Comparison of the Power of Procalcitonin and C-Reactive Protein to Discriminate between Different Aetiologies of Fever in Prolonged Profound Neutropenia: A Single-Centre Prospective Observational Study
1 Department of Haematology, Antwerp University Hospital, Edegem, Belgium.
2 Department of Clinical Biology, Antwerp University Hospital, Edegem, Belgium.
3 Clinical Trial Center (CTC), Clinical Research Center (CRC) Antwerp, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.
4 Vaccine & Infectious Disease Institute, Faculty of Medicine & Health Sciences, University of Antwerp, Antwerp, Belgium.
5 StatUa, Center for Statistics, University of Antwerp, Edegem, Belgium.
Received: November 19, 2018
Accepted: February 1, 2019
Mediterr J Hematol Infect Dis 2019, 11(1): e2019023 DOI 10.4084/MJHID.2019.023
| This is an Open Access article distributed
under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
of fever in prolonged, profound neutropenia remains challenging with
many possible infectious and non-infectious causes. We investigated
whether procalcitonin (PCT) is superior to C-reactive protein (CRP) in
discriminating between different aetiologies of fever in this setting.
In clinical practice, C-reactive protein (CRP) is currently used in the decision-making process when treating patients with febrile neutropenia. However, it is part of the nonspecific acute-phase response to most forms of tissue damage, infection, inflammation and malignant neoplasia. Procalcitonin (PCT) is a 116-aminoacid precursor peptide for the hormone calcitonin expressed by the CALC1-gene. During infection, the combination of microbial products (e.g. lipopolysaccharides) and pro-inflammatory cytokines results in an up-regulation of the gene expression of the CALC1-gene and PCT is released from nearly all tissues and cell types in the body. PCT promptly increases within 6 to 12 hours upon stimulation and circulating PCT levels halve daily when the infection is controlled by the host immune system or antibiotic therapy.
Procalcitonin (PCT) has demonstrated superior diagnostic accuracy when compared to CRP as a biomarker of infection in non-haematological populations.[10-13] It has been used successfully in algorithms for antimicrobial therapy in acute respiratory infections and management of sepsis in intensive care units. In 2008 Sakr et al. reviewed the available literature on the use of PCT in febrile neutropenia, concluding that this biomarker may be helpful in differentiating infection and sepsis from non-infectious causes of fever. However, due to the heterogeneity of study populations, the specific value of PCT assessment in adults with prolonged, profound neutropenia following intensive chemotherapy remains uncertain.
With this study, we wanted to compare the evolution of CRP and PCT with daily measurements in a large cohort of patients with prolonged, profound neutropenia. This differs from older studies where PCT values were often tested at intervals of 3 to 5 days or daily only for a few days around a febrile episode. With this design, we hoped to find medications or clinical situations that affect CRP and PCT values differently. Furthermore, we aimed to clarify whether PCT has superior reliability in comparison to CRP in the clinical management of febrile patients in the setting of prolonged profound neutropenia.
Material and Methods
Data collection. Results of daily CRP and PCT measurements were recorded, as well as administration of drugs that could potentially influence their values such as corticosteroids, cytarabine, antithymocyte globulin and immunosuppressive therapy in case of allogeneic HSCT. CRP was measured daily by nephelometry using the Dimension Vista® 1500 System (Siemens Healthcare, Munich, Germany). PCT was measured daily using the Elecsys® BRAHMS PCT Assay on the Modular E170 instrument (Roche Diagnostics, Rotkreuz, Switzerland). This automated test is performed in human serum using the ECLIA (ElectroChemiLuminiscence ImmunoAssay) technique with a detection limit of 0.02 µg/L and an upper limit of normal (ULN) of 0.5 µg/L.
Definitions and infectious work-up. Febrile neutropenia was defined as an axillary temperature of ≥38.3°C on a single occasion or ≥38.0°C sustained over a 2 hour period during neutropenia defined as an absolute neutrophil count < 500/µL. A new febrile episode was defined as a relapsing fever after more than 72 hours of apyrexia (<38.0°C).
For each febrile episode, the initial diagnostic workup consisted of a thorough physical examination, one set of aerobic and anaerobic blood cultures drawn by phlebotomy and one set via each lumen of the central venous line, urine culture and chest X-ray. Blood cultures were obtained repeatedly during the first three fever spikes, galactomannan antigenemia was measured twice weekly, and additional specific investigations were performed according to the clinical presentation. When fever persisted for more than four days, the diagnostic reassessment included a thoraco-abdominal CT-scan and bronchoscopy with BAL in the presence of a lung infiltrate.
Febrile episodes were classified into four categories based on clinical and microbiological findings without any knowledge of the analysed PCT values: 1) microbiologically documented infection (MDI, i.e. proven microbial pathogen with or without microbiologically defined site of infection); 2) clinically documented infection (CDI, i.e. diagnosed site of infection without proven microbiologic pathogenesis); 3) proven or probable invasive fungal disease (IFD); 4) fever of unknown origin (FUO).[16,17]
Statistical analysis. All data were analysed using a statistical software package (IBM SPSS Statistics 23, Chicago, IL). Continuous variables were compared using the Mann-Whitney (2-group comparison) or Kruskall Wallis (multiple-group comparison) non-parametric tests. Categorical variables were compared with the X2 or Fischer’s exact test, as appropriate. A linear mixed model using R was performed to evaluate the effects of different variables on the values of CRP and PCT over time. A two-sided p-value of less than 0.05 was considered as statistically significant. The peak values of PCT and CRP were considered for analysis of their performance in distinguishing aetiologies of fever in receiver operating characteristic (ROC) curves and by calculation of sensitivity, specificity, positive & negative predictive values and efficiency. The best cut-off was defined on the basis of the highest calculated efficiency.
|Table 1. Characteristics of patients, neutropenic and febrile episodes.|
Comparison of PCT and CRP evolution during prolonged, profound neutropenia. In a first analysis, the individual curves of CRP and PCT evolution during the 93 hospitalisation periods were reviewed visually. In 31 out of 93 neutropenic episodes (33.3%) their pattern of evolution appeared similar, whereas in 61 neutropenic episodes (66.7%) their evolution was clearly different. CRP seemed to be a more volatile parameter, rising above its ULN (3 mg/L) during every single neutropenic episode. Its reactivity to stimuli was also quite pronounced with a median of 2 surges above 100 mg/L per neutropenic episode. In contrast, PCT did not rise above its ULN of 0.5 ng/mL in 50 out of 93 neutropenic episodes (53.8%).
The present study, to evaluate the influence of confounding factors on the evolution of CRP and PCT, utilises a linear mixed model fitting with the neutropenic episode as a random effect. The logarithm of the outcomes was modelled as residual assumptions are better met in this way. This model included the following parameters: temperature, white blood cell count (WBC), absolute neutrophil count (ANC), administration of ATG, corticosteroids, cytarabine, cyclosporine A, mycophenolate & methotrexate and presence of cytarabine-induced dermatitis or engraftment syndrome. We found that many of these factors had a statistically significant effect on both the CRP and PCT values. However, the only one with a clinically relevant large effect size was ATG: administration of ATG resulted in an 11-fold increase [95% CI (8.7, 15.1)] of the PCT value one day later versus only a 2-fold increase [95% CI (1.4, 2.9)] of the CRP value.
Comparison of PCT and CRP evolution during febrile episodes. Figure 1 and Table 2 show the kinetics of PCT & CRP for different aetiologies of febrile neutropenia.
|Figure 1. Kinetics of CRP and PCT for different aetiologies of febrile neutropenia.|
|Table 2. Kinetics of PCT and CRP for different etiologies of neutropenic fever (median/range).|
Initial diagnostic assessment. On the day of fever onset, no significant difference in PCT values was observed between the different categories (p=0.314). Nine FE presented with a PCT value ≥ 0.5 ng/mL: 2 MDI, 1 CDI, 4 FUO and 2 FUO with ATG. None of these FE was associated with severe clinical signs such as hypotension, hypoxia and the need for transfer to intensive care facilities. Thirteen FE, which were complicated by a severe clinical course, showed a median PCT value of 0.15 ng/mL (range 0.09 - 0.34 ng/mL) on the day of fever onset.
CRP values were significantly higher on the day of fever onset in patients suffering from IFD versus all other aetiologies (median 98,75 mg/L versus 28.8 mg/L, p=0.027). Thirteen FE presented with a CRP value ≥ 100 mg/L: 3 MDI, 1 CDI, 5 FUO and 4 IFD. Three of these FE ran a severe clinical course. Median CRP on the day of fever onset was 36.6 mg/L (range < 2.9 - 137 mg/L) in the thirteen FE complicated by a severe clinical course.
Diagnostic reassessment. Both PCT and CRP reached their peak value at a median of 2 days [95% CI (1,10) for PCT & 95% CI (1,7) for CRP respectively]. PCT values on day 2 were significantly higher in FUO after ATG versus all other aetiologies (median 2.72 ng/mL versus 0.21 ng/mL, p<0.001). In cases of MDI and IFD, median PCT values rose > 0.25 ng/mL on day 2. In contrast, in cases of CDI or FUO without ATG, they stayed lower. Thirteen FE that were complicated by a severe clinical course showed a median PCT value on day 2 of 0.35 ng/mL (range 0.09 - 7.67 ng/mL) versus 0.22 ng/mL (range 0.06 - 29.59 ng/mL) in all other uncomplicated cases (p=0.139).
CRP values on day 2 were significantly higher in IFD versus all other aetiologies (median 172 mg/L versus 78.4 mg/L, p=0.002). In cases of MDI, median CRP values rose > 100 mg/L on day 2. In contrast, in cases of CDI or FUO (with/without ATG), they stayed lower. Thirteen FE that were complicated by a severe clinical course showed a median CRP value on day 2 after onset of fever of 182 mg/L (range 75.4 - 276 mg/L) versus 59.5 mg/L (range 4.1 – 259 mg/L) in all other uncomplicated cases (p<0.001).
When looking at the 28 episodes of MDI, 15 were caused by gram-positive bacteraemia, eight by gram-negative bacteraemia and the remaining five by urinary tract infection and viral or bacterial pneumonia. The median values of CRP and PCT did not differ depending on the underlying cause of MDI or specific bacterial isolate.
Differential diagnosis between FUO and IFD. ROC curves were computed to see whether PCT and/or CRP were able to discriminate between FUO and IFD. Figure 2 demonstrates that the discriminatory power of CRP on day two after the onset of fever was superior to that of PCT. Table 3 shows the predictive value of CRP for IFD at different cut-offs. With the cut-off set at 200 mg/L, CRP on day 2 has a positive predictive value of 66.7% and a negative predictive value of 94.2% for the diagnosis of IFD versus FUO. This leads to an efficiency of 92%.
|Figure 2. ROC curves.|
|Table 3. Predictive value of CRP on day 2 after onset of fever for IFD.|
On the day of fever onset, both CRP and PCT were not able to differentiate between the aetiologies of febrile episodes nor were they able to predict the severity of the clinical picture (including hypotension, hypoxia and the need for transfer to intensive care facilities). As such, the decision whether or not to start antibiotics when febrile neutropenia occurs cannot be delayed even with low values of CRP and/or PCT. However, after two days of febrile neutropenia, reassessment needs to be performed to decide on (dis)continuation of broad-spectrum antibiotics. In our study, median CRP values at this time were significantly higher in the case of IFD as well as MDI in contrast to CDI and FUO where they stayed below 100 mg/L. The CRP value on day 2 was significantly higher in episodes of febrile neutropenia running a severe clinical course, whereas this was not the case for PCT. Median PCT values at this point were especially high in case of FUO with ATG, which confirms previous findings by Brodska et al. & Hambach et al.[18-19] In IFD and MDI they rose above 0.25 ng/mL, whereas they did not in case of CDI and FUO without ATG. However, these differences were not statistically significant, and PCT surpassed the threshold of 0.5 ng/mL only in 9 out of 23 FE (39.1%) caused by bacteraemia on day two after fever onset.
These findings contrast the results of three prior studies discussing the value and/or dynamics of PCT in this specific patient population. Gac et al. prospectively studied 29 patients with 39 instances of chemotherapy and found that all neutropenic episodes with bacteraemia reached a PCT value of 0.5 ng/mL at 15 days after the onset of chemotherapy. Robinson et al. prospectively studied 194 consecutive febrile episodes during 125 neutropenic episodes in 90 patients. They observed that a PCT threshold of 0.5 ng/mL on day two after the onset of fever allowed the best discrimination of severe infections from infections due to coagulase-negative staphylococci (CoNS), superficial infections or fever of unknown origin. Koivula et al. analysed 90 episodes of febrile neutropenia in 66 patients and concluded that an elevated level of PCT above 0.5 ng/mL within 24 hours after onset of fever was able to predict bacteraemia and Gram-negative bacteraemia with a sensitivity of 57% & 70% and a specificity of 81% & 77% respectively.
Contrasting results have also been reported in the setting of allogeneic HSCT, where studies by Pihush et al. and Koya et al. concluded that PCT has a superior discriminatory power for detection of systemic infection and can differentiate infection from other transplant-related complications such as GvHD despite steroid therapy. However, these results contradict older studies by Blijlevens et al., Hambach et al. and Ortega et al.[19,25-26] All three studies concluded that the diagnostic value of PCT was not superior to that of CRP in the detection of infections after allogeneic HSCT and did not facilitate the differential diagnosis of febrile episodes.
A possible explanation for these conflicting results could be the presence of severe neutropenia whereas peripheral blood mononuclear cells have been described as a major source for PCT release in sepsis. Some authors reported low sensitivity of PCT levels in patients with a WBC count < 1x109/L and previous studies confirmed a correlation of PCT with low neutrophil count.[26,28] However, we could not confirm this correlation in our dataset. Another possible confounding factor could be the fact that in many studies PCT samples were frozen and analysed in batch at a later time. In our study, we performed daily measurements on fresh samples as this would be the way one would eventually implement it into real life daily practice and decision making.
From a practical point of view, MDI and CDI are usually already diagnosed by day two based on clinical examination, chest X-ray and microbiological cultures. As such the most important differential diagnosis at this point concerns FUO versus IFD, coupled with the decision to discontinue antibiotics and/or initiate antifungal treatment. Current guidelines suggest diagnostics for IFD to be performed after four days of persistent febrile neutropenia. However, in our study, a CRP value above 200 mg/L showed a positive predictive value of 66.7% and a negative predictive value of 94.2% for the diagnosis of IFD versus FUO (when MDI and CDI were ruled out by diagnostic workup). A high CRP in the absence of a clear focus of infection might prompt earlier investigation for IFD, leading to earlier treatment initiation and lower mortality. Given the low numbers of IFD in our study, these findings should be confirmed in a larger patient population.
- Klastersky J. Management of fever in neutropenic
patients with different risks of complications. Clin Infect Dis.
2004;39:S32-7. https://doi.org/10.1086/383050 PMid:15250018
G, Micozzi A, Menichetti F, Martino P, Dionisi MS, Martinelli G, et al.
Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Infection
Program. Levofloxacin to prevent bacterial infection in patients with
cancer and neutropenia. N Engl J Med. 2005;353:977-87. https://doi.org/10.1056/NEJMoa044097 PMid:16148283
A, Jansens H, Goossens H, van de Velde AL, Schroyens WA, Berneman ZN,
et al. Clinical and microbiological impact of discontinuation of
fluoroquinolone prophylaxis in patients with prolonged profound
neutropenia. Eur J Haematol. 2014;93:302-8. https://doi.org/10.1111/ejh.12345 PMid:24750350
I, Kern W, Livermore D on behalf of ECIL-4, a joint venture of EBMT,
EORTC, ICHS and ESGICH of ESCMID. The role of antibiotic stewardship in
limiting antibacterial resistance in haematology patients.
Haematologica. 2013;98:1821-5. https://doi.org/10.3324/haematol.2013.091769 PMid:24323982 PMCid:PMC3856956
- Bhatt V, Viola G, Ferrajoli A. Invasive Fungal Infections in Acute Leukemia. Ther Adv Haematol. 2011;2:231-47. https://doi.org/10.1177/2040620711410098 PMid:23556092 PMCid:PMC3573411
MB, Baltz ML. Acute phase proteins with special reference to C-reactive
protein and related proteins (pentaxins) and serum amyloid A protein.
Adv Immunol. 1983;34:141-212. https://doi.org/10.1016/S0065-2776(08)60379-X
Moullec JM, Jullienne A, Chenais J, Lasmoles F, Guliana JM, Milhaud G,
et al. The complete sequence of human preprocalcitonin. FEBS Lett.
B, White JC, Nylén ES, Snider RH, Becker KL, Habener JF. Ubiquitous
expression of the calcitonin I gene in multiple tissues in response to
sepsis. J Clin Endocrinol Metab. 2001;86:396-404 https://doi.org/10.1210/jc.86.1.396
KL, Nylén ES, White JC, Müller B, Snider RH Jr. Procalcitonin and the
calcitonin gene family of peptides in inflammation, infection, and
sepsis: a journey from calcitonin back to its precursors. J Clin
Endocrinol Metab. 2004;89:1512-25. https://doi.org/10.1210/jc.2002-021444 PMid:15070906
L, Gauvin F, Amre DK, Saint-Louis P, Lacroix J. Serum procalcitonin and
C-reactive protein levels as markers of bacterial infection: a
systematic review and meta-analysis. Clin Infect Dis. 2004;39:206-17. https://doi.org/10.1086/421997 PMid:15307030
M, de Kruif MD, Duits AJ, Brandjes DP, van Gorp EC. The diagnostic role
of procalcitonin and other biomarkers in discriminating infectious from
noninfectious fever. J Infect. 2010;60:409-16. https://doi.org/10.1016/j.jinf.2010.03.016 PMid:20347867
- Gilbert DN. Use of plasma procalcitonin levels as an adjunct to clinical microbiology. J Clin Microbiol. 2010;48:2325-9. https://doi.org/10.1128/JCM.00655-10 PMid:20421436 PMCid:PMC2897488
- Reinhart K, Meisner M. Biomarkers in the critically ill patient: procalcitonin. Crit Care Clin. 2011;27:253-63. https://doi.org/10.1016/j.ccc.2011.01.002 PMid:21440200
Y, Sponholz C, Tuche F, Brunkhorst F, Reinhart K. The role of
procalcitonin in febrile neutropenic patients: review of the
literature. Infection. 2008;36:396-407. https://doi.org/10.1007/s15010-008-7374-y PMid:18759057
J, de Naurois J, Rolston K, Rapoport B, Maschmeyer G, Aapro M, et al.
On behalf of the ESMO Guidelines Committee. Management of febrile
neutropaenia: ESMO Clinical Practice Guidelines. Annals of Oncology.
2016; 27:v111-8. https://doi.org/10.1093/annonc/mdw325 PMid:27664247
From the Immunocompromised Host Society. The design, analysis, and
reporting of clinical trials on the empirical antibiotic management of
the neutropenic patient. Report of a consensus panel. J Infect Dis.
1990;161:397-401. https://doi.org/10.1093/infdis/161.3.397 PMid:2179421
Pauw B, Walsh T, Donnelly P, Stevens DA, Edwards JE, Calandra T, et al.
Revised Definitions of Invasive Fungal Disease from the European
Organization for Research and Treatment of Cancer/Invasive Fungal
Infections Cooperative Group and the National Institute of Allergy and
Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group.
Clin Infect Dis. 2008;46:1813-21. https://doi.org/10.1086/588660 PMid:18462102 PMCid:PMC2671227
H, Drabek T, Malickova K, Kazda A, Vitek A, Zima T, Markova M. Marked
increase of procalcitonin after the administration of anti-thymocyte
globulin in patients before hematopoietic stem cell transplantation
does not indicate sepsis: a prospective study. Crit Care
2009;13(2):R37. https://doi.org/10.1186/cc7749 PMid:19291300 PMCid:PMC2689473
L, Eder M, Dammann E, Schrauder A, Sykora KW, Dieterich C, et al.
Diagnostic value of procalcitonin serum levels in comparison with
C-reactive protein in allogeneic stem cell transplantation.
Haematologica. 2002;87:643-51. PMid:12031922
AC, Parienti JJ, Chantepie S, Fradin S, Le Coutour X, Leclercq R, et
al. Dynamics of procalcitonin and bacteremia in neutropenic adults with
acute myeloid leukemia. Leuk Res. 2011;35:1294-6. https://doi.org/10.1016/j.leukres.2011.05.035 PMid:21831426
JO, Lamoth F, Bally F, Knaup M, Calandra T, Marchetti O. Monitoring
procalcitonin in febrile neutropenia: what is its utility for initial
diagnosis of infection and reassessment in persistent fever? PLoS One.
2011;6:e18886. https://doi.org/10.1371/journal.pone.0018886 PMid:21541027 PMCid:PMC3081821
I, Hämäläinen S, Jantunen E, Pulkki K, Kuittinen T, Nousiainen T, et
al. Elevated procalcitonin predicts Gram-negative sepsis in
haematological patients with febrile neutropenia. Scand J Infect Dis.
2011;43:471-8. https://doi.org/10.3109/00365548.2011.554855 PMid:21299364
M, Pihusch R, Fraunberger P, Pihusch V, Andreesen R, Kolb HJ, et al.
Evaluation of C-reactive protein, interleukin-6, and procalcitonin
levels in allogeneic hematopoietic stem cell recipients. Eur J
Haematol. 2006;76:93-101. https://doi.org/10.1111/j.0902-4441.2005.00568.x PMid:16405429
J, Nannya Y, Ichikawa M, Kurokawa M. The clinical role of procalcitonin
in hematopoietic SCT. Bone Marrow Transplant. 2012;47:1326-31. https://doi.org/10.1038/bmt.2012.18 PMid:22343672
NM, Donnelly JP, Meis JF, De Keizer MH, De Pauw BE. Procalcitonin does
not discriminate infection from inflammation after allogeneic bone
marrow transplantation. Clin Diagn Lab Immunol. 2000;7:889-92. https://doi.org/10.1128/CDLI.7.6.889-892.2000
M, Rovira M, Filella X, Almela M, Puig de la Bellacasa J, Carreras E,
et al. Prospective evaluation of procalcitonin in adults with febrile
neutropenia after haematopoietic stem cell transplantation. Br J
Haematol. 2004;126:372-6. https://doi.org/10.1111/j.1365-2141.2004.05053.x PMid:15257709
M, Stonans I, Russwurm S, Stonane E, Vogelsang H, Junker U, et al.
Procalcitonin expression in human peripheral blood mononuclear cells
and its modulation by lipopolysaccharides and sepsis-related cytokines
in vitro. J Lab Clin Med 1999; 134:49-55. https://doi.org/10.1016/S0022-2143(99)90053-7
M, Hirber J, Lanthaler AI, Mayr O, Faes S, Peer E & Mitterer M.
Procalcitonin-reduced sensitivity and specificity in heavily leucopenic
and immunosuppressed patients. British Journal of Haematology 2001;
115:53-57. https://doi.org/10.1046/j.1365-2141.2001.03083.x PMid:11722409