reduction and is not justifiable for routine screening.24,29 Disclosures Presenters have documented that they have nothing to disclose. References 1. Vergnano S, Embleton N, Collinson A, Menson E, Russell AB, Heath P. Missed opportunities for preventing group B Streptococcus infection. Arch Dis Child Fetal Neonatal Ed. 2010;95(1):F72-3, http://dx.doi.org/10.1136/adc.2009.160333. 2. Stoll BJ, Hansen NI, Sanchez PJ, et al. Early onset neonatal sepsis: the burden of group B Streptococcal and E. coli disease continues. Pediatrics. 2011;127(5): 817-26, http://dx.doi.org/10.1542/peds.2010-2217. 3. Simonsen KA, Anderson-Berry AL, Delair SF, Davies HD. Early-onset neonatal sepsis. Clin Microbiol Rev. 2014;27:21-47, http://dx.doi.org/10.1128/CMR.00031-13. 4. Shane AL, Stoll BJ. Neonatal sepsis: progress towards improved outcomes. J Infect. 2014;68:S24-32, http://dx.doi.org/10.1016/j.jinf.2013.09.011. 5. Narava S, Rajaram G, Ramadevi A, Prakash GV, Mackenzie S. Prevention of perinatal group B streptococcal infections: a review with an Indian perspective. Indian J Med Microbiol. 2014;32:6-12, http://dx.doi.org/10.4103/0255-0857.124286. 6. Matsubara K, Hoshina K, Suzuki Y. Early-onset and late-onset group B streptococcal disease in Japan: a nationwide surveillance study, 2004–2010. Int J Infect Dis. 2013;17:e379-84, http://dx.doi.org/10.1016/j.ijid.2012.11.027. 7. Verani JR, McGee L, Schrag SJ, Division of Bacterial Diseases NCfI, Respiratory Diseases CfDC, Prevention. Prevention of perinatal group B streptococcal disease–revised guidelines from CDC, 2010. MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports / Centers for Disease Control. 2010;59(RR-10):1-36. 8. Committee on Infectious, D.. Policy statement—recommendations for the prevention of perinatal group B streptococcal (GBS) disease. Pediatrics. 2011;128: 611-6, http://dx.doi.org/10.1542/peds.2011-1466.
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