Clin Rheumatol DOI 10.1007/s10067-014-2773-1
ORIGINAL ARTICLE
Evaluation of serum procalcitonin and C-reactive protein levels as biomarkers of Henoch-Schönlein purpura in pediatric patients Xu Teng & Yang Wang & Nan Lin & Mei Sun & Jie Wu
Received: 10 February 2014 / Revised: 27 August 2014 / Accepted: 3 September 2014 # International League of Associations for Rheumatology (ILAR) 2014
Abstract Henoch-Schönlein purpura (HSP) is a vasculitic disorder resulting from autoinflammatory-mediated tissue injury. Procalcitonin (PCT) and C-reactive protein (CRP) are two biomarkers of the immune response that recognize bacterial infection and inflammation, respectively. This study tested whether levels of PCT and CRP were associated with selected clinical features, disease severity, and organ damage in HSP. Eighty-nine pediatric patients with HSP were analyzed for clinical manifestations and organ damage. Serum CRP, PCT, and occult blood in the urine and stool (prior to steroid therapy) were measured. Disease severity was classified according to previously established clinical classifications. Sixty patients (67.4 %) had a low clinical score (LCS) of 0.05
Group B
u value p
higher PCT levels in group D patients (group D: median= 0.09, range=0.05–1.02 vs. group C: median=0.05, range= 0.05–0.32 ng/ml; u=2.849). We observed no difference in CRP levels between groups C and D, respectively (group C: median=4.66, range=1.00–144.00 vs. group D: median= 9.44, range=1.06–124.00 mg/l; u=1.783) (Table 5). We observed a significant positive correlation between the serum concentrations of PCT and CRP in all patients examined (r= 0.721, p=0.002).
Discussion In this study, we examined whether PCT and CRP levels could serve as effective biomarkers to identify HSP disease severity in pediatric patients. Overall, the serum PCT levels in HSP patients were within ranges of localized inflammation or infection (0.5 ng/ml) from this underlying autoimmune disease. Serum PCT levels were higher in patients with GI bleeds (group D) than in cases without alimentary tract hemorrhage (group C). The observed increase in PCT levels (>0.05 ng/ml) in HSP patients with a GI bleed may reflect a low-grade, nonspecific but systemic inflammatory response that occurs as a result of the disease. Because patients with alimentary tract hemorrhage have severe mucosal barrier injuries, the presence of a GI bleed may directly stimulate PCT synthesis. It is currently unclear whether the increased circulating PCT in HSP is merely an epiphenomenon or the direct consequence of HSP pathogenesis. In this study, we have shown that serum CRP levels were not an indicator of disease severity in HSP patients, despite the fact that changes in CRP concentration followed a similar pattern as the observed changes in PCT synthesis. In contrast to results presented by Makay et al. [6], our results showed that CRP levels were not associated with HSP GI bleeding. Elevated CRP likely serves as a non-specific marker of inflammatory activity. Changes in serum CRP reflected a uniform response after inflammatory impairment without any significant association with damage or severity. Because we are pediatric gastroenterologists, patients admitted to our
department have GI manifestations and thus, bias our research towards GI involvement. Given the retrospective nature of this study, a GI bias was unavoidable and represents a limitation of our study. As we previously noted, nephritic syndrome is one of the predominant manifestations of pediatric HSP, which can ultimately lead to onset of renal insufficiency. Because only five patients presented with nephritic syndrome in this study, we did not analyze the levels of PCT and CRP. In the future, we plan to conduct a multicenter study to avoid the bias. Acknowledgments We thank Medjaden Bioscience Limited for assisting in the preparation of this manuscript. Disclosures None.
References 1. Gardner-Medwin JM, Dolezalova P, Cummins C, Southwood TR (2002) Incidence of Henoch-Schonlein purpura, Kawasaki disease, and rare vasculitides in children of different ethnic origins. Lancet 360(9341):1197–1202 2. Bressan S, Gomez B, Mintegi S, Da Dalt L, Blazquez D, Olaciregui I, de la Torre M, Palacios M, Berlese P, Ruano A (2012) Diagnostic performance of the lab-score in predicting severe and invasive bacterial infections in well-appearing young febrile infants. Pediatr Infect Dis J 31(12):1239–1244 3. Becker KL, Snider R, Nylen ES (2008) Procalcitonin assay in systemic inflammation, infection, and sepsis: clinical utility and limitations. Crit Care Med 36(3):941–952 4. Schützle H, Forster J, Superti-Furga A, Berner R (2009) Is serum procalcitonin a reliable diagnostic marker in children with acute respiratory tract infections? A retrospective analysis. Eur J Pediatr 168(9):1117–1124 5. Cevey-Macherel M, Galetto-Lacour A, Gervaix A, Siegrist CA, Bille J, Bescher-Ninet B, Kaiser L, Krahenbuhl JD, Gehri M (2009) Etiology of community-acquired pneumonia in hospitalized children based on WHO clinical guidelines. Eur J Pediatr 168(12):1429–1436 6. Makay B, Turkyilmaz Z, Duman M, Unsal E (2009) Mean platelet volume in Henoch-Schonlein purpura: relationship to gastrointestinal bleeding. Clin Rheumatol 28(10):1225–1228 7. Delevaux I, Andre M, Colombier M, Albuisson E, Meylheuc F, Begue RJ, Piette JC, Aumaitre O (2003) Can procalcitonin measurement help in differentiating between bacterial infection and other kinds of inflammatory processes? Ann Rheum Dis 62(4):337–340 8. Volanakis JE (2001) Human C-reactive protein: expression, structure, and function. Mol Immunol 38(2–3):189–197 9. Kasperska-Zajac A, Sztylc J, Machura E, Jop G (2011) Plasma IL-6 concentration correlates with clinical disease activity and serum Creactive protein concentration in chronic urticaria patients. Clin Exp Allergy 41(10):1386–1391 10. Ozen S, Ruperto N, Dillon MJ, Bagga A, Barron K, Davin JC, Kawasaki T, Lindsley C, Petty RE, Prieur AM, Ravelli A, Woo P (2006) EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides. Ann Rheum Dis 65(7):936–941 11. De Mattia D, Penza R, Giordano P, Del Vecchio GC, Aceto G, Altomare M, Schettini F (1995) von Willebrand factor and factor XIII in children with Henoch-Schonlein purpura. Pediatr Nephrol 9(5):603–605 12. Aikawa N, Fujishima S, Endo S, Sekine I, Kogawa K, Yamamoto Y, Kushimoto S, Yukioka H, Kato N, Totsuka K, Kikuchi K, Ikeda T,
Clin Rheumatol
13.
14.
15.
16.
17.
Ikeda K, Harada K, Satomura S (2005) Multicenter prospective study of procalcitonin as an indicator of sepsis. J Infect Chemother 11(3): 152–159 Eberhard OK, Haubitz M, Brunkhorst FM, Kliem V, Koch KM, Brunkhorst R (1997) Usefulness of procalcitonin for differentiation between activity of systemic autoimmune disease (systemic lupus erythematosus/systemic antineutrophil cytoplasmic antibodyassociated vasculitis) and invasive bacterial infection. Arthritis Rheum 40(7):1250–1256 Maier M, Wutzler S, Lehnert M, Szermutzky M, Wyen H, Bingold T, Henrich D, Walcher F, Marzi I (2009) Serum procalcitonin levels in patients with multiple injuries including visceral trauma. J Trauma 66(1):243–249 Lanoix JP, Bourgeois AM, Schmidt J, Desblache J, Salle V, Smail A, Maziere JC, Betsou F, Choukroun G, Duhaut P, Ducroix JP (2011) Serum procalcitonin does not differentiate between infection and disease flare in patients with systemic lupus erythematosus. Lupus 20(2):125–130 Meisner M, Adina H, Schmidt J (2006) Correlation of procalcitonin and C-reactive protein to inflammation, complications, and outcome during the intensive care unit course of multiple-trauma patients. Crit Care 10(1):R1 Okada Y, Minakami H, Tomomasa T, Kato M, Inoue Y, Kozawa K, Kimura H, Morikawa A (2004) Serum procalcitonin concentration in patients with Kawasaki disease. J Infect 48(2):199– 205
18. Yoshikawa H, Nomura Y, Masuda K, Koriya C, Arata M, Hazeki D, Yanagimoto K, Ueno K, Eguchi T, Kawano Y (2012) Serum procalcitonin value is useful for predicting severity of Kawasaki disease. Pediatr Infect Dis J 31(5):523–525 19. Chen DY, Chen YM, Ho WL, Chen HH, Shen GH, Lan JL (2009) Diagnostic value of procalcitonin for differentiation between bacterial infection and non-infectious inflammation in febrile patients with active adult-onset Still’s disease. Ann Rheum Dis 68(6):1074–1075 20. Uzzan B, Cohen R, Nicolas P, Cucherat M, Perret GY (2006) Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: a systematic review and meta-analysis. Crit Care Med 34(7):1996–2003 21. Russwurm S, Wiederhold M, Oberhoffer M, Stonans I, Zipfel PF, Reinhart K (1999) Molecular aspects and natural source of procalcitonin. Clin Chem Lab Med 37(8):789–797 22. Yang RZ, Lee MJ, Hu H, Pollin TI, Ryan AS, Nicklas BJ, Snitker S, Horenstein RB, Hull K, Goldberg NH, Goldberg AP, Shuldiner AR, Fried SK, Gong DW (2006) Acute-phase serum amyloid A: an inflammatory adipokine and potential link between obesity and its metabolic complications. PLoS Med 3(6):e287 23. Ha TS (2005) The role of tumor necrosis factor-alpha in HenochSchonlein purpura. Pediatr Nephrol 20(2):149–153 24. Yang YH, Lai HJ, Huang CM, Wang LC, Lin YT, Chiang BL (2004) Sera from children with active Henoch-Schonlein purpura can enhance the production of interleukin 8 by human umbilical venous endothelial cells. Ann Rheum Dis 63(11):1511–1513
ORIGINAL ARTICLE
Evaluation of serum procalcitonin and C-reactive protein levels as biomarkers of Henoch-Schönlein purpura in pediatric patients Xu Teng & Yang Wang & Nan Lin & Mei Sun & Jie Wu
Received: 10 February 2014 / Revised: 27 August 2014 / Accepted: 3 September 2014 # International League of Associations for Rheumatology (ILAR) 2014
Abstract Henoch-Schönlein purpura (HSP) is a vasculitic disorder resulting from autoinflammatory-mediated tissue injury. Procalcitonin (PCT) and C-reactive protein (CRP) are two biomarkers of the immune response that recognize bacterial infection and inflammation, respectively. This study tested whether levels of PCT and CRP were associated with selected clinical features, disease severity, and organ damage in HSP. Eighty-nine pediatric patients with HSP were analyzed for clinical manifestations and organ damage. Serum CRP, PCT, and occult blood in the urine and stool (prior to steroid therapy) were measured. Disease severity was classified according to previously established clinical classifications. Sixty patients (67.4 %) had a low clinical score (LCS) of 0.05
Group B
u value p
higher PCT levels in group D patients (group D: median= 0.09, range=0.05–1.02 vs. group C: median=0.05, range= 0.05–0.32 ng/ml; u=2.849). We observed no difference in CRP levels between groups C and D, respectively (group C: median=4.66, range=1.00–144.00 vs. group D: median= 9.44, range=1.06–124.00 mg/l; u=1.783) (Table 5). We observed a significant positive correlation between the serum concentrations of PCT and CRP in all patients examined (r= 0.721, p=0.002).
Discussion In this study, we examined whether PCT and CRP levels could serve as effective biomarkers to identify HSP disease severity in pediatric patients. Overall, the serum PCT levels in HSP patients were within ranges of localized inflammation or infection (0.5 ng/ml) from this underlying autoimmune disease. Serum PCT levels were higher in patients with GI bleeds (group D) than in cases without alimentary tract hemorrhage (group C). The observed increase in PCT levels (>0.05 ng/ml) in HSP patients with a GI bleed may reflect a low-grade, nonspecific but systemic inflammatory response that occurs as a result of the disease. Because patients with alimentary tract hemorrhage have severe mucosal barrier injuries, the presence of a GI bleed may directly stimulate PCT synthesis. It is currently unclear whether the increased circulating PCT in HSP is merely an epiphenomenon or the direct consequence of HSP pathogenesis. In this study, we have shown that serum CRP levels were not an indicator of disease severity in HSP patients, despite the fact that changes in CRP concentration followed a similar pattern as the observed changes in PCT synthesis. In contrast to results presented by Makay et al. [6], our results showed that CRP levels were not associated with HSP GI bleeding. Elevated CRP likely serves as a non-specific marker of inflammatory activity. Changes in serum CRP reflected a uniform response after inflammatory impairment without any significant association with damage or severity. Because we are pediatric gastroenterologists, patients admitted to our
department have GI manifestations and thus, bias our research towards GI involvement. Given the retrospective nature of this study, a GI bias was unavoidable and represents a limitation of our study. As we previously noted, nephritic syndrome is one of the predominant manifestations of pediatric HSP, which can ultimately lead to onset of renal insufficiency. Because only five patients presented with nephritic syndrome in this study, we did not analyze the levels of PCT and CRP. In the future, we plan to conduct a multicenter study to avoid the bias. Acknowledgments We thank Medjaden Bioscience Limited for assisting in the preparation of this manuscript. Disclosures None.
References 1. Gardner-Medwin JM, Dolezalova P, Cummins C, Southwood TR (2002) Incidence of Henoch-Schonlein purpura, Kawasaki disease, and rare vasculitides in children of different ethnic origins. Lancet 360(9341):1197–1202 2. Bressan S, Gomez B, Mintegi S, Da Dalt L, Blazquez D, Olaciregui I, de la Torre M, Palacios M, Berlese P, Ruano A (2012) Diagnostic performance of the lab-score in predicting severe and invasive bacterial infections in well-appearing young febrile infants. Pediatr Infect Dis J 31(12):1239–1244 3. Becker KL, Snider R, Nylen ES (2008) Procalcitonin assay in systemic inflammation, infection, and sepsis: clinical utility and limitations. Crit Care Med 36(3):941–952 4. Schützle H, Forster J, Superti-Furga A, Berner R (2009) Is serum procalcitonin a reliable diagnostic marker in children with acute respiratory tract infections? A retrospective analysis. Eur J Pediatr 168(9):1117–1124 5. Cevey-Macherel M, Galetto-Lacour A, Gervaix A, Siegrist CA, Bille J, Bescher-Ninet B, Kaiser L, Krahenbuhl JD, Gehri M (2009) Etiology of community-acquired pneumonia in hospitalized children based on WHO clinical guidelines. Eur J Pediatr 168(12):1429–1436 6. Makay B, Turkyilmaz Z, Duman M, Unsal E (2009) Mean platelet volume in Henoch-Schonlein purpura: relationship to gastrointestinal bleeding. Clin Rheumatol 28(10):1225–1228 7. Delevaux I, Andre M, Colombier M, Albuisson E, Meylheuc F, Begue RJ, Piette JC, Aumaitre O (2003) Can procalcitonin measurement help in differentiating between bacterial infection and other kinds of inflammatory processes? Ann Rheum Dis 62(4):337–340 8. Volanakis JE (2001) Human C-reactive protein: expression, structure, and function. Mol Immunol 38(2–3):189–197 9. Kasperska-Zajac A, Sztylc J, Machura E, Jop G (2011) Plasma IL-6 concentration correlates with clinical disease activity and serum Creactive protein concentration in chronic urticaria patients. Clin Exp Allergy 41(10):1386–1391 10. Ozen S, Ruperto N, Dillon MJ, Bagga A, Barron K, Davin JC, Kawasaki T, Lindsley C, Petty RE, Prieur AM, Ravelli A, Woo P (2006) EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides. Ann Rheum Dis 65(7):936–941 11. De Mattia D, Penza R, Giordano P, Del Vecchio GC, Aceto G, Altomare M, Schettini F (1995) von Willebrand factor and factor XIII in children with Henoch-Schonlein purpura. Pediatr Nephrol 9(5):603–605 12. Aikawa N, Fujishima S, Endo S, Sekine I, Kogawa K, Yamamoto Y, Kushimoto S, Yukioka H, Kato N, Totsuka K, Kikuchi K, Ikeda T,
Clin Rheumatol
13.
14.
15.
16.
17.
Ikeda K, Harada K, Satomura S (2005) Multicenter prospective study of procalcitonin as an indicator of sepsis. J Infect Chemother 11(3): 152–159 Eberhard OK, Haubitz M, Brunkhorst FM, Kliem V, Koch KM, Brunkhorst R (1997) Usefulness of procalcitonin for differentiation between activity of systemic autoimmune disease (systemic lupus erythematosus/systemic antineutrophil cytoplasmic antibodyassociated vasculitis) and invasive bacterial infection. Arthritis Rheum 40(7):1250–1256 Maier M, Wutzler S, Lehnert M, Szermutzky M, Wyen H, Bingold T, Henrich D, Walcher F, Marzi I (2009) Serum procalcitonin levels in patients with multiple injuries including visceral trauma. J Trauma 66(1):243–249 Lanoix JP, Bourgeois AM, Schmidt J, Desblache J, Salle V, Smail A, Maziere JC, Betsou F, Choukroun G, Duhaut P, Ducroix JP (2011) Serum procalcitonin does not differentiate between infection and disease flare in patients with systemic lupus erythematosus. Lupus 20(2):125–130 Meisner M, Adina H, Schmidt J (2006) Correlation of procalcitonin and C-reactive protein to inflammation, complications, and outcome during the intensive care unit course of multiple-trauma patients. Crit Care 10(1):R1 Okada Y, Minakami H, Tomomasa T, Kato M, Inoue Y, Kozawa K, Kimura H, Morikawa A (2004) Serum procalcitonin concentration in patients with Kawasaki disease. J Infect 48(2):199– 205
18. Yoshikawa H, Nomura Y, Masuda K, Koriya C, Arata M, Hazeki D, Yanagimoto K, Ueno K, Eguchi T, Kawano Y (2012) Serum procalcitonin value is useful for predicting severity of Kawasaki disease. Pediatr Infect Dis J 31(5):523–525 19. Chen DY, Chen YM, Ho WL, Chen HH, Shen GH, Lan JL (2009) Diagnostic value of procalcitonin for differentiation between bacterial infection and non-infectious inflammation in febrile patients with active adult-onset Still’s disease. Ann Rheum Dis 68(6):1074–1075 20. Uzzan B, Cohen R, Nicolas P, Cucherat M, Perret GY (2006) Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: a systematic review and meta-analysis. Crit Care Med 34(7):1996–2003 21. Russwurm S, Wiederhold M, Oberhoffer M, Stonans I, Zipfel PF, Reinhart K (1999) Molecular aspects and natural source of procalcitonin. Clin Chem Lab Med 37(8):789–797 22. Yang RZ, Lee MJ, Hu H, Pollin TI, Ryan AS, Nicklas BJ, Snitker S, Horenstein RB, Hull K, Goldberg NH, Goldberg AP, Shuldiner AR, Fried SK, Gong DW (2006) Acute-phase serum amyloid A: an inflammatory adipokine and potential link between obesity and its metabolic complications. PLoS Med 3(6):e287 23. Ha TS (2005) The role of tumor necrosis factor-alpha in HenochSchonlein purpura. Pediatr Nephrol 20(2):149–153 24. Yang YH, Lai HJ, Huang CM, Wang LC, Lin YT, Chiang BL (2004) Sera from children with active Henoch-Schonlein purpura can enhance the production of interleukin 8 by human umbilical venous endothelial cells. Ann Rheum Dis 63(11):1511–1513
