|Year : 2019 | Volume
| Issue : 2 | Page : 118-123
Serum level of midregional fragment of proadrenomedullin as an early sepsis marker in severely neutropenic patients with hematologic malignancies
Maggie M Fawzi MD 1, Alaa A Omran1, Botheina A Masood2
1 Department of Clinical Pathology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
2 Department of Pediatrics, Faculty of Medicine, Zagazig University, Zagazig, Egypt
|Date of Submission||03-Nov-2018|
|Date of Acceptance||10-Jan-2019|
|Date of Web Publication||15-Nov-2019|
Maggie M Fawzi
Department of Clinical Pathology, Faculty of Medicine, Zagazig University, Zagazig, 11435
Source of Support: None, Conflict of Interest: None
Background Early diagnosis of sepsis is vital for neutropenic patients with hematologic malignancies. However, finding an early marker is still a challenge.
Aim The aim of this study was to assess the utility of midregional fragment of proadrenomedullin (MR-proADM), compared with C-reactive protein (CRP), as an early marker for sepsis in severely neutropenic young patients with hematologic malignancies.
Patients and methods A total of 100 severely neutropenic patients with hematologic malignancies, 1–15 years old, admitted to the Pediatric Hematology and Oncology Unit (Zagazig University, Zagazig, Egypt), and developed fever, were randomly recruited. Blood samples, taken on the first day of each febrile episode, were cultured. In addition, on the first and second febrile days, serum CRP and serum MR-proADM levels were estimated.
Results Patients constituted two groups: a bacteremia/sepsis (BS) group of 36 patients with 47 febrile episodes, and pyrexia of unknown origin (PUO) group of 64 patients with 88 febrile episodes. CRP levels were not statistically different between the BS and PUO groups on either days 1 or 2. However, MR-proADM levels were significantly different between the two groups on both days. On receiver operating characteristic curve analysis, CRP was a poor differentiator between BS and PUO. Area under the receiver operating characteristic curve for CRP on days 1 and 2, were 0.509 and 0.529, respectively, whereas MR-proADM had higher discriminatory power from day 1 (area under the curve=0.939).
Conclusion This study adds to the recently increasing literature indicating that MR-proADM is a promising early marker for sepsis in severely neutropenic young patients with hematologic malignancies.
Keywords: biomarker, C-reactive protein, hematologic malignancies, proadrenomedullin, sepsis
|How to cite this article:|
Fawzi MM, Omran AA, Masood BA. Serum level of midregional fragment of proadrenomedullin as an early sepsis marker in severely neutropenic patients with hematologic malignancies. Egypt J Haematol 2019;44:118-23
|How to cite this URL:|
Fawzi MM, Omran AA, Masood BA. Serum level of midregional fragment of proadrenomedullin as an early sepsis marker in severely neutropenic patients with hematologic malignancies. Egypt J Haematol [serial online] 2019 [cited 2020 Jul 14];44:118-23. Available from: http://www.ehj.eg.net/text.asp?2019/44/2/118/271081
| Introduction|| |
Infection is a leading cause of death in children with hematologic malignancies . Susceptibility to infection is increased in such patients who may have to receive intensive chemotherapy, and consequently, they often develop immunosuppression and neutropenia. Early diagnosis of sepsis is vital for improved management outcome. However, this has remained a challenge. The vagueness of the initial clinical manifestations may cause a delay in accurate diagnosis. Elevated count of white blood cells has low diagnostic value, and obviously, this parameter cannot be applied to define sepsis in neutropenic patients under chemotherapy . Blood culture, which is considered the gold standard in diagnosing sepsis, is time consuming and associated with a high risk of false-negative rates . To date, a standardized test for the early detection of sepsis has not been generally approved, though multitudes of biomarkers have been examined .
Nonetheless, C-reactive protein (CRP) has remained for decades one of the most clinically used tests to help in the diagnosis of infection and extensively exploited tool in research as a comparator for other biomarkers . CRP is an acute-phase reactant produced primarily by the liver in response to inflammation. The test for CRP is widely available, inexpensive, easy to use, and reproducible, but it has also long been maintained that CRP may not be a good predictor of infection, especially in neutropenic patients . The arduous search for alternative markers for early diagnosis of sepsis, however, has never stopped.
Midregional proadrenomedullin (MR-proADM), a more stable fragment of its precursor adrenomedullin peptide, appears to be one of the most promising new biomarkers . Only a few studies have so far assessed the potential of MR-proADM to early diagnose infection in the critically ill , and some of these studies have even gone to the opposite extreme claiming that the performance of MR-proADM as a diagnostic marker is ‘very poor’ .
In this study, therefore, we aimed to assess the use of serum level of MR-proADM, compared with CRP, as an early marker for sepsis in severely neutropenic patients with hematologic malignancies.
| Patients and methods|| |
This study was performed, from March 2017 to August 2018, at the Pediatric Hematology and Oncology Unit and the Clinical Pathology Department, Zagazig University, Zagazig, Egypt. A random sample of 100 severely neutropenic patients with hematologic malignancies, in the age range of 1–15 years, who developed one or more episodes of fever during their hospital stay, was recruited for this prospective study. Severe neutropenia was considered to be present when absolute neutrophil count was less than or equal to 500 cells/mm3 and fever when oral temperature of at least 38.5°C was recorded once or when two or more temperature recordings of more than 38°C were obtained within a 6 h period. Detection of microbial growth in a blood culture bottle signified a case of bacteremia. Sepsis, the body’s response to infection, was clinically identified if fever was associated with tachycardia, tachypnea, or other manifestations of the systemic inflammatory response syndrome . Sepsis was considered severe if associated with acute failure of one or more organs. Severe sepsis could proceed to septic shock if complicated with acute circulatory failure.
Subsequent episodes of febrile neutropenia after more than 72 h of temperature below 38°C in the same patient were considered as separate episodes. Patients who had received antibiotics in the week before admission were excluded from the study.
Parents (or guardians of patients, as appropriate) had to provide written informed consent before study inclusion. Approval of the study protocol was also obtained from the Research Ethics Committee of the Faculty of Medicine, Zagazig University, before the study was initiated. All accepted recruits completed the study.
- Blood cultures: Within the first day of each febrile episode, and before starting the antibiotic treatment, two venous blood samples were aseptically drawn, from two different peripheral veins. If antibiotics were already started, then drawing of blood samples was scheduled to be before the next antibiotic dose time. Collected blood samples were processed by BacT/Alert and VITEK2 automated culture detection systems (bioMérieux, Marcy l’Etoile, France). Negative bottles were kept incubated for seven continuous days, subcultured, and gram stained before declaring them as sterile.
- In addition to the initial blood sample, drawn within the first day of a febrile episode, another blood sample, on the second day, was taken from each participant for further laboratory analysis. Samples were allowed to clot for 2 h at room temperature before serum was separated by centrifugation at 1000g for 15 min and stored at −70°C until analysis. At the time of analysis, frozen sera were thawed, mixed well, and immediately used.
- Measurement of CRP levels: high-sensitivity CRP levels were measured in serum using an immunoturbidimetric method on Roche/COBAS INTEGRA system 400 (Roche Diagnostics Corp., Indianapolis, Indiana, USA) as described elsewhere . The lower detection limit was 0.5 mg/l. The intra-assay coefficient of variability (CV) was less than 7.5%, and the interassay CV was less than 10.3%.
- Measurement of MR-proADM: commercially available kits for sandwich enzyme-linked immunosorbent assay method were used, as instructed by the manufacturer (DRG International Inc., Springfield, New Jersey, USA), to measure serum MR-proADM levels. The lower detection limit was 0.08 nmol/l. The intra-assay CV was less than 8%, and the interassay CV was less than 12.
- Routine laboratory analyses (e.g. complete blood count) were also performed using conventional laboratory methods. Further tests and imaging studies were also conducted as clinically indicated.
Continuous measures were expressed as the arithmetic mean±SD, whereas categorical measures were presented as numbers (%). For the continuous data, the Kolmogorov–Smirnov test was used to assess data normality, and the Student’s t-test or the Mann–Whitney nonparametric test, as appropriate, to compare two groups. Qualitative data were compared using the χ2-test. Receiver operating characteristic (ROC) curves were plotted for CRP and MR-proADM. Their optimal cutoff values as markers for infection (maximum sum of specificity and sensitivity), positive predictive value (PPV), and negative predictive value (NPV) were also calculated. An area under the receiver operating characteristic curve (AUC) of more than 0.9 was graded as ‘excellent’; 0.8–0.9: ‘very good’; 0.7–0.8: ‘good’; 0.6–0.7: ‘average’; and <0.6: ‘poor’. Statistical analysis was performed using the IBM SPSS Statistics for Windows software, version 21.0 (IBM Corp., Armonk, New York, USA). A two-tailed P value less than 0.05 was considered significant.
| Results|| |
Characteristics of patients
Of the 100 patients enrolled in this study, 36 patients were allocated to a bacteremia/sepsis (BS) group, having a positive blood culture and clinically identified sepsis. In this group, 47 febrile episodes were observed. Gram-positive organisms were recovered in 34 (72.3%) of these episodes, whereas gram-negative and mixed organisms were found in 13 (27.7%) episodes.
The rest of the participants (64 patients) had negative blood culture and constituted a second group, designated as ‘pyrexia of unknown origin’ (PUO) group. Patients in this group developed 88 febrile episodes. The characteristics of the two groups and the total sample are given in [Table 1]. All reported episodes of febrile neutropenia in the 100 (135 episodes) patients were further analyzed.
As shown in [Table 2], serum levels of CRP were not statistically different between BS and PUO groups on either days 1 or 2. However, concerning serum levels of MR-proADM, there were statistically significant differences between the two groups on both days 1 and 2.
|Table 2 Levels of C-reactive protein and midregional proadrenomedullin in the two study groups on days 1 and 2|
Click here to view
On ROC analysis, CRP was again poor differentiator between BS and PUO in febrile neutropenic patients with hematologic malignancies on day 1 (AUC=0.509), and on day 2 of fever (AUC=0.529). By contrast, as presented in [Figure 1] and [Table 3], the discriminatory power of MR-proADM was graded as ‘excellent’ (AUC=0.939) on day 1, and ‘very good’ (AUC=0.830) on day 2. The sensitivity, specificity, PPV, and NPV of CRP and MR-proADM are shown in [Table 4].
|Figure 1 Receiver operating characteristic (ROC) curve analysis of levels of C-reactive protein (CRP) and midregional fragment of proadrenomedullin (MR-proADM) on days 1 and 2.|
Click here to view
|Table 3 Areas under the curve for C-reactive protein and midregional proadrenomedullin in relation to the presence of bacteremia/sepsis on days 1 and 2|
Click here to view
|Table 4 Sensitivity, specificity, positive predictive values and negative predictive values for C-reactive protein and midregional proadrenomedullin on days 1 and 2|
Click here to view
| Discussion|| |
Biomarkers are increasingly recognized as the way to improve the diagnostic accuracy of early infections. One of the most promising novel biomarkers is the MR-proADM . This optimism is not shared by few investigators, who argue that the MR-proADM is a very poor diagnostic marker . By contrast, most previous studies of biomarkers, though involved other clinical scenarios, mainly pulmonary infections ,,,,,,,,, provide good support to our findings. We investigated a relatively large cohort of severely neutropenic patients with hematologic malignancies and found a significant rise in serum levels of MR-proADM, from the first day, in patients with positive blood cultures (BS group) compared with those with negative cultures (PUO group). We also examined our patients using the CRP, but we found that serum CRP levels were insignificantly higher in patients with negative, rather than positive, blood cultures. This failure to differentiate between the BS and PUO groups with CRP is consistent with the suggestion that CRP is a nonspecific test. It rises in both infective and noninfective conditions, such as drug allergy, autoimmune disease, and surgical trauma ,.In addition, we used ROC curve analysis to select the best cutoff values. As for serum MR-proADM on day 1, this was 2.4 nmol/l, which provided high sensitivity (91.6%), specificity (85.1%), PPV (83.3%), and NPV (92.4%). For serum CRP, the best cutoff value on day 1 was 94 mg/l, which had, in comparison with MR-proADM, much lower sensitivity (52.6%), specificity (70.9%), PPV (40.7%), and NPV (79.2%). Therefore, in line with most other studies , our data indicate that MR-proADM is a biomarker that could be relied upon for early detection or ruling out true infection in febrile neutropenic patients with hematologic malignancies. They also concede with other studies suggesting that the utility of serum CRP measurement is quite limited ,,,, particularly as an early detector of infection because its synthesis by the liver in response to infection is delayed .
Some limitations of this study have to be acknowledged. First, it is a single-center study. Therefore, the generalizability of the results may be limited. Second, the inclusion of a control group of healthy individuals or afebrile patients could have helped in the interpretation of the results. Third, serial measurements of MR-proADM and CRP and follow-up of patients for periods longer than just 2 days might have been more useful. Thus, although we investigated the role of MR-proADM and CRP as early markers for sepsis, we could not, because of the study design, evaluate the prognostic value of these markers.
| Conclusion|| |
This study adds to the recently increasing literature indicating that the novel biomarker MR-proADM has a promising role, and is more useful than CRP in assisting clinicians in early detection of bacteremia and sepsis in the severely neutropenic critically ill patients with hematologic malignancies.
Further prospective studies would be required to investigate the utility of these biomarkers as clinical bedside monitors for improved outcomes. Nonetheless, the progressively accumulating data about MR-proADM and other biomarkers should serve in the provision of informed next steps for research in Egypt.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bailey LC, Reilly AF, Rheingold SR. Infections in pediatric patients with hematologic malignancies. Semin Hematol
Penack O, Becker C, Buchheidt D, Christopeit M, Kiehl M, von Lilienfeld-Toal M et al.
Management of sepsis in neutropenic patients: 2014 updated guidelines from the Infectious Diseases Working Party of the German Society of Hematology and Medical Oncology (AGIHO). Ann Hematol
Sinha M, Jupe J, Mack H, Coleman TP, Lawrence SM, Fraley SI. Emerging technologies for molecular diagnosis of sepsis. Clin Microbiol Rev
Jensen JU, Lundgren JD. Novel biomarkers of infection in critically ill cancer patients: certainties and doubts. Crit Care Med
Kojic D, Siegler BH, Uhle F, Lichtenstern C, Nawroth PP, Weigand MA et al.
Are there new approaches for diagnosis, therapy guidance and outcome prediction of sepsis? World J Exp Med
Engel A, Mack E, Kern P, Kern WV. An analysis of interleukin-8, interleukin-6 and C-reactive protein serum concentrations to predict fever, gram-negative bacteremia and complicated infection in neutropenic cancer patients. Infection
Struck J, Tao C, Morgenthaler NG, Bergmann A. Identification of an adrenomedullin precursor fragment in plasma of sepsis patients. Peptides
Al Shuaibi M, Bahu RR, Chaftari AM, Al Wohoush I, Shomali W, Jiang Y et al.
Pro-adrenomedullin as a novel biomarker for predicting infections and response to antimicrobials in febrile patients with hematologic malignancies. Clin Infect Dis
Benito J, Luaces-Cubells C, Mintegi S, Astobiza E, Martinez-Indart L et al.
Lack of value of midregional pro-adrenomedullin and C-terminal pro-endothelin-1 for prediction of severe bacterial infections in infants with fever without a source. Eur J Pediatr
Goldstein B, Giroir B, Randolph A; International Consensus Conference on Pediatric Sepsis. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med
Fawzi MH, Fawzi MM, Fawzi MM, Said NS. C-reactive protein serum level in drug-free male Egyptian patients with schizophrenia. Psychiatry Res
Liu D, Xie L, Zhao H, Liu X, Cao J. Prognostic value of mid-regional pro-adrenomedullin (MR-proADM) in patients with community-acquired pneumonia: a systematic review and meta-analysis. BMC Infect Dis
Huang DT, Angus DC, Kellum JA, Pugh NA, Weissfeld LA, Struck J et al.
Midregional proadrenomedullin as a prognostic tool in community-acquired pneumonia. Chest
Courtais C, Kuster N, Dupuy AM, Folschveiller M, Jreige R, Bargnoux AS et al.
Proadrenomedullin, a useful tool for risk stratification in high Pneumonia Severity Index score community acquired pneumonia. Am J Emerg Med
Bello S, Lasierra AB, Mincholé E, Fandos S, Ruiz MA, Vera E et al.
Prognostic power of proadrenomedullin in community-acquired pneumonia is independent of aetiology. Eur Respir J
Gordo-Remartínez S, Calderón-Moreno M, Fernández-Herranz J, Castuera-Gil A, Gallego-Alonso-Colmenares M, Puertas-López C et al.
Usefulness of midregional proadrenomedullin to predict poor outcome in patients with community acquired pneumonia. PLoS ONE
España PP, Capelastegui A, Mar C, Bilbao A, Quintana JM, Diez R et al.
Performance of pro-adrenomedullin for identifying adverse outcomes in community-acquired pneumonia. J Infect
Renaud B, Schuetz P, Claessens YE, Labarère J, Albrich W, Mueller B. Proadrenomedullin improves risk of early admission to ICU score for predicting early severe community-acquired pneumonia. Chest
Haaf P, Twerenbold R, Reichlin T, Faoro J, Reiter M, Meune C et al.
Mid-regional pro-adrenomedullin in the early evaluation of acute chest pain patients. Int J Cardiol
Korkmaz MF, Güzel A, Açıkgöz M, Okuyucu A, Alaçam H. Reliability of pro-adrenomedullin and interleukin 1β in predicting severity of community-acquired pneumonia in pediatric patients. Ann Clin Lab Sci
Scherer MA, Neumaier M, von Gumppenberg S. C-reactive protein in patients who had operative fracture treatment. Clin Orthop Relat Res
Vincent JL, Donadello K, Schmit X. Biomarkers in the critically ill patient: C-reactive protein. Crit Care Clin
Debiane L, Hachem RY, Al Wohoush I, Shomali W, Bahu RR, Jiang Y et al.
The utility of proadrenomedullin and procalcitonin in comparison to C-reactive protein as predictors of sepsis and bloodstream infections in critically ill patients with cancer. Crit Care Med
Luzzani A, Polati E, Dorizzi R, Rungatscher A, Pavan R, Merlini A. Comparison of procalcitonin and C-reactive protein as markers of sepsis. Crit Care Med
Rey C, Los Arcos M, Concha A, Medina A, Prieto S, Martinez P et al.
Procalcitonin and C-reactive protein as markers of systemic inflammatory response syndrome severity in critically ill children. Intensive Care Med
Fioretto JR, Martin JG, Kurokawa CS, Carpi MF, Bonatto RC, de Moraes MA et al.
Comparison between procalcitonin and C-reactive protein for early diagnosis of children with sepsis or septic shock. Inflamm Res
Hofer N, Zacharias E, Müller W, Resch B. An update on the use of C-reactive protein in early-onset neonatal sepsis: current insights and new tasks. Neonatology
[Table 1], [Table 2], [Table 3], [Table 4]