Prognostic value of mid-regional pro-adrenomedullin (MR-proADM) in patients with community-acquired pneumonia: a systematic review and meta-analysis

Dan Liu, Lixin Xie, Haiyan Zhao, Xueyao Liu, Jie Cao, Dan Liu, Lixin Xie, Haiyan Zhao, Xueyao Liu, Jie Cao

Abstract

Background: The early identification of patients at risk of dying from community-acquired pneumonia (CAP) is critical for their treatment and for defining hospital resource consumption. Mid-regional pro-adrenomedullin (MR-proADM) has been extensively investigated for its prognostic value in CAP. However, the results are conflicting. The purpose of the present meta-analysis was to explore the diagnostic accuracy of MR-proADM for predicting mortality in patients suffering from CAP, particularly emergency department (ED) patients.

Method: We systematically searched the PubMed, Embase, Web of Knowledge and Cochrane databases. Studies were included if a 2 × 2 contingency table could be constructed based on both the MR-proADM level and the complications or mortality of patients diagnosed with CAP. The prognostic accuracy of MR-proADM in CAP was assessed using the bivariate meta-analysis model. We used the Q-test and I (2) index to evaluate heterogeneity.

Results: MR-proADM displayed moderate diagnostic accuracy for predicting complications in CAP, with an overall area under the SROC curve (AUC) of 0.74 (95 % CI: 0.70-0.78). Eight studies with a total of 4119 patients in the emergency department (ED) were included. An elevated MR-proADM level was associated with increased risk of death from CAP (RR 6.16, 95 % CI 4.71-8.06); the I (2) value was 0.0 %, and a fixed-effects model was used to pool RR. The pooled sensitivity and specificity were 0.74 (95 % CI: 0.67-0.79) and 0.73 (95 % CI: 0.70-0.77), respectively. The positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were 2.8 (95 % CI, 2.3-3.3) and 0.36 (95 % CI, 0.29-0.45), respectively. In addition, the diagnostic odds ratio (DOR) was 8 (95 % CI, 5-11), and the overall area under the SROC curve was 0.76 (95 % CI, 0.72-0.80).

Conclusions: Our study has demonstrated that MR-proADM is predictive of increased complications and higher mortality rates in patients suffering from CAP. Future studies are warranted to determine the prognostic accuracy of MR-proADM in conjunction with severity scores or other biomarkers and to determine an optimal cut-off level.

Keywords: CAP; MR-ProADM; Meta-analysis; Prognosis.

Figures

Fig. 1
Fig. 1
Flow chart of the study selection process
Fig. 2
Fig. 2
Forest plot of association of MR-proADM to predict mortality in CAP. The overall pooled RR was 6.16 (95 % CI, 4.71–8.06)
Fig. 3
Fig. 3
Forest plot of the sensitivity and specificity of MR-proADM to predict mortality in CAP. The pooled sensitivity and specificity were 0.74 (95 % CI: 0.67–0.79) and 0.73 (95 % CI: 0.70–0.77), respectively
Fig. 4
Fig. 4
Summary receiver operating characteristic (SROC) curve for the included studies. The numbers in the circle refer to the included studies; Line = regression; the overall area under the SROC curve was 0.76 (95 % CI, 0.72–0.80)
Fig. 5
Fig. 5
Univariate meta-regression and subgroup analyses (Sample size was significantly associated with the heterogeneity of SEN, whereas Consecutive, Sample size, Prevalence and Blinded were significantly associated with the heterogeneity of SPE)

References

    1. Mizgerd JP. Acute lower respiratory tract infection. N Engl J Med. 2008;358(7):716–27. doi: 10.1056/NEJMra074111.
    1. Kolditz M, Ewig S, Höffken G. Management-based risk prediction in community-acquired pneumonia by scores and biomarkers. Eur Respir J. 2013;41:974–84. doi: 10.1183/09031936.00104412.
    1. Ewig S, Bauer T, Richter K, Szenscenyi J, Heller G, Strauss R, Welte T. Prediction of in-hospital death from community-acquired pneumonia by varying CRB-age groups. Eur Respir J. 2013;41:917–22. doi: 10.1183/09031936.00065212.
    1. Hohenthal U, Hurme S, Helenius H, Heiro M, Meurman O, Nikoskelainen J, Kotilainen P. Utility of C-reactive protein in assessing the disease severity and complications of community-acquired pneumonia. Clin Microbiol Infect. 2009;15(11):1026–32. doi: 10.1111/j.1469-0691.2009.02856.x.
    1. van Vugt SF, Broekhuizen BD, Lammens C, Zuithoff NP, de Jong PA, Coenen S, Ieven M, Butler CC, Goossens H, Little P, Verheij TJ. Use of serum C reactive protein and procalcitonin concentrations in addition to symptoms and signs to predict pneumonia in patients presenting to primary care with acute cough: Diagnostic study. BMJ. 2013;346:f2450. doi: 10.1136/bmj.f2450.
    1. Povoa P, Coelho L, Almeida E, Fernandes A, Mealha R, Moreira P, Sabino H. Early identification of intensive care unit-acquired infections with daily monitoring of C-reactive protein: a prospective observational study. Crit Care. 2006;10(2):R63. doi: 10.1186/cc4892.
    1. Menendez R, Martínez R, Reyes S, Mensa J, Filella X, Marcos MA, Martínez A, Esquinas C, Ramirez P, Torres A. Biomarkers improve mortality prediction by prognostic scales in community-acquired pneumonia. Thorax. 2009;64(7):587–91. doi: 10.1136/thx.2008.105312.
    1. Ishimitsu T, Kojima M, Kangawa K, Hino J, Matsuoka H, Kitamura K, Eto T, Matsuo H. Genomic structure of human adrenomedullin gene. Biochem Biophys Res Commun. 1994;203(1):631–9. doi: 10.1006/bbrc.1994.2229.
    1. Linscheid P, Seboek D, Zulewski H, Keller U, Müller B. Autocrine/paracrine role of inflammation-mediated calcitonin gene-related peptide and adrenomedullin expression in human adipose tissue. Endocrinology. 2005;146(6):2699–708. doi: 10.1210/en.2004-1424.
    1. Hinson JP, Kapas S, Smith DM. Adrenomedullin, a multifunctional regulatory peptide. Endocr Rev. 2000;21(2):138–67.
    1. Eto T. A review of the biological properties and clinical implications of adrenomedullin and proadrenomedullin N-terminal 20 peptide (PAMP), hypotensive and vasodilating peptides. Peptides. 2001;22:1693–711. doi: 10.1016/S0196-9781(01)00513-7.
    1. Kitamura K, Sakata J, Kangawa K, Kojima M, Matsuo H, Eto T. Cloning and characterization of cDNA encoding a precursor for human adrenomedullin. Biochem Biophys Res Commun. 1993;194:720–5. doi: 10.1006/bbrc.1993.1881.
    1. Di Somma S, Magrini L, Travaglino F, Lalle I, Fiotti N, Cervellin G, Avanzi GC, Lupia E, Maisel A, Hein F, Wagner F, Lippi G. Opinion paper on innovative approach of biomarkers for infectious diseases and sepsis management in the emergency department. Clin Chem Lab Med. 2013;51(6):1167–75. doi: 10.1515/cclm-2012-0795.
    1. Struck J, Tao C, Morgenthaler NG, Bergmann A. Identification of an Adrenomedullin precursor fragment in plasma of sepsis patients. Peptides. 2004;25:1369–72. doi: 10.1016/j.peptides.2004.06.019.
    1. Schuetz P, Christ-Crain M, Morgenthaler NG, Struck J, Bergmann A, Müller B. Circulating precursor levels of endothelin-1 and adrenomedullin, two endothelium-derived, counteracting substances, in sepsis. Endothelium. 2007;14(6):345–51. doi: 10.1080/10623320701678326.
    1. Christ-Crain M, Morgenthaler NG, Struck J, Harbarth S, Bergmann A, Müller B. Mid-regional pro-adrenomedullin as a prognostic marker in sepsis: an observational study. Crit Care. 2005;9(6):R816–24. doi: 10.1186/cc3885.
    1. Schuetz P, Wolbers M, Christ-Crain M, Thomann R, Falconnier C, Widmer I, Neidert S, Fricker T, Blum C, Schild U, Morgenthaler NG, Schoenenberger R, Henzen C, Bregenzer T, Hoess C, Krause M, Bucher HC, Zimmerli W, Mueller B. Prohormones for prediction of adverse medical outcome in community-acquired pneumonia and lower respiratory tract infections. Crit Care. 2010;14(3):R106. doi: 10.1186/cc9055.
    1. Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, Coley CM, Marrie TJ, Kapoor WN. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med. 1997;336:243–50. doi: 10.1056/NEJM199701233360402.
    1. Yealy DM, Auble TE, Stone RA, Lave JR, Meehan TP, Graff LG, Fine JM, Obrosky DS, Mor MK, Whittle J, Fine MJ. Effect of increasing the intensity of implementing pneumonia guidelines: a randomized, controlled trial. Ann Intern Med. 2005;143:881–94. doi: 10.7326/0003-4819-143-12-200512200-00006.
    1. Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, Leeflang MM, Sterne JA, Bossuyt PM. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011;155(8):529–36. doi: 10.7326/0003-4819-155-8-201110180-00009.
    1. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88. doi: 10.1016/0197-2456(86)90046-2.
    1. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58. doi: 10.1002/sim.1186.
    1. Cucherat M, Boissel JP, Leizorovicz A, Haugh MC. EasyMA: a program for the meta-analysis of clinical trials. Comput Methods Programs Biomed. 1997;53:187–90. doi: 10.1016/S0169-2607(97)00016-3.
    1. Whiting P, Rutjes AW, Reitsma JB, Bossuyt PM, Kleijnen J. The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. J BMC Med Res Methodol. 2003;3:25. doi: 10.1186/1471-2288-3-25.
    1. Reitsma JB, Glas AS, Rutjes AW, Scholten RJ, Bossuyt PM, Zwinderman AH. Bivariate analysis of sensitivity and specificity produces informative summary measures in diagnostic reviews. J Clin Epidemiol. 2005;58:982–90. doi: 10.1016/j.jclinepi.2005.02.022.
    1. Moses LE, Shapiro D, Littenberg B. Combining independent studies of a diagnostic test into a summary ROC curve: data-analytic approaches and some additional considerations. Stat Med. 1993;12:1293–316. doi: 10.1002/sim.4780121403.
    1. Albrich, Dusemund F, Rüegger K, Christ-Crain M, Zimmerli W, Bregenzer T, Irani S, Buergi U, Reutlinger B, Mueller B, Schuetz P. Enhancement of CURB65 score with proadrenomedullin (CURB65-A) for outcome prediction in lower respiratory tract infections: derivation of a clinical algorithm. BMC Infect Dis. 2011;11:112. doi: 10.1186/1471-2334-11-112.
    1. Bello, Lasierra AB, Mincholé E, Fandos S, Ruiz MA, Vera E, de Pablo F, Ferrer M, Menendez R, Torres A. Prognostic power of proadrenomedullin in community-acquired pneumonia is independent of aetiology. Eur Respir J. 2012;39(5):1144–55. doi: 10.1183/09031936.00080411.
    1. Christ-Crain, Morgenthaler NG, Stolz D, Müller C, Bingisser R, Harbarth S, Tamm M, Struck J, Bergmann A, Müller B. Pro-adrenomedullin to predict severity and outcome in community-acquired pneumonia ISRCTN04176397. Crit Care. 2006;10(3):R96. doi: 10.1186/cc4955.
    1. Courtais, Kuster N, Dupuy AM, Folschveiller M, Jreige R, Bargnoux AS, Guiot J, Lefebvre S, Cristol JP, Sebbane M. Proadrenomedullin, a useful tool for risk stratification in high Pneumonia Severity Index score community acquired pneumonia. Am J Emerg Med. 2013;31(1):215–21. doi: 10.1016/j.ajem.2012.07.017.
    1. Huang DT, Angus DC, Kellum JA, Pugh NA, Weissfeld LA, Struck J, Delude RL, Rosengart MR, Yealy DM. Midregional proadrenomedullin as a prognostic tool in community-acquired pneumonia. Chest. 2009;136(3):823–31. doi: 10.1378/chest.08-1981.
    1. Kolditz, Halank M, Schulte-Hubbert B, Bergmann S, Albrecht S, Höffken G. Copeptin predicts clinical deterioration and persistent instability in community-acquired pneumonia. Respir Med. 2012;106(9):1320–8. doi: 10.1016/j.rmed.2012.06.008.
    1. Kruger, Ewig S, Giersdorf S, Hartmann O, Suttorp N, Welte T. Cardiovascular and inflammatory biomarkers to predict short- and long-term survival in community-acquired pneumonia: Results from the German Competence Network, CAPNETZ. Am J Respir Crit Care Med. 2010;182(11):1426–34. doi: 10.1164/rccm.201003-0415OC.
    1. Julian-Jimenez, Timón Zapata J, Laserna Mendieta EJ, Sicilia-Bravo I, Palomo-de Los Reyes MJ, Cabezas-Martínez A, Laín-Terés N, Estebaran-Martín J, Lozano-Ancín A, Cuena-Boy R. Diagnostic and prognostic power of biomarkers to improve the management of community acquired pneumonia in the emergency department. Enferm Infecc Microbiol Clin. 2014;32(4):225–35. doi: 10.1016/j.eimc.2013.04.015.
    1. Suberviola B, Castellanos-Ortega A, Llorca J, Ortiz F, Iglesias D, Prieto B. Prognostic value of proadrenomedullin in severe sepsis and septic shock patients with community-acquired pneumonia. Swiss Med Wkly. 2012;142:w13542.
    1. Lacoma A, Bas A, Tudela P, Giménez M, Mòdol JM, Pérez M, Ausina V, Dominguez J, Prat-Aymerich C. Correlation of inflammatory and cardiovascular biomarkers with pneumonia severity scores. Enferm Infecc Microbiol Clin. 2014;32(3):140–6. doi: 10.1016/j.eimc.2013.07.006.
    1. Urbietaa EB, Medinaa CM, Sáizb AC, Yandiolab Pedro Pablo Espana, Morentína IA, Vrotsouc K. C reactive protein, procalcitonin and proadrenomedullin in the outcome of hospitalized pneumonia patients. Revista del Laboratorio Clinico. 2011;4(1):23–9. doi: 10.1016/j.labcli.2010.11.008.
    1. Renaud B, Schuetz P, Claessens Y-E, Labarère J, Albrich W, Mueller B. Proadrenomedullin improves Risk of Early Admission to ICU score for predicting early severe community-acquired pneumonia. Chest. 2012;142(6):1447–54. doi: 10.1378/chest.11-2574.
    1. Morgenthaler NG, Struck J, Alonso C, Bergmann A. Measurement of midregional proadrenomedullin in plasma with an immunoluminometric assay. Clin Chem. 2005;51(10):1823–9. doi: 10.1373/clinchem.2005.051110.
    1. Mandell LA. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(Suppl 2):S27–72. doi: 10.1086/511159.
    1. Aronsky D. Assessing the quality of clinical data in a computer-based record for calculating the pneumonia severity index. J Am Med Inform Assoc. 2000;7:55–65. doi: 10.1136/jamia.2000.0070055.
    1. Loke YK. Value of severity scales in predicting mortality from community-acquired pneumonia: systematic review and meta-analysis. Thorax. 2010;65(10):884–90. doi: 10.1136/thx.2009.134072.
    1. Marrie TJ. Admission is not always necessary for patients with community-acquired pneumonia in risk classes IV and V diagnosed in the emergency room. Can Respir J. 2007;14(4):212–6. doi: 10.1155/2007/451417.
    1. Albrich WC. Biomarker-enhanced triage in respiratory infections: a proof-of-concept feasibility trial. Eur Respir J. 2013;42:1064–75. doi: 10.1183/09031936.00113612.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa