Cardiac Biomarkers in Pediatrics

Bottom Line Up Front (BLUF):

1. Compared to healthy adults, the serum troponin and BNP levels in healthy neonates and infants less than 1 year have normal ranges with 99th percentiles nearly two orders of magnitude greater.
2. HIGH-SENSITIVITY TROPONIN-T (hs-cTnT)
   1. As a biomarker, troponin occupies a relatively unique position in medicine. Unlike most biomarker cut-offs, which are based upon a desired sensitivity/specificity for diagnosis of a condition, troponin cut-offs are an arbitrarily chosen percentile of the values observed in a healthy population. A troponin value above the 99th percentile in healthy persons is the DEFINITION of "myocardial injury" (regardless of the clinical situation of the individual patient). Therefore, the troponin cut-off does not have a sensitivity/specificity for "myocardial injury," it simply IS myocardial injury. This is a relatively unique role for a serum biomarker, outranking even the concept of "gold standard".
   2. As of January 2022, studies have only recently begun to quantify the distributions and normal ranges of troponin levels in healthy infants and children. At less than one year of age, the 99th percentile is markedly higher than in adults. At around one year the 99th percentiles are similar, and after one year the 99th percentiles are lower than in adults. Though sex-adjusting the 99th percentiles is not problematic, age-adjusting is: a hs-cTnT of 70 would be POSITIVE at 60 days old but NEGATIVE at 61 days old. In such a setting, decision making is less clear and the definition of "myocardial injury" starts seeming rather arbitrary (if not meaningless).
   3. Myocardial injury is NOT synonymous with ischemia. Numerous non-ischemic causes of myocardial injury exist, such as infiltrative diseases, trauma, inflammation, etc. In fact, non-ischemic etiologies are greatly predominant in all pediatric age groups.
3. N-PRO-TERMINAL BNP (N-Pro-BNP): Diagnostic cut-offs have been published for several disease conditions in some pediatric age groups, but few have been validated.
4. Indeed, considering the markedly higher normal ranges, and as argued by Assandro et al in 2013, these cardiac biomarkers may lack the ability to distinguish disease from non-disease in some (or all) pediatric age groups.
5. No one should order a cardiac biomarker in a pediatric patient with the intent to rule-in or rule-out disease without:
   • Evidence that the marker can distinguish disease from non-disease (as represented by the AUROC) in the age group in question.
   • Knowledge of the diagnostic cut-off for the disease in question, as well as the sensitivity and specificity associated with that cut-off.
6. False-positive interpretation of cardiac biomarkers can lead to unnecessary invasive testing, which is itself a harm, but which also carries a non-negligible risk of additional harm (i.e. procedural complications).
7. If a consultant recommends ordering a troponin or BNP in one of these age groups, the consulting provider should inquire about the diagnostic cut-off, the sensitivity, and the specificity; if the consultant cannot provide this information, further research and/or additional consultants should be strongly considered prior to ordering these tests. There is very little clinical utility to a test result which no one knows how to interpret, and there is a risk of harm from a test result which is likely to be misinterpreted.

hs-cTnT

Biochemistry

Released due to multiple types of myocardial injury (ischemia, necrosis, apoptosis, cytotoxicity, inflammation). Certain levels, in the proper context, constitute the definition of myocardial infarction. However, troponin can undergo non-ischemic release during heart failure, inflammation, and other conditions (such as infiltrative diseases).[REF]

N-Pro-BNP

Biochemistry

Released solely due to myocardial stretch/strain of the left ventricle, which is usually synonymous with heart failure.[REF]

METHODS

Literature searches were performed for the specific test types available at YKDRH:

1. high-sensitivity Troponin T
2. N-Terminal pro-BNP

Broader searches, such as for troponin in general are prone to return results for conventional low sensitivity troponin or for troponin-I; data from these are not applicable to interpretation of high-sensitivity troponin-T. Similarly, data regarding B-type natriuretic peptide (BNP) cannot be applied to the test which we have, which is N-Terminal Pro-BNP.

Troponin-T PubMed Search

(pediatric*[Title] OR neonat*[Title] OR infant*[Title] OR child*[Title] or adolescant*[Title]) AND ("high-sensitivity"[Title] AND "troponin T"[Title]) Search

with diagnostic outcomes:

(pediatric*[Title] OR neonat*[Title] OR infant*[Title] OR child*[Title] or adolescant*[Title]) AND ("high-sensitivity"[Title] AND "troponin T"[Title]) AND ("receiver operating characteristic"[Title/Abstract] OR "ROC curve"[Title/Abstract] OR AUROC[Title/Abstract] OR specificity[Title/Abstract] OR cut-off[Title/Abstract] OR cutoff[Title/Abstract]) Search

BNP PubMed Search

(pediatric*[Title] OR neonat*[Title] OR infant*[Title] OR child*[Title] or adolescant*[Title]) AND ("N-Terminal pro-B-Type Natriuretic Peptide"[Title]) Search

with diagnostic outcomes:

(pediatric*[Title] OR neonat*[Title] OR infant*[Title] OR child*[Title] or adolescant*[Title]) AND ("N-Terminal pro-B-Type Natriuretic Peptide"[Title]) AND ("receiver operating characteristic"[Title/Abstract] OR "ROC curve"[Title/Abstract] OR AUROC[Title/Abstract] OR specificity[Title/Abstract] OR cut-off[Title/Abstract] OR cutoff[Title/Abstract]) Search

REFERENCES

Keywords

Cardiac Biomarker Troponin BNP Pediatric Neonate Infant Toddler Child Adolescant

Author[s]

Andrew W. Swartz, MD

Reviewer[s]

Leslie Herrmann, MD