G Model
YPRRV-1040; No. of Pages 2 Paediatric Respiratory Reviews xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
Mini-symposium: Biomarkers and Phenotype – Editorial
Biomarkers for Paediatric Respiratory Diseases
One of the consequences of our increasing understanding of the cellular and molecular basis for normal development and physiology, on the one hand, and disease on the other, has been the development of biomarkers. I still remember that when my now adult son was diagnosed with ALL in 1988, the pathologists were unable to agree about the FAB classification of his leukemic cells. It wasn’t until the follow-up bone marrow examination weeks later that we were confident that the right diagnosis and therapy were chosen. Now, immunophenotyping defines the exact type for which the optimal therapy can be prescribed, and can detect residual disease and risk of recurrence with great accuracy [1]. For example, knowing how the right heart can produce natriuretic peptides [2] has led to their use as markers for treatment success in chronic heart failure [3]. To be useful, a biomarker needs to be objectively measurable. It needs to be sufficiently sensitive so as not to miss a significant number of cases and sufficiently specific to avoid over diagnosis, especially when the disease is uncommon. If needed sequentially, it should be relatively easy to obtain. Biomarkers can be used for diagnosis, disease activity and measurement of therapeutic effect. The search for biomarkers has been as active in pulmonary diseases as in other conditions. Perhaps best known in patients with cystic fibrosis is the G551D CFTR mutation where biomarkers have assisted in demonstrating ivacaftor effectiveness [4]. This symposium focuses on biomarkers in five paediatric respiratory diseases: asthma, cystic fibrosis, interstitial lung diseases, pulmonary hypertension and respiratory syncytial virus (RSV) bronchiolitis. We chose not to include bronchopulmonary dysplasia as its biomarkers were recently reviewed in this journal [5]. In the section on asthma biomarkers, Moschin and colleagues classify biomarkers based on their source (blood, urine and exhaled breath) [6]. In general, blood markers related to eosinophilia lack specificity. Markers of eosinophil activation, such as beta 1 integrin, have been correlated to asthma but may have limited clinical applicability [7]. Periostin, an extracellular matrix protein, is another blood biomarker under investigation. From the urine, leukotriene E4 measurements may help identify asthmatics who could benefit from anti-leukotriene therapy. The major portion of their review is dedicated to what can be measured from the exhaled breath of asthmatics. A short but comprehensive review of the state of exhaled nitric oxide (FENO) points out its limitations for asthma in general, in line with other recent analyses [8]. The authors then turn their attention to what can be collected in exhaled breath condensate (EBC). This method has several advantages, such as being user-friendly even in young children, and limitations such as a lack of standard methodologies,
despite a now decade old set of recommendations from the ATS/ ETS [9]. EBC biomarkers reviewed include oxidative stress products, inflammatory mediators and products, pH and small metabolic molecules such as formate. Finally, the authors examine a systems biology approach using metalabomics and proteonomics to analyze EBC. The review lists over 17 specific markers that differ between children with asthma or with specific asthma subtypes and normal controls, but none have yet proven sufficiently discriminatory for clinical use. The review on cystic fibrosis biomarkers by Ramsay and colleagues begins with the standard sweat chloride measurements [10]. This frames the discussion of other biomarkers in a functional context. Following a review of the various sampling sources (bronchoalveolar lavage, sputum, exhaled breath condensate [EBC] and blood), analysis of inflammation factors, such as free neutrophil elastase and IL-8, it is suggested that these biomarkers have strong potential to be useful when evaluating the natural history of lung disease and responses to therapy. These biomarkers are from either invasive bronchoalveolar lavage or sputum, and since induced sputum production is reliable only after ten years of age [11], there are limits on their usefulness in young children. On the other hand, EBC can be performed in young children and EBC studies measuring pathogen-derived volatile organic compounds, such as hydrogen cyanide from P. aeruginosa, are promising. Combining markers of infection or activity with species identification via microbiome analysis has further potential. Additionally, harbingers of pulmonary exacerbations, such as IP-10 and CCSP (also called CC16), have been investigated in adults. Interstitial lung diseases (ILD) represent a heterogeneous group of individually rare diseases that together effect children and adults of all ages. All have features involving repeated epithelial injury and disordered repair [12]. Nathan and colleagues, in their review, highlight how there are common pathophysiological mechanisms that produce clinical ILD and why these can provide useful biomarkers for these conditions [13]. They begin with genetic markers, with an emphasis on surfactant, its proteins, and its production/secretion pathways. ILDs are an example, in all likelihood, of two hits; a genetic propensity and an environmental trigger [14]. Consequently, genes alone are insufficient and acute biomarkers are necessary to better delineate the evolution of ILD. Markers associated with lung parenchyma dysfunction are more intriguing. For example, levels of the matrix metalloproteinase MMP7 have correlated with immediate lung function and long term survival. Similarly, serum Surfactant Protein D (SP-D) concentrations correlate with lung function deterioration. Other candidates include mucin related factors (KL-6 and MUC5B) and
http://dx.doi.org/10.1016/j.prrv.2015.04.001 1526-0542/ß 2015 Published by Elsevier Ltd.
Please cite this article in press as: Rozycki HJ. Biomarkers for Paediatric Respiratory Diseases. Paediatr. Respir. Rev. (2015), http:// dx.doi.org/10.1016/j.prrv.2015.04.001
G Model
YPRRV-1040; No. of Pages 2 2
Editorial / Paediatric Respiratory Reviews xxx (2015) xxx–xxx
immunomodulators such as CCL-18 and YKL-40. Almost all of these studies involve adults, but KL-6 and SP-D levels were significantly higher in a group of children with ILD compared to controls, and SP-D and SP-A correlated with disease severity [15]. Natriuretic peptides, mentioned above in relation to heart failure, are also one of the consistent biomarkers for pulmonary hypertension (PH), described in the contribution of Lohani and colleagues to this mini-symposium [16]. This condition has some unique biomarker candidates, reflecting that the endothelium is the targeted cell as opposed to the pulmonary epithelium. The effect of this on circulating cells is considered, including red cell distribution width (RDW) which has been favourably compared to other putative biomarkers of survival in adults with PH [17]. Particles from damaged red blood cells, white cells, platelets and circulating endothelial cells have correlated with survival and disease severity. These authors have included micro-ribonucleic acids [miRNAs], non-coding short RNA strands that help regulate gene expression, and describe some very preliminary results, similar to what has been described across the wide variety of conditions in which they have been studied [18]. Finally, they review imaging by echocardiography, computerized tomography [CT] and magnetic resonance imaging [MRI]. Strictly speaking, these may not qualify as biomarkers but their day to day utility is currently equal to or better than more invasive measures that meet the definition. RSV bronchiolitis is a significant cause of childhood pulmonary morbidity and worldwide mortality, so finding a biomarker or set of biomarkers to identify the disease or, more importantly, to stratify its severity and need for therapy is very important as reviewed by Brown and colleagues [19]. The immune response to infection is a fertile area for biomarkers, and similar to asthma, CF and ILD, airway fluid and blood levels of several different immune modulators are more elevated in patients with severe RSV pulmonary infection than with mild disease. There are also some unique putative marker candidates for RSV disease. The initial site of infection is usually the nose, and nasal washings are a relatively non-invasive source. Studies have found that nasal IFN-g, leukotriene LTC4, and LDH changes correlate with disease severity. These authors review work done on neurotrophins, hormones produced by pulmonary neuroendocrine cells, in both animals and humans and present data that both neurotrophins and their receptors are much higher in bronchoalveolar lavage fluid from infants with RSV bronchiolitis compared to those with similar clinical conditions caused by other microorganisms. This is a promising and specific finding, though invasive. Blood levels were also higher, but this may be less specific to RSV as elevated blood BDNF levels have been described in children with asthma [20]. These reviews reflect the current state of our knowledge. They are best thought of as ‘‘works in progress’’ in areas of intense research that are likely to lead to clinical tools in the future. Like pre-clinical studies of drugs in the pipelines of pharmaceutical companies, most will not eventually make it into the hands of paediatric pulmonologists, but while it is difficult to identify the best candidates now, being familiar with the state of the science
should help shepherd them into validation and use in the near future. References [1] Bacher U, Schnittger S, Haferlach C, Haferlach T. Molecular diagnostics in acute leukemias. Clin Chem Lab Med 2009;47:1333–41. [2] Cantin M, Genest J. The heart and the atrial natriuretic factor. Endocr Rev 1985;6:107–27. [3] Savarese G, Trimarco B, Dellegrottaglie S, Prastaro M, Gambardella F, Rengo G, et al. Natriuretic peptide-guided therapy in chronic heart failure: a metaanalysis of 2,686 patients in 12 randomized trials. PLoS One 2013;8:e58287. [4] Sermet-Gaudelus I. Ivacaftor treatment in patients with cystic fibrosis and the G551D-CFTR mutation. Eur Respir Rev 2013;22:66–71. [5] Bhandari A, Bhandari V. Biomarkers in bronchopulmonary dysplasia. Paediatr Respir Rev 2013;14:173–9. [6] Moschino L, Zanconato S, Bozzetto S, Baraldi E, Carraro S. Childhood asthma biomarkers: Present knowledge and future steps. Paediatr Respir Rev 2015. XX. [7] Johansson MW1, Han ST, Gunderson KA, Busse WW, Jarjour NN, Mosher DF. Platelet activation, P-selectin, and eosinophil b1-integrin activation in asthma. Am J Respir Crit Care Med 2012;185:498–507. [8] Turner S. Exhaled nitric oxide and the management of childhood asthma - yet another promising biomarker ‘‘has been’’ or a misunderstood gem. Paediatr Respir Rev 2014. pii: S1526-0542(14)00083-9. doi:10.1016/j.prrv.2014.07.005. [9] Horva´th I, Hunt J, Barnes PJ. ATS/ERS Task Force on Exhaled Breath Condensate. Exhaled breath condensate: methodological recommendations and unresolved questions. Eur Respir J 2005;26:523–48. [10] Ramsay KA, Schultz A. StickSM. Biomarkers in Cystic Fibrosis Lung Disease. Paediatr Respir Rev 2015. XX. [11] Sagel SD, Kapsner R, Osberg I, Sontag MK, Accurso FJ. Airway Inflammation in Children with Cystic Fibrosis and Healthy Children Assessed by Sputum Induction. Am J Resp Crit Care Med 2001;164:1425–31. [12] Clement A, Nathan N, Epaud R, Fauroux B, Corvol H. Interstitial lung diseases in children. Orphanet J Rare Dis 2010;5:22. [13] Nathan N, Corvol H, Amselem S, Clement A. Biomarkers in interstitial lung diseases. Paediatr Respir Rev 2015. xx. [14] Selman M, Pardo A, King Jr TE. Hypersensitivity pneumonitis: insights in diagnosis and pathobiology. Am J Respir Crit Care Med 2012;186:314–24. [15] Al-Salmi QA, Walter JN, Colasurdo GN, Sockrider MM, Smith EO, Takahashi H, Fan LL. Serum KL-6 and surfactant proteins A and D in pediatric interstitial lung disease. Chest 2005;127:403–7. [16] Lohani O, Colvin KL, Yeager ME. Biomarkers for paediatric pulmonary arterial hypertension: challenges and recommendations. Paediatr Respir Rev 2015. xx. [17] Rhodes CJ, Wharton J, Howard LS, Gibbs JS, Wilkins MR. Red cell distribution width outperforms other potential circulating biomarkers in predicting survival in idiopathic pulmonary arterial hypertension. Heart 2011;97: 1054–6. [18] Witwer KW. Circulating microRNA biomarker studies: pitfalls and potential solutions. Clin Chem 2015;61:56–63. [19] Brown PM, Schneeberger DL, Piedimonte G. Biomarkers of respiratory syncytial virus (RSV) infection: specific neurotropin and cytokine levels provide increased accuracy in predicting disease severity. Paediatr Respir Rev 2015. XX. [20] Mu¨ller GC, Pitrez PM, Teixeira AL, Pires PS, Jones MH, Stein RT, Bauer ME. Plasma brain-derived neurotrophic factor levels are associated with clinical severity in school age children with asthma. Clin Exp Allergy 2010;40:1755–9.
Henry J. Rozycki* Associate Professor of Pediatrics, Division of Neonatal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA *Division of Neonatal Medicine, Department of Pediatrics, Virginia Commonwealth University School of Medicine, Box 980276, Richmond, VA 23298-0276. Tel.: +1 804-828-9964; fax: +1 804-828-6662 E-mail address: [email protected] (H.J. Rozycki).
Please cite this article in press as: Rozycki HJ. Biomarkers for Paediatric Respiratory Diseases. Paediatr. Respir. Rev. (2015), http:// dx.doi.org/10.1016/j.prrv.2015.04.001
YPRRV-1040; No. of Pages 2 Paediatric Respiratory Reviews xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
Mini-symposium: Biomarkers and Phenotype – Editorial
Biomarkers for Paediatric Respiratory Diseases
One of the consequences of our increasing understanding of the cellular and molecular basis for normal development and physiology, on the one hand, and disease on the other, has been the development of biomarkers. I still remember that when my now adult son was diagnosed with ALL in 1988, the pathologists were unable to agree about the FAB classification of his leukemic cells. It wasn’t until the follow-up bone marrow examination weeks later that we were confident that the right diagnosis and therapy were chosen. Now, immunophenotyping defines the exact type for which the optimal therapy can be prescribed, and can detect residual disease and risk of recurrence with great accuracy [1]. For example, knowing how the right heart can produce natriuretic peptides [2] has led to their use as markers for treatment success in chronic heart failure [3]. To be useful, a biomarker needs to be objectively measurable. It needs to be sufficiently sensitive so as not to miss a significant number of cases and sufficiently specific to avoid over diagnosis, especially when the disease is uncommon. If needed sequentially, it should be relatively easy to obtain. Biomarkers can be used for diagnosis, disease activity and measurement of therapeutic effect. The search for biomarkers has been as active in pulmonary diseases as in other conditions. Perhaps best known in patients with cystic fibrosis is the G551D CFTR mutation where biomarkers have assisted in demonstrating ivacaftor effectiveness [4]. This symposium focuses on biomarkers in five paediatric respiratory diseases: asthma, cystic fibrosis, interstitial lung diseases, pulmonary hypertension and respiratory syncytial virus (RSV) bronchiolitis. We chose not to include bronchopulmonary dysplasia as its biomarkers were recently reviewed in this journal [5]. In the section on asthma biomarkers, Moschin and colleagues classify biomarkers based on their source (blood, urine and exhaled breath) [6]. In general, blood markers related to eosinophilia lack specificity. Markers of eosinophil activation, such as beta 1 integrin, have been correlated to asthma but may have limited clinical applicability [7]. Periostin, an extracellular matrix protein, is another blood biomarker under investigation. From the urine, leukotriene E4 measurements may help identify asthmatics who could benefit from anti-leukotriene therapy. The major portion of their review is dedicated to what can be measured from the exhaled breath of asthmatics. A short but comprehensive review of the state of exhaled nitric oxide (FENO) points out its limitations for asthma in general, in line with other recent analyses [8]. The authors then turn their attention to what can be collected in exhaled breath condensate (EBC). This method has several advantages, such as being user-friendly even in young children, and limitations such as a lack of standard methodologies,
despite a now decade old set of recommendations from the ATS/ ETS [9]. EBC biomarkers reviewed include oxidative stress products, inflammatory mediators and products, pH and small metabolic molecules such as formate. Finally, the authors examine a systems biology approach using metalabomics and proteonomics to analyze EBC. The review lists over 17 specific markers that differ between children with asthma or with specific asthma subtypes and normal controls, but none have yet proven sufficiently discriminatory for clinical use. The review on cystic fibrosis biomarkers by Ramsay and colleagues begins with the standard sweat chloride measurements [10]. This frames the discussion of other biomarkers in a functional context. Following a review of the various sampling sources (bronchoalveolar lavage, sputum, exhaled breath condensate [EBC] and blood), analysis of inflammation factors, such as free neutrophil elastase and IL-8, it is suggested that these biomarkers have strong potential to be useful when evaluating the natural history of lung disease and responses to therapy. These biomarkers are from either invasive bronchoalveolar lavage or sputum, and since induced sputum production is reliable only after ten years of age [11], there are limits on their usefulness in young children. On the other hand, EBC can be performed in young children and EBC studies measuring pathogen-derived volatile organic compounds, such as hydrogen cyanide from P. aeruginosa, are promising. Combining markers of infection or activity with species identification via microbiome analysis has further potential. Additionally, harbingers of pulmonary exacerbations, such as IP-10 and CCSP (also called CC16), have been investigated in adults. Interstitial lung diseases (ILD) represent a heterogeneous group of individually rare diseases that together effect children and adults of all ages. All have features involving repeated epithelial injury and disordered repair [12]. Nathan and colleagues, in their review, highlight how there are common pathophysiological mechanisms that produce clinical ILD and why these can provide useful biomarkers for these conditions [13]. They begin with genetic markers, with an emphasis on surfactant, its proteins, and its production/secretion pathways. ILDs are an example, in all likelihood, of two hits; a genetic propensity and an environmental trigger [14]. Consequently, genes alone are insufficient and acute biomarkers are necessary to better delineate the evolution of ILD. Markers associated with lung parenchyma dysfunction are more intriguing. For example, levels of the matrix metalloproteinase MMP7 have correlated with immediate lung function and long term survival. Similarly, serum Surfactant Protein D (SP-D) concentrations correlate with lung function deterioration. Other candidates include mucin related factors (KL-6 and MUC5B) and
http://dx.doi.org/10.1016/j.prrv.2015.04.001 1526-0542/ß 2015 Published by Elsevier Ltd.
Please cite this article in press as: Rozycki HJ. Biomarkers for Paediatric Respiratory Diseases. Paediatr. Respir. Rev. (2015), http:// dx.doi.org/10.1016/j.prrv.2015.04.001
G Model
YPRRV-1040; No. of Pages 2 2
Editorial / Paediatric Respiratory Reviews xxx (2015) xxx–xxx
immunomodulators such as CCL-18 and YKL-40. Almost all of these studies involve adults, but KL-6 and SP-D levels were significantly higher in a group of children with ILD compared to controls, and SP-D and SP-A correlated with disease severity [15]. Natriuretic peptides, mentioned above in relation to heart failure, are also one of the consistent biomarkers for pulmonary hypertension (PH), described in the contribution of Lohani and colleagues to this mini-symposium [16]. This condition has some unique biomarker candidates, reflecting that the endothelium is the targeted cell as opposed to the pulmonary epithelium. The effect of this on circulating cells is considered, including red cell distribution width (RDW) which has been favourably compared to other putative biomarkers of survival in adults with PH [17]. Particles from damaged red blood cells, white cells, platelets and circulating endothelial cells have correlated with survival and disease severity. These authors have included micro-ribonucleic acids [miRNAs], non-coding short RNA strands that help regulate gene expression, and describe some very preliminary results, similar to what has been described across the wide variety of conditions in which they have been studied [18]. Finally, they review imaging by echocardiography, computerized tomography [CT] and magnetic resonance imaging [MRI]. Strictly speaking, these may not qualify as biomarkers but their day to day utility is currently equal to or better than more invasive measures that meet the definition. RSV bronchiolitis is a significant cause of childhood pulmonary morbidity and worldwide mortality, so finding a biomarker or set of biomarkers to identify the disease or, more importantly, to stratify its severity and need for therapy is very important as reviewed by Brown and colleagues [19]. The immune response to infection is a fertile area for biomarkers, and similar to asthma, CF and ILD, airway fluid and blood levels of several different immune modulators are more elevated in patients with severe RSV pulmonary infection than with mild disease. There are also some unique putative marker candidates for RSV disease. The initial site of infection is usually the nose, and nasal washings are a relatively non-invasive source. Studies have found that nasal IFN-g, leukotriene LTC4, and LDH changes correlate with disease severity. These authors review work done on neurotrophins, hormones produced by pulmonary neuroendocrine cells, in both animals and humans and present data that both neurotrophins and their receptors are much higher in bronchoalveolar lavage fluid from infants with RSV bronchiolitis compared to those with similar clinical conditions caused by other microorganisms. This is a promising and specific finding, though invasive. Blood levels were also higher, but this may be less specific to RSV as elevated blood BDNF levels have been described in children with asthma [20]. These reviews reflect the current state of our knowledge. They are best thought of as ‘‘works in progress’’ in areas of intense research that are likely to lead to clinical tools in the future. Like pre-clinical studies of drugs in the pipelines of pharmaceutical companies, most will not eventually make it into the hands of paediatric pulmonologists, but while it is difficult to identify the best candidates now, being familiar with the state of the science
should help shepherd them into validation and use in the near future. References [1] Bacher U, Schnittger S, Haferlach C, Haferlach T. Molecular diagnostics in acute leukemias. Clin Chem Lab Med 2009;47:1333–41. [2] Cantin M, Genest J. The heart and the atrial natriuretic factor. Endocr Rev 1985;6:107–27. [3] Savarese G, Trimarco B, Dellegrottaglie S, Prastaro M, Gambardella F, Rengo G, et al. Natriuretic peptide-guided therapy in chronic heart failure: a metaanalysis of 2,686 patients in 12 randomized trials. PLoS One 2013;8:e58287. [4] Sermet-Gaudelus I. Ivacaftor treatment in patients with cystic fibrosis and the G551D-CFTR mutation. Eur Respir Rev 2013;22:66–71. [5] Bhandari A, Bhandari V. Biomarkers in bronchopulmonary dysplasia. Paediatr Respir Rev 2013;14:173–9. [6] Moschino L, Zanconato S, Bozzetto S, Baraldi E, Carraro S. Childhood asthma biomarkers: Present knowledge and future steps. Paediatr Respir Rev 2015. XX. [7] Johansson MW1, Han ST, Gunderson KA, Busse WW, Jarjour NN, Mosher DF. Platelet activation, P-selectin, and eosinophil b1-integrin activation in asthma. Am J Respir Crit Care Med 2012;185:498–507. [8] Turner S. Exhaled nitric oxide and the management of childhood asthma - yet another promising biomarker ‘‘has been’’ or a misunderstood gem. Paediatr Respir Rev 2014. pii: S1526-0542(14)00083-9. doi:10.1016/j.prrv.2014.07.005. [9] Horva´th I, Hunt J, Barnes PJ. ATS/ERS Task Force on Exhaled Breath Condensate. Exhaled breath condensate: methodological recommendations and unresolved questions. Eur Respir J 2005;26:523–48. [10] Ramsay KA, Schultz A. StickSM. Biomarkers in Cystic Fibrosis Lung Disease. Paediatr Respir Rev 2015. XX. [11] Sagel SD, Kapsner R, Osberg I, Sontag MK, Accurso FJ. Airway Inflammation in Children with Cystic Fibrosis and Healthy Children Assessed by Sputum Induction. Am J Resp Crit Care Med 2001;164:1425–31. [12] Clement A, Nathan N, Epaud R, Fauroux B, Corvol H. Interstitial lung diseases in children. Orphanet J Rare Dis 2010;5:22. [13] Nathan N, Corvol H, Amselem S, Clement A. Biomarkers in interstitial lung diseases. Paediatr Respir Rev 2015. xx. [14] Selman M, Pardo A, King Jr TE. Hypersensitivity pneumonitis: insights in diagnosis and pathobiology. Am J Respir Crit Care Med 2012;186:314–24. [15] Al-Salmi QA, Walter JN, Colasurdo GN, Sockrider MM, Smith EO, Takahashi H, Fan LL. Serum KL-6 and surfactant proteins A and D in pediatric interstitial lung disease. Chest 2005;127:403–7. [16] Lohani O, Colvin KL, Yeager ME. Biomarkers for paediatric pulmonary arterial hypertension: challenges and recommendations. Paediatr Respir Rev 2015. xx. [17] Rhodes CJ, Wharton J, Howard LS, Gibbs JS, Wilkins MR. Red cell distribution width outperforms other potential circulating biomarkers in predicting survival in idiopathic pulmonary arterial hypertension. Heart 2011;97: 1054–6. [18] Witwer KW. Circulating microRNA biomarker studies: pitfalls and potential solutions. Clin Chem 2015;61:56–63. [19] Brown PM, Schneeberger DL, Piedimonte G. Biomarkers of respiratory syncytial virus (RSV) infection: specific neurotropin and cytokine levels provide increased accuracy in predicting disease severity. Paediatr Respir Rev 2015. XX. [20] Mu¨ller GC, Pitrez PM, Teixeira AL, Pires PS, Jones MH, Stein RT, Bauer ME. Plasma brain-derived neurotrophic factor levels are associated with clinical severity in school age children with asthma. Clin Exp Allergy 2010;40:1755–9.
Henry J. Rozycki* Associate Professor of Pediatrics, Division of Neonatal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA *Division of Neonatal Medicine, Department of Pediatrics, Virginia Commonwealth University School of Medicine, Box 980276, Richmond, VA 23298-0276. Tel.: +1 804-828-9964; fax: +1 804-828-6662 E-mail address: [email protected] (H.J. Rozycki).
Please cite this article in press as: Rozycki HJ. Biomarkers for Paediatric Respiratory Diseases. Paediatr. Respir. Rev. (2015), http:// dx.doi.org/10.1016/j.prrv.2015.04.001
