Accessible Requires Authentication Published by De Gruyter October 20, 2015

Evaluating the use of procalcitonin in an asymptomatic, HIV-infected antiretroviral therapy-naïve, South African cohort

Dineo V. Phatlhane, Hayley Ipp, Rajiv T. Erasmus and Annalise E. Zemlin

Abstract

Background: The chronic stage of human immunodeficiency virus (HIV) infection, although clinically asymptomatic, is characterized by activation of the immune system and persistent inflammation. Procalcitonin (PCT) has been studied in HIV infection as a marker of bacterial infection. Our aim was to assess the effect of persistent immune activation on PCT levels in asymptomatic treatment naïve HIV infected subjects.

Methods: This was a cross-sectional study of 68 asymptomatic antiretroviral therapy-naive HIV infected participants and 42 uninfected controls. Stored serum samples were used to measure: PCT, interleukin-6 (IL-6), lipopolysaccharide binding protein (LBP), high sensitivity C-reactive protein (hsCRP), immunoglobulin G (IgG) and albumin. PCT was correlated with markers of: disease progression (CD4 count and viral load), immune activation (CD 38 on CD8+ T cells, IgG and LBP), inflammation (IL-6, hsCRP and albumin).

Results: IL-6, IgG and CD8/38 were all significantly increased while albumin and CD4 counts were significantly lower in the HIV infected group. PCT levels were not significantly different between the two groups. There was no significant difference in LBP and hsCRP; however, their levels were increased in both groups. PCT correlated only with LBP (p=0.0001). IL-6 and LBP correlated positively with hsCRP and IgG. Albumin correlated inversely with IL-6 and viral load. Only IgG and CD8/38 correlated inversely with CD4 counts.

Conclusions: We demonstrated the activation of the innate (raised LBP), humoral (raised IgG) and cellular immune systems (increased CD8/38 T cells). Despite a state of persistent inflammation, PCT levels are not elevated in asymptomatic untreated HIV infection.


Corresponding author: Annalise E. Zemlin, MBChB, FCPath (SA) (Chem), MMed (Chem Path), National Health Laboratory Service (NHLS), Department of Chemical Pathology, University of Stellenbosch, Tygerberg Hospital, Cape Town, P.O. Box 19113, Tygerberg, 7505, South Africa, Phone: +27(21)9384254, Fax: +27(21)9384640, E-mail:

Acknowledgments

We wish to thank the patients and staff of the Emavundleni Prevention Center of the Desmond Tutu HIV Center Crossroads Cape Town for their participation. In addition, we would like to thank Michael McCaul of the Biostatistics Unit at Stellenbosch University for his help with the statistical analysis.

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: This research was supported by the following funding bodies: National Health Laboratory Services (NHLS) (Grant/Award Number: 94435). Research Trust, NHLS K-funding, and Harry Crossley Foundation.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

Ethical approval: The study was approved by University of Stellenbosch Ethics Committee (HREC S14/04/078) and performed according to the Declaration of Helsinki. All participants signed informed consent explained to them in their language of choice.

References

1. Appay V, Sauce D. Immune activation and inflammation in HIV-1 infection: causes and consequences. J Pathol 2008;214:231–41. Search in Google Scholar

2. Nasi M, Pinti M, Mussini C, Cossarizza A. Persistent inflammation in HIV infection: established concepts, new perspectives. Immunol Lett 2014;161:184–8. Search in Google Scholar

3. Ipp H, Zemlin A. The paradox of the immune response in HIV infection: when inflammation becomes harmful. Clin Chim Acta Int J Clin Chem 2013;416:96–9. Search in Google Scholar

4. Paiardini M, Frank I, Pandrea I, Apetrei C, Silvestri G. Mucosal immune dysfunction in AIDS pathogenesis. AIDS Rev 2008;10:36–46. Search in Google Scholar

5. De Milito A, Nilsson A, Titanji K, Thorstensson R, Reizenstein E, Narita M, et al. Mechanisms of hypergammaglobulinemia and impaired antigen-specific humoral immunity in HIV-1 infection. Blood 2004;103:2180–6. Search in Google Scholar

6. Ipp H, Zemlin AE, Erasmus RT, Glashoff RH. Role of inflammation in HIV-1 disease progression and prognosis. Crit Rev Clin Lab Sci 2014;51:98–111. Search in Google Scholar

7. Veazey R, Lackner A. The mucosal immune system and HIV-1 infection. AIDS Rev 2003;5:245–52. Search in Google Scholar

8. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006;12:1365–71. Search in Google Scholar

9. Anton PA, Elliott J, Poles MA, McGowan IM, Matud J, Hultin LE, et al. Enhanced levels of functional HIV-1 co-receptors on human mucosal T cells demonstrated using intestinal biopsy tissue. AIDS Lond Engl 2000;14:1761–5. Search in Google Scholar

10. Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, Beilman GJ, et al. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med 2004;200:749–59. Search in Google Scholar

11. Liu Z, Cumberland WG, Hultin LE, Prince HE, Detels R, Giorgi JV. Elevated CD38 antigen expression on CD8+ T cells is a stronger marker for the risk of chronic HIV disease progression to AIDS and death in the Multicenter AIDS Cohort Study than CD4+ cell count, soluble immune activation markers, or combinations of HLA-DR and CD38 expression. J Acquir Immune Defic Syndr Hum Retrovirol 1997;16:83–92. Search in Google Scholar

12. Giorgi JV, Hultin LE, McKeating JA, Johnson TD, Owens B, Jacobson LP, et al. Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J Infect Dis 1999;179:859–70. Search in Google Scholar

13. Froebel KS, Raab GM, D’Alessandro C, Armitage MP, MacKenzie KM, Struthers M, et al. A single measurement of CD38CD8 cells in HIV+, long-term surviving injecting drug users distinguishes those who will progress to AIDS from those who will remain stable. Clin Exp Immunol 2000;122:72–8. Search in Google Scholar

14. Hazenberg MD, Otto SA, van Benthem BH, Roos MT, Coutinho RA, Lange JM, et al. Persistent immune activation in HIV-1 infection is associated with progression to AIDS. AIDS Lond Engl 2003;17:1881–8. Search in Google Scholar

15. Deeks SG, Kitchen CM, Liu L, Guo H, Gascon R, Narvaez AB, et al. Immune activation set point during early HIV infection predicts subsequent CD4+. Blood 2004;104:942–7. Search in Google Scholar

16. Ipp H, Zemlin AE, Glashoff RH, van Wyk J, Vanker N, Reid T, et al. Serum adenosine deaminase and total immunoglobulin G correlate with markers of immune activation and inversely with CD4 counts in asymptomatic, treatment-naive HIV infection. J Clin Immunol 2013;33:605–12. Search in Google Scholar

17. De Milito A. B lymphocyte dysfunctions in HIV infection. Curr HIV Res 2004;2:11–21. Search in Google Scholar

18. Decrion AZ, Dichamp I, Varin A, Herbein G. HIV and inflammation. Curr HIV Res 2005;3:243–59. Search in Google Scholar

19. Leeansyah E, Malone DF, Anthony DD, Sandberg JK. Soluble biomarkers of HIV transmission, disease progression and comorbidities. Curr Opin HIV AIDS 2013;8:117–24. Search in Google Scholar

20. Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane HC, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med 2008;5:e203. doi:10.1371/journal.pmed.0050203. Search in Google Scholar

21. Eastburn A, Scherzer R, Zolopa AR, Benson C, Tracy R, Do T, et al. Association of low level viremia with inflammation and mortality in HIV-infected adults. PloS One 2011;6:e26320. Search in Google Scholar

22. El-Sadr WM, Lundgren JD, Neaton JD, Gordin F, Abrams D, Arduino RC, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006;355:2283–96. Search in Google Scholar

23. Boulware DR, Hullsiek KH, Puronen CE, Rupert A, Baker JV, French MA, et al. Higher levels of CRP, D-dimer, IL-6, and hyaluronic acid before initiation of antiretroviral therapy (ART) are associated with increased risk of AIDS or death. J Infect Dis 2011;203:1637–46. Search in Google Scholar

24. Prucha M, Bellingan G, Zazula R. Sepsis biomarkers. Clin Chim Acta Int J Clin Chem 2015;440:97–103. Search in Google Scholar

25. Mikula T, Lipowski D, Stańczak W. The serum concentration of procalcitonin (PCT) in various infections in HIV positive patients. HIV AIDS Rev 2008;7:5–9. Search in Google Scholar

26. Nijsten MW, Olinga P, The TH, de Vries EG, Koops HS, Groothuis GM, et al. Procalcitonin behaves as a fast responding acute phase protein in vivo and in vitro. Crit Care Med 2000;28:458–61. Search in Google Scholar

27. Ammori BJ, Becker KL, Kite P, Snider RH, Nylen ES, White JC, et al. Calcitonin precursors: early markers of gut barrier dysfunction in patients with acute pancreatitis. Pancreas 2003;27:239–43. Search in Google Scholar

28. Gerard Y, Hober D, Assicot M, Alfandari S, Ajana F, Bourez JM, et al. Procalcitonin as a marker of bacterial sepsis in patients infected with HIV-1. J Infect 1997;35:41–6. Search in Google Scholar

29. Schleicher GK, Herbert V, Brink A, Martin S, Maraj R, Galpin JS, et al. Procalcitonin and C-reactive protein levels in HIV-positive subjects with tuberculosis and pneumonia. Eur Respir J 2005;25:688–92. Search in Google Scholar

30. Nyamande K, Lalloo UG. Serum procalcitonin distinguishes CAP due to bacteria, Mycobacterium tuberculosis and PJP. Int J Tuberc Lung Dis 2006;10:510–5. Search in Google Scholar

31. Tokman S, Barnett CF, Jarlsberg LG, Taub PR, den Boon S, Davis JL, et al. Procalcitonin predicts mortality in HIV-infected Ugandan adults with lower respiratory tract infections. Respirol Carlton Vic 2014;19:382–8. Search in Google Scholar

32. Hoffmann C, Hoffmann P, Zimmermann M. Diagnostic testing for a high-grade inflammation: parameter dynamics and novel markers. Clin Chem Lab Med 2015;53:541–7. Search in Google Scholar

33. Zhydkov A, Christ-Crain M, Thomann R, Hoess C, Henzen C, Werner Z, et al. Utility of procalcitonin, C-reactive protein and white blood cells alone and in combination for the prediction of clinical outcomes in community-acquired pneumonia. Clin Chem Lab Med 2015;53:559–66. Search in Google Scholar

34. Plebani M, Fabbri LM. Procalcitonin-guided antibiotic therapy: a potentially effective and efficient strategy. Clin Chem Lab Med 2015;53:519–20. Search in Google Scholar

35. Schuetz P, Balk R, Briel M, Kutz A, Christ-Crain M, Stolz D, et al. Economic evaluation of procalcitonin-guided antibiotic therapy in acute respiratory infections: a US health system perspective. Clin Chem Lab Med 2015;53:583–92. Search in Google Scholar

36. Mikula T, Cianciara J, Wiercinska-Drapalo A. Is there any influence of immune deficit on procalcitonin results? Hum Immunol 2011;72:1194–7. Search in Google Scholar

37. Bipath P, Viljoen M, Levay PF. Levels of procalcitonin, C-reactive protein and neopterin in patients with advanced HIV-1 infection. South Afr J HIV Med 2012;13:78–82 Search in Google Scholar

38. Neuhaus J, Jacobs DR, Baker JV, Calmy A, Duprez D, La Rosa A, et al. Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection. J Infect Dis 2010;201:1788–95. Search in Google Scholar

39. Gruys E, Toussaint MJ, Niewold TA, Koopmans SJ. Acute phase reaction and acute phase proteins. J Zhejiang Univ Sci B 2005;6:1045–56. Search in Google Scholar

40. Cassol E, Malfeld S, Mahasha P, van der Merwe S, Cassol S, Seebregts C, et al. Persistent microbial translocation and immune activation in HIV-1-infected South Africans receiving combination antiretroviral therapy. J Infect Dis 2010;202:723–33. Search in Google Scholar

41. Redd AD, Dabitao D, Bream JH, Charvat B, Laeyendecker O, Kiwanuka N, et al. Microbial translocation, the innate cytokine response, and HIV-1 disease progression in Africa. Proc Natl Acad Sci USA 2009;106:6718–23. Search in Google Scholar

42. Glennie SJ, Nyirenda M, Williams NA, Heyderman RS. Do multiple concurrent infections in African children cause irreversible immunological damage? Immunology 2012;135:125–32. Search in Google Scholar

43. Moir S, Fauci AS. B cells in HIV infection and disease. Nat Rev Immunol 2009;9:235–45. Search in Google Scholar

44. Lugada ES, Mermin J, Asjo B, Kaharuza F, Downing R, Langeland N, et al. Immunoglobulin levels amongst persons with and without human immunodeficiency virus type 1 infection in Uganda and Norway. Scand J Immunol 2004;59:203–8. Search in Google Scholar

Received: 2015-6-12
Accepted: 2015-8-4
Published Online: 2015-10-20
Published in Print: 2016-3-1

©2016 by De Gruyter