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Children as Biomarker Orphans: Progress in the Field of Pediatric Biomarkers

2017; Elsevier BV; Volume: 193; Linguagem: Inglês

10.1016/j.jpeds.2017.08.077

1097-6833

Darla R. Shores, Allen D. Everett,

Birth, Development, and Health

Biomarkers are incorporated ubiquitously into clinical practice as surrogate endpoints of physiologic and pathologic processes that cannot be measured directly. For example, a lipid panel is used to evaluate cardiovascular disease but does not measure vascular heath directly. Biomarkers monitor health, detect exposures, diagnose disease, predict disease severity and outcome, and monitor treatment effects. The potential utility of biomarkers in pediatrics is high. Children are not only at risk of developing unique illnesses, but prevalent chronic diseases previously thought of as "adult" illness, including obesity, cardiovascular disease, and type 2 diabetes, have their origins in childhood. 1 Yajnik C. Interactions of perturbations in intrauterine growth and growth during childhood on the risk of adult-onset disease. Proc Nutr Soc. 2000; 59: 257-265 Crossref PubMed Google Scholar , 2 Shonkoff J.P. Boyce W.T. McEwen B.S. Neuroscience, molecular biology, and the childhood roots of health disparities: building a new framework for health promotion and disease prevention. JAMA. 2009; 301: 2252-2259 Crossref PubMed Scopus (963) Google Scholar In an era in which precision, or personalized, medicine is becoming a priority, testing that leads to early intervention and curbs the severity of disease may have an immense impact on population health and the use of healthcare resources. Table 1 highlights examples of commonly used and recent biomarkers in pediatrics. Despite this potential, biomarker discovery in pediatrics has been limited. In 2010, the barriers to pediatric biomarker discovery were reviewed. 21 Savage W.J. Everett A.D. Biomarkers in pediatrics: children as biomarker orphans. Proteomics Clin Appl. 2010; 4: 915-921 Crossref PubMed Scopus (0) Google Scholar In this updated review, we will discuss the progress, as well as remaining challenges specific to pediatrics, and potential strategies for moving forward. Table 1Examples of pediatric biomarkers in clinical use Authors Year Test Screening/diagnostic utility Comments Biospecimen Bortolotti et al 3 Bortolotti F. Muratori L. Jara P. Hierro L. Verucchi G. Giacchino R. et al. Hepatitis C virus infection associated with liver-kidney microsomal antibody type 1 (LKM1) autoantibodies in children. J Pediatr. 2003; 142: 185-190 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar 2003 anti-LKM Autoimmune hepatitis, chronic hepatitis C Positive in type 2 autoimmune hepatitis and in 10% of hepatitis C Serum/blood Roberts 4 Roberts E.A. Autoimmune hepatitis from the paediatric perspective. Liver Int. 2011; 31: 1424-1431 Crossref PubMed Scopus (0) Google Scholar 2011 Dalrymple and Moore 5 Dalrymple A.M. Moore T.L. Laboratory evaluation in pediatric autoimmune diseases. Pediatr Rev. 2015; 36: 496-501 Crossref PubMed Google Scholar 2015 ANA Multiple rheumatologic and autoimmune disorders: systemic lupus erythematosus, rheumatoid arthritis, dermatomyositis, idiopathic thrombocytopenic purpura, autoimmune hepatitis, and thyroiditis Low titers in up to 20% healthy children; Positive in >90% of connective tissue disorders; elevations can occur with drug reactions and some viral infections Serum/blood Breda et al 6 Breda L. Nozzi M. De Sanctis S. Chiarelli F. Laboratory tests in the diagnosis and follow-up of pediatric rheumatic diseases: an update. Semin Arthritis Rheum. 2010; 40: 53-72 Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar 2010 Nir et al 7 Nir A. Lindinger A. Rauh M. Bar-Oz B. Laer S. Schwachtgen L. et al. NT-pro-B-type natriuretic peptide in infants and children: reference values based on combined data from four studies. Pediatr Cardiol. 2009; 30: 3-8 Crossref PubMed Scopus (119) Google Scholar 2009 BNP Heart disease and failure Normally elevated in the first few days of life then decrease; levels correlate with pulmonary-to-systemic flow and vascular resistance ratios, mean pulmonary artery pressure, obstructive lesions, and allograft disease after transplant Serum/blood Henderson et al 8 Henderson P. Anderson N.H. Wilson D.C. The diagnostic accuracy of fecal calprotectin during the investigation of suspected pediatric inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol. 2014; 109: 637-645 Crossref PubMed Scopus (77) Google Scholar 2014 Calprotectin Intestinal inflammation Used for screening and treatment response in inflammatory bowel disease; also may be elevated with intestinal infection, cystic fibrosis, and juvenile polyps. Normal values are highly variable in infants born premature Stool Zoppelli et al 9 Zoppelli L. Guttel C. Bittrich H.J. Andree C. Wirth S. Jenke A. Fecal calprotectin concentrations in premature infants have a lower limit and show postnatal and gestational age dependence. Neonatology. 2012; 102: 68-74 Crossref PubMed Scopus (19) Google Scholar 2012 Jones and Hattersley 10 Jones A.G. Hattersley A.T. The clinical utility of C-peptide measurement in the care of patients with diabetes. Diabet Med. 2013; 30: 803-817 Crossref PubMed Scopus (103) Google Scholar 2013 C-peptide Diabetes mellitus Approximates endogenous insulin production, helps differentiate type Serum/blood Breda et al 6 Breda L. Nozzi M. De Sanctis S. Chiarelli F. Laboratory tests in the diagnosis and follow-up of pediatric rheumatic diseases: an update. Semin Arthritis Rheum. 2010; 40: 53-72 Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar 2010 CRP Acute and chronic inflammation from severe bacterial infection, tissue injury, autoimmune disease Highly sensitive, but not specific, increases more quickly compared with ESR Serum/blood Elsayed and Reilly 11 Elsayed E.F. Reilly R.F. Rhabdomyolysis: a review, with emphasis on the pediatric population. Pediatr Nephrol. 2010; 25: 7-18 Crossref PubMed Scopus (52) Google Scholar 2010 CK Muscle injury Elevated in rhabdomyolysis, myopathies, and myositis Serum/blood Gatheridge et al 12 Gatheridge M.A. Kwon J.M. Mendell J.M. Scheuerbrandt G. Moat S.J. Eyskens F. et al. Identifying non-Duchenne muscular dystrophy-positive and false negative results in prior Duchenne muscular dystrophy newborn screening programs: a review. JAMA Neurol. 2016; 73: 111-116 Crossref PubMed Scopus (0) Google Scholar 2016 Breda et al 6 Breda L. Nozzi M. De Sanctis S. Chiarelli F. Laboratory tests in the diagnosis and follow-up of pediatric rheumatic diseases: an update. Semin Arthritis Rheum. 2010; 40: 53-72 Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar 2010 Ferritin Iron deficiency anemia (low)Hemophagocytic lymphohistiocytosis (high) May be elevated as an acute-phase reactant in sepsis and shock Serum/blood Malope et al 13 Malope B.I. MacPhail A.P. Alberts M. Hiss D.C. The ratio of serum transferrin receptor and serum ferritin in the diagnosis of iron status. Br J Haematol. 2001; 115: 84-89 Crossref PubMed Scopus (0) Google Scholar 2011 Tang et al 14 Tang S., Xie Y., Yuan C., Sun X., Cui Y. Fractional exhaled nitric oxide for the diagnosis of childhood asthma: a systematic review and meta-analysis. Clin Rev Allergy Immunol, in press. Google Scholar 2016 FENO Asthma Marker of eosinophilic inflammation used for diagnosis and treatment response Breath test Petsky et al 15 Petsky H.L. Kew K.M. Chang A.B. Exhaled nitric oxide levels to guide treatment for children with asthma. Cochrane Database Syst Rev. 2016; (CD011439) Google Scholar 2016 Lehrnbecher et al 16 Lehrnbecher T. Robinson P.D. Fisher B.T. Castagnola E. Groll A.H. Steinbach W.J. et al. Galactomannan, beta-D-glucan, and polymerase chain reaction-based assays for the diagnosis of invasive fungal disease in pediatric cancer and hematopoietic stem cell transplantation: a systematic review and meta-analysis. Clin Infect Dis. 2016; 63: 1340-1348 Crossref PubMed Scopus (0) Google Scholar 2016 Galactomannan Aspergillus infection (immunocompromised patients) Less sensitive for other fungal infections Serum/blood Copeland et al 17 Copeland K.C. Silverstein J. Moore K.R. Prazar G.E. Raymer T. Shiffman R.N. et al. Management of newly diagnosed type 2 diabetes mellitus (T2DM) in children and adolescents. Pediatrics. 2013; 131: 364-382 Crossref PubMed Scopus (115) Google Scholar 2013 Hemoglobin A1C Diabetes mellitus Used for diagnosis and to guide dosing of insulin Serum/blood Fine-Goulden and Durward 18 Fine-Goulden M.R. Durward A. How to use lactate. Arch Dis Child Educ Pract Ed. 2014; 99: 17-22 Crossref PubMed Google Scholar 2014 Lactate Ischemia, sepsis, lactic acidosis/metabolic crisis Elevation may predict mortality in acutely ill or trauma patients Serum/blood Breda et al 6 Breda L. Nozzi M. De Sanctis S. Chiarelli F. Laboratory tests in the diagnosis and follow-up of pediatric rheumatic diseases: an update. Semin Arthritis Rheum. 2010; 40: 53-72 Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar 2010 Procalcitonin Sepsis/severe bacterial infection, shock More specific to bacterial sepsis than CRP in children Serum/blood Lautz et al 19 Lautz A.J. Dziorny A.C. Denson A.R. O'Connor K.A. Chilutti M.R. Ross R.K. et al. Value of procalcitonin measurement for early evidence of severe bacterial infections in the pediatric intensive care unit. J Pediatr. 2016; 179 (e2): 74-81 Abstract Full Text Full Text PDF PubMed Google Scholar 2016 Breda et al 6 Breda L. Nozzi M. De Sanctis S. Chiarelli F. Laboratory tests in the diagnosis and follow-up of pediatric rheumatic diseases: an update. Semin Arthritis Rheum. 2010; 40: 53-72 Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar 2010 ESR Acute and chronic inflammation from autoimmune disease or infection Acute-phase reactant with high sensitivity but low specificity for any one disease, increases more slowly compared with CRP Serum/blood Kelly et al 20 Kelly C.P. Bai J.C. Liu E. Leffler D.A. Advances in diagnosis and management of celiac disease. Gastroenterology. 2015; 148: 1175-1186 Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar 2015 TTG Celiac disease Highly sensitive and specific; used for screening and treatment response Serum/blood ANA, Antinuclear antibody; anti-LKM, Anti-liver kidney microsomal antibody; BNP, Brain natriuretic peptide; CK, Creatine kinase; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; FENO, Fractional exhaled nitric oxide; TTG, Tissue transglutaminase. Open table in a new tab ANA, Antinuclear antibody; anti-LKM, Anti-liver kidney microsomal antibody; BNP, Brain natriuretic peptide; CK, Creatine kinase; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; FENO, Fractional exhaled nitric oxide; TTG, Tissue transglutaminase.