UEF//eRepository
DSpace https://erepo.uef.fi
Rinnakkaistallenteet Terveystieteiden tiedekunta
2018
Interleukin-1 receptor antagonist as a biomarker of sepsis in neutropenic haematological patients
Intke, Carina
Wiley
Tieteelliset aikakauslehtiartikkelit
© John Wiley & Sons A/S All rights reserved
http://dx.doi.org/10.1111/ejh.13161
https://erepo.uef.fi/handle/123456789/7432
Downloaded from University of Eastern Finland's eRepository
Accepted Article
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as DR. AUNI JUUTILAINEN (Orcid ID : 0000-0003-0271-4368)
Article type : Original Article
Interleukin-1 receptor antagonist as a biomarker of sepsis in neutropenic haematological patients
Carina Intke1*, Sini Korpelainen2*,Sari Hämäläinen1, Matti Vänskä3, Irma Koivula1, Esa Jantunen1,2,4, Kari Pulkki5,6, Auni Juutilainen1,2†
*With equal contribution; †Corresponding author
Running title: IL-1Ra in febrile neutropenia
1 Department of Medicine, Kuopio University Hospital, Puijonlaaksontie 2, 70210 Kuopio, Finland
2 Institute of Clinical Medicine/Internal Medicine, University of Eastern Finland, Yliopistonranta 1, 70210 Kuopio, Finland
3 Department of Internal Medicine, Tampere University Hospital, Teiskontie 35, 33521 Tampere, Finland
4 Siun Sote – Hospital District of North Carelia, Tikkamäentie 16, 80210, Joensuu, Finland
5 Eastern Finland Laboratory Centre, Kuopio, Finland; PO POX 1700, 70211 Kuopio
6 Laboratory Division, Turku University Hospital, and Clinical Chemistry, Faculty of Medicine, University of Medicine, Kiinamyllynkatu 10, 20521, Turku, Finland
E-mail addresses of authors:
carinaintke@gmail.com; sinik@student.uef.fi; sari.hamalainen@kuh.fi; vanska.matti.j@
student.uta.fi; irma.koivula@kuh.fi; esa.jantunen@kuh.fi; kari.pulkki@utu.fi;
auni.juutilainen@kuh.fi
Accepted Article
Corresponding author:
Auni Juutilainen, MD, PhD, auni.juutilainen@kuh.fi; Mailing address: P.O.B. 100, 70029 KYS, Kuopio, Finland; Institute of Clinical Medicine/Internal Medicine and Department of Medicine, Kuopio University Hospital Kuopio, Finland; phone +358 17 7174827
Abstract
Objective: The study aim was to compare the performance of interleukin-1 receptor antagonist (IL- 1Ra) to C-reactive protein (CRP) and procalcitonin (PCT) in early prediction of the clinical course of febrile neutropenia.
Methods: The study population consisted of 86 consecutive patients with febrile neutropenia who received intensive chemotherapy for haematological malignancy between November 2009 and November 2012 at the adult haematology ward of Kuopio University Hospital. Twenty-three (27%) patients had acute myeloid leukemia and 63 (73%) patients were autologous stem cell transplant recipients. IL-1Ra, CRP and procalcitonin were measured at the onset of fever (d0), on day 1 (d1) and on day 2 (d2).
Results: Eight patients developed severe sepsis, including three patients with septic shock. Eighteen patients had bacteremia. After the onset of febrile neutropenia Youden´s indices (with their 95%
confidence intervals) to identify severe sepsis were for IL-1Ra on d0 0.57 (0.20-0.71) and on d1 0.65 (0.28-0.78), for CRP on d0 0.41 (0.04-0.61) and on d1 0.47 (0.11-0.67) and for PCT on d0 0.39 (0.05- 0.66) and on d1 0.52 (0.18-0.76).
Conclusions: In haematological patients IL-1Ra has a comparable capacity with CRP and PCT to predict severe sepsis at the early stages of febrile neutropenia.
Keywords: biomarkers of sepsis; febrile neutropenia; haematological patients; interleukin-1 receptor antagonist; procalcitonin; severe sepsis
Accepted Article
INTRODUCTION
Patients receiving intensive chemotherapy for haematological malignancies have a considerable risk for febrile neutropenia and severe sepsis (1, 2). At worst, septic shock develops in a few hours, and the outcome may be fatal. The inflammatory and biological response to sepsis, including changes in the levels of inflammatory mediators, is distinct in patients with neutropenia (3). There is still an unmet need for fast and exact diagnostic and prognostic methods for this patient group.
Plasma interleukin-1 receptor antagonist (IL-1Ra) belongs to IL-1 cytokine family (4).It is an inhibitory anti-inflammatory cytokine that antagonizes the proinflammatory effects of IL-1 alpha and beta at the IL-1 receptor and follows the changes of e.g. IL-1α/β and IL-6 (5, 6). Several clinical implications of IL- 1Ra have been observed. IL-1Ra is an important natural anti-inflammatory protein for example in arthritis (7), colitis (8)and granulomatous pulmonary disease (9). In patients with cystic fibrosis IL-1Ra decreases inflammasome-mediated inflammation (10). The level of IL-1Ra has been found to increase in fulminant liver failure and in acute hepatitis (11) and it has been employed as a non- invasive inflammatory marker of non-alcoholic steatohepatitis (12). Moreover, IL-1Ra was associated with arterial stiffness (13), cardiovascular mortality (14), and with adverse changes in insulin sensitivity and with total mortality (15). Surviving patients in an intensive care unit (ICU) had very high IL-1Ra levels in plasma, but the non-survivors had lower levels of IL-1Ra (16). Although IL-1Ra is an anti-inflammatory cytokine, it increases rapidly enough even for robust clinical measurements.
Only limited and contradictory data are available on the prognostic role of IL-1Ra in haematological patients with febrile neutropenia (17). We postulated that IL1-Ra might function as an early biomarker for complicated course of febrile neutropenia after intensive chemotherapy in patients with haematological malignancies, and compared its predictive capacity to that of conventional biomarkers.
Accepted Article
PATIENTS AND METHODS
Patients
The study population consisted of adult in-patients at the adult haematology ward of Kuopio University Hospital between November 2009 and November 2012. The study included 86 patients with febrile neutropenia after intensive chemotherapy. The baseline characteristics are expressed in Table 1. All the patients included in the study gave their written informed consent.
Development of febrile neutropenia, severe sepsis and septic shock were registered prospectively.
Blood samples were collected at the onset of fever (day 0), and on the two following mornings (day 1 and day 2). The patients were carefully monitored until recovery of neutropenia (median 7 days, range 4-35 days), and daily examined for possible signs of severe sepsis. The time from the start of the fever to the possible development of severe sepsis was registered. Blood pressure, heart rate, body temperature, oxygen saturation and respiratory frequency were monitored by the nursing staff at the haematological ward.
The initial empirical antibiotic therapy for febrile neutropenia included a combination of intravenous ceftriaxone and tobramycin. Ceftazidime or piperacillin/tazobactam was used if a patient had acute myeloid leukaemia or lymphoma with autologous stem cell transplantation (ASCT). Vancomycin was considered only if there were signs of infection in the central venous catheter, or microbiological results suggested gram-positive bacteria. Antimicrobial therapy was re-evaluated according to microbiological findings. New blood cultures were taken if the fever persisted for 3–5 days. In the case of prolonged fever, caspofungin was combined to empirically cover a possible fungal infection.
Mucosal symptoms and signs of fungal infection were treated with oral fluconazole. Trimethoprim- sulfamethoxazole was used as Pneumocystis jiroveci prophylaxis for four months after ASCT. Non- Hodgkin lymphoma patients (NHL) receiving ASCT were treated with oral ciprofloxacin as a part of the clinical protocol (500 mg bid starting two days before ASCT). The prophylaxis continued until the recovery of neutropenia or introduction of focus-guided antimicrobial treatment.
Accepted Article
Febrile neutropenia was defined applying the criteria from Infectious Diseases Society of America (18). Neutropenia was defined as a neutrophil count less than 0.5 x 109/L or a predicted decrease to less than 0.5 x 109/L. Fever was defined as a single oral temperature of 38.3°C or higher, or a temperature of 38.0°C or higher for at least 1 h.
Sepsis and septic shock were defined according to the guidelines of the American College of Chest Physicians Consensus, valid during the study entry (19). Sepsis was defined as a syndrome in which systemic inflammatory response is present with infection diagnosed clinically or microbiologically, valid at the time of the inclusion of study patients. Septic shock was defined as a subtype of sepsis, if hypoperfusion (systolic arterial pressure was < 90 mmHg, a mean arterial pressure < 60 mmHg or a reduction in systolic blood pressure of < 40 mmHg from baseline) was present despite adequate volume resuscitation in the absence of other causes of hypotension. Severe sepsis was defined as a subset of sepsis with sepsis-induced organ dysfunction (19). The primary endpoint of the study was the development of severe sepsis. The secondary endpoint was the complicated course of febrile neutropenia with blood culture positivity, septic shock, or death for sepsis.
Methods
Blood cultures were processed using the automated blood culture system Bactec 9240 (Becton Dickinson, Sparks, MD, USA). The incubation episode was 7 d for both aerobic and anaerobic bottle and 42 d for MYCO F/Lytic bottles.
Blood samples for IL1-Ra, C-reactive protein (CRP) and procalcitonin (PCT) were collected at the onset of febrile neutropenia (d0) and in the following next two mornings (d1 and d2). Serum was separated and samples were stored frozen at -70 °C until analysed.
Measurement of concentrations of IL1-Ra was performed with R&D Systems Quantikine ELISA (R&D Systems, Inc., Minneapolis, MN, USA).The range of concentration of plasma IL1-Ra in this assay was 31.2 – 2000 ng/L. The sensitivity of the test was 18 ng/L. The intra-assay and inter-assay coefficient of variation (CV) were 4.9% and 9.0% (at 66.9 ng/L to 82.5 ng/L), and 3.7% and 6.7% (at 1,627 ng/L to 1,663 ng/L), respectively.
Accepted Article
The concentration of CRP was measured with a Konelab60i Clinical Chemistry Analyzer (Lab systems CLD, Konelab, Helsinki, Finland) or Cobas 6000-analyzer (Hitachi, Tokyo, Japan). The between-run variations varied from 2.3% to 4.3%. The upper reference limit of serum or plasma CRP of a healthy reference population is 5 mg/L.
Plasma PCT was analysed with Cobas 6000-analyzer (Hitachi, Tokyo, Japan). The sensitivity of the assay was 0.06 µg/L. The respective within- and between-assay CVs for PCT analyses were 1.4%
and 3.0% for 0.46 µg/L of PCT and 1.1% and 2.6% for 9.4 µg/L of PCT. The lower limit for PCT indicating a possible systemic infection is 0.5 µg/L. The upper reference limit of serum or plasma PCT of a healthy reference population is 0.05 µg/L.
Statistical analysis
Data analyses were conducted with SPSS version 23 for Windows (SPSS, Chicago, IL, USA).
Categorical variables were given as absolute counts or frequencies. Correlations between continuous variables were analysed by the Spearman’s correlation test. IL-1Ra, PCT and CRP were reported as medians and interquartile ranges (IQRs) according to the presence of complications of febrile neutropenia. The nonparametric Mann-Whitney U-test was used to evaluate the differences of continuous variables between the groups. Receiver operating characteristic curve (ROC) analysis was carried out to evaluate the prognostic ability of IL-1Ra, PCT and CRP, providing values for the area under the curve (AUC) with 95% confidence intervals (CI). The significance of differences between the AUCs for each day was tested according to Hanley and McNeil (20). Sensitivity, specificity, positive and negative predictive value were defined for each variable on each day.
Youden’s indices (sensitivity + specificity - 1) were used when defining the optimal cut-off value for IL- 1Ra, PCT and CRP on each study day from day 0 to day 2. The confidence intervals for Youden’s indicis were calculated according to Shan (21). Youden’s index was also used in the comparison of diagnostic properties of IL-1Ra, PCT and CRP. A P-value of less than 0.05 was considered significant.
Accepted Article
Ethical approval: This study is conducted according to the principles expressed in the Declaration of Helsinki and was approved by Ethical Board of North Savo Hospital District (100/2006).
RESULTS
Of the 86 patients with febrile neutropenia, 18 patients (21%) had a positive blood culture finding.
Gram-negative bacteremia was found in three patients (17 % out of all positive blood culture findings) and Gram-positive bacteremia in 14 patients (78%, respectively). One patient had Candida krusei fungemia, which was the only positive fungal culture found. Another patient had a radiologically suspected fungal pulmonary infection with negative fungal blood culture. The Gram-negative findings included Escherichia coli (n=1), Klebsiella oxytoca (n=1) and Pseudomonas aeruginosa (n=1). The Gram-positive findings included Enterococcus faecium (n=5), Staphylococcus epidermidis (n=3), Staphylococcus haemolyticus (n=2), Streptococcus mitis (n=2), Streptococcus salivarius (n=1) and Gemella morbillorum (n=1).
Eight patients (9%) developed severe sepsis with signs of organ failure and three patients developed septic shock (3%). Among the patients with severe sepsis (n=8), altogether six patients had a microbiologically proven infection. Their blood culture findings included Pseudomonas aeruginosa (n=1), Enterococcus faecium (n=3), Streptococcus mitis (n=1) and Staphylococcus epidermidis (n=1).
In two patients with severe sepsis the blood cultures remained negative. Of these patients all those with septic shock (n=3) had a microbiologically proven infection. Their blood culture findings included Enterococcus faecium (n=2) and Pseudomonas aeruginosa (n=1). Three patients died, one due to respiratory syncytial virus pneumonia and respiratory failure on d10 (IL-1Ra 504-545-573 ng/L from d0 to d2), one due to severe sepsis on d2 (IL-1Ra 5151-20000 ng/L from d0 to d1) and one due to septic complications on d12 (IL-1Ra 1070-922-908 ng/L from d0 to d2). The median time from the start of the fever to the development of severe sepsis or septic shock was three days.
The results of the correlation analysis between IL-1Ra, CRP and PCT from d0 to d2, are shown in Supplemental Table 1. Statistically significant correlations were encountered between IL-1Ra and PCT on each day. On d0 and d1, the correlations between IL-1Ra with next day PCT were high,
Accepted Article
highest between IL-1Ra d1 with PCT d2. The highest correlation between IL-1Ra and CRP was observed between d1 IL-1Ra and d2 CRP. Overall, an earlier day IL-1Ra seems to correlate best with a later day PCT or CRP.
Results from the ROC curve analysis from d0 to d2 for IL-1Ra, CRP and PCT to predict severe sepsis are shown in Table 2. IL-1Ra was the only of the three biomarkers with a statistically significant AUC already on d0 (AUC 0.768, 95% CI 0.593 ‒ 0.944, P = 0.013). On d1 after the onset of febrile neutropenia IL-1Ra showed higher absolute AUC values for severe sepsis (AUC 0.822, 95% CI 0.631
‒ 1.00, P = 0.003) than CRP or PCT (Figure 1). When comparing the results of the ROC curve analysis from d0 to d2 between IL-1Ra and CRP and between IL-1Ra and PCT according Hanley and McNeil method, the differences did not quite reach statistical significance (Supplemental Table 2).
The results from the ROC curve analysis from d0 to d2 for IL-1Ra, CRP and PCT to predict blood culture positivity or severe sepsis (including septic shock or death from sepsis) are shown in Supplemental Table 3. IL-1Ra showed highest absolute AUC value on d0 (AUC 0.71, 95% CI 0.59 ‒ 0.83, P = 0.005), remaining statistically significant on d1.
The diagnostic characteristics including sensitivity, specificity, positive and negative predictive values for IL-1Ra, CRP and procalcitonin to predict severe sepsis on d0-d2 from the onset of febrile neutropenia are presented in Table 3. After the onset of febrile neutropenia Youden´s indices (with their 95% confidence intervals) to identify severe sepsis were for IL-1Ra on d0 0.57 (0.20-0.71) and on d1 0.65 (0.28-0.78), for CRP on d0 0.41 (0.04-0.61) and on d1 0.47 (0.11-0.67) and for PCT on d0 0.39 (0.05-0.66) and on d1 0.52 (0.18-0.76).
The means with standard errors according to the development of severe sepsis are depicted in Figure 2. It shows the peak value of IL-1Ra on d1 whereas the rise of CRP and PCT was less rapid.
Medians (IQRs) of IL1-Ra, CRP and PCT were compared by the development of severe sepsis (Supplemental Table 4). The patients developing severe sepsis had higher IL-1Ra levels than those without it on d0 and on d1. The d1 IL1-Ra median (IQR) was 3064 (552–9301) ng/L in severe sepsis compared to 256 (198-470) ng/L in patients without it. Significant differences according to the
Accepted Article
presence of severe sepsis were observed in the level of CRP on d1, and of PCT on d1 and d2. Of note, IL-1Ra was the only of these three markers that showed an early difference already on d0 between the patients with and without severe sepsis.
Statistically significant differences (higher IL-1Ra levels) were also observed in patients with positive vs. negative blood culture findings on d0 and d1 (Table 4). Respective differences in the levels of PCT were observed on d0, on d1 and on d2. As to CRP, the only slight statistically significant difference was observed on d1 (P = 0.039).
In the small group (n = 3) of patients who developed septic shock IL-1Ra levels were higher in comparison to the patients without septic shock (n = 83). The medians with interquartile ranges (IQR) of IL-1Ra (ng/L) on d0, d1, and d2 were 1070 (793-5151), 8667 (922-20000), and 3344 (908-5780) in patients with septic shock. The respective values in patients without septic shock were 263 (74-6203), 283 (90-9512), and 264 (75-11748), with P-values for differences 0.005, 0.003 and 0.032.
DISCUSSION
Our study group has previously investigated several biomarkers for predicting the development of febrile neutropenia to sepsis, but so far none of them has been accepted in routine clinical use apart from PCT and CRP (22-31). Rapid diagnostic tools are needed to single out patients at highest risk for complications at the first hours and days of febrile neutropenia. In this prospective study IL-1Ra was found to be a prompt biomarker in haematological patients with febrile neutropenia after intensive chemotherapy. It predicts the development of severe sepsis earlier than CRP or PCT. Its diagnostic capacity was best on d1 from the start of fever, and it showed predictiveness already on d0.
CRP is widely used to indicate infection. However, at the early stages, it reacts too slowly for prognostic use (22). An earlier study on patients with febrile neutropenia showed that CRP rises within 48-72 hours in neutropenic infection (32). Significant increase was observed on day 2 in patients who developed demonstrable infection such as bacterial or fungal infection with or without positive blood culture findings. This is in agreement with our results showing that the increase of CRP
Accepted Article
is quite slow and not observed until on day 2 from the start of febrile neutropenia, suggesting that the role of CRP as an early prognostic marker in this patient population is doubtful. Furthermore, it is non- specific for bacterial infections, mainly because of its capacity to increase also in other conditions such as tissue damage (33). PCT seems to be useful in the differentiation of sepsis from non- infectious causes in febrile neutropenia (34). To detect bacteraemia, culture methods are needed, but they are time-consuming and often give false negative results or the results may only indicate microbial contamination (35).
As in most previous studies, in the present study PCT had a better diagnostic capacity than CRP to predict complicated course of febrile neutropenia (29, 36). Meidani et al. (36) compared PCT and CRP in febrile neutropenic patients with haematological malignancies. Sensitivity and specificity in ROC curve analysis for patients who developed sepsis was higher for PCT (92.5% and 97.3%, respectively). In our study, an early peak in the concentration of PCT was not as distinct as in that of IL-1Ra in patients with febrile neutropenia and severe sepsis.
In 2004, a new biomarker sCD14-subtype (presepsin) was found. In several studies, presepsin seems to have a better sensitivity and specificity in the early diagnosis of sepsis compared to other markers, such as CRP and PCT (37). It is also suitable for assessment of the severity and the prognosis of sepsis (38). However, presepsin levels are affected by other conditions such as kidney dysfunction (39). The source of presepsin, CD14, a cell surface glycoprotein is expressed in innate immune response cells (40). It is unclear how neutropenia affects the level of presepsin, and there are only a few studies concerning presepsin as a biomarker for sepsis in patients with febrile neutropenia. So far the results have not been encouraging for clinical use (41, 42).
Not even the current guidelines (43) for clinical criteria of sepsis have helped to recognize patients with febrile neutropenia at risk for high mortality (44). In our previous study, the Quick Sequential Organ Failure Assessment (qSOFA) scoring showed very low sensitivity, as only one out of eight patients developing severe sepsis received 3 quick SOFA points predicting high risk for in-hospital mortality (28). The focus of the study was in observing even a slight change towards septic hemodynamics or multiple organ failure. The patient care took place at a haematological ward, not in
Accepted Article
an intensive care unit, and the treatment protocol was proactive, aiming at early recognition of sepsis by screening potentially septic patients who may benefit from early intervention. Therefore, we chose to keep in old definition for sepsis possibly with a better sensitivity but less specificity.
Although therapeutic use of IL1-Ra (anakinra) has been adopted in treating autoimmune rheumatoid arthritis (45), the treatment of sepsis with recombinant IL-1Ra has showed no benefit in most previous clinical trials in sepsis (46, 47). However, Shakoory et al. recently reported a significant improvement in survival of sepsis patients with features of macrophage activation syndrome after reanalysis of previous data from the phase III randomized recombinant IL1-Ra trial in patients with severe sepsis (48). Moreover, a recent retrospective analysis of randomized controlled trial showed that the initial plasma level of IL-1Ra predicted the effect of treatment with recombinant human IL-1Ra on 28-day mortality in sepsis: patients only with a higher baseline level of IL-1Ra had approximately 12%
mortality reduction (49). The authors state that early plasma IL-1Ra level may act as an enrichment factor to select patients who may benefit from treatment with human recombinant IL-1Ra.
Reilly et al. (3) reported similar levels of IL-1Ra in neutropenic and non-neutropenic patients with severe sepsis at admission to ICU. IL-1Ra medians were 1049 ng/L in 29 neutropenic patients and 1269 ng/L in 216 non-neutropenic patients, respectively. In 13 neutropenic patients with no exogenous granulocyte colony stimulating factor use, the median IL-1Ra level was 534 ng/L, which is a quite similar level observed in our neutropenic study population on d0. However, Reilly et al. did not report the IL-1Ra profile during the first days of febrile neutropenia. The concentrations of IL-1Ra from d0 to d2 in patients with febrile neutropenia seem to be available only in our present study revealing a peak concentration on d1. This finding represents a suitable time-frame for a clinically useful prognostic biomarker of febrile neutropenia.
The strengths of this study included homogenous patient group consisting of neutropenic haematological patients with a recent history of intensive chemotherapy, early and well scheduled sampling and prospective data collected for over three years. The main limitation of the study was the relatively small number of patients with septic shock or death. Even though the ROC curve analyses showed highest AUC values for IL-1Ra both on d0 and d1, statistically significant differences in
Accepted Article
comparison to CRP and PCT could not be shown between the AUCs, when tested separately for each day according to Hanley and Neil method (20). Furthermore, when comparing the Youden’s indices between IL-1Ra, CRP and PCT on d0-d1 for severe sepsis, IL-1Ra had the highest absolute values but the confidence intervals were crossing. However, in comparison to the other two biomarkers, the predictive ability of IL-1Ra was systematically highest on d0-d1, which is of major clinical importance. Polymorphism of IL-1 receptor antagonist gene was not measured. Such polymorphism has been suggested to influence not only the levels of plasma IL1-Ra, but also to the survival from severe sepsis or septic shock (50). Analysis on gene polymorphism of IL1-Ra and other central molecules of the innate immunity would expand the perspective of the biology of neutropenic sepsis.
In conclusion, close monitoring and early initiation of therapy are imperative in reducing morbidity and mortality of febrile neutropenic haematological patients at risk for severe sepsis. A biomarker recognizing complications early enough has been sought intensively. The requirements of such a biomarker include not only good diagnostic properties, but also a suitable time-frame for clinical purposes. In febrile neutropenia, IL-1Ra is a potential biomarker for severe sepsis fulfilling both of these requirements, and could therefore help to select those septic patients who benefit from early intensified treatment. Further and larger studies would be helpful to confirm these findings.
Acknowledgements: The authors acknowledge the technical assistance of Ms Raija Isomäki and Anu Holopainen, MSc. The study was financially supported by a State Research Funding (VTR) grant from the North Savo Hospital District.
Conflict of interest: The authors declare that they have no conflict of interest in relation to the work described.
Accepted Article
References
1. Hämäläinen S, Kuittinen T, Matinlauri I, Nousiainen T, Koivula I, Jantunen E. Severe sepsis in autologous stem cell transplant recipients: microbiological aetiology, risk factors and outcome. Scand J Infect Dis 2009, 41(1):14-20.
2. Hämäläinen S, Kuittinen T, Matinlauri I, Nousiainen T, Koivula I, Jantunen E.
Neutropenic fever and severe sepsis in adult acute myeloid leukemia (AML) patients receiving intensive chemotherapy: Causes and consequences. Leuk Lymphoma 2008, 49(3):495-501.
3. Reilly JP, Anderson BJ, Hudock KM, Dunn TG, Kazi A, Tommasini A, Charles D, Shashaty MG, Mikkelsen ME, Christie JD, Meyer NJ. Neutropenic sepsis is associated with distinct clinical and biological characteristics: a cohort study of severe sepsis. Crit Care 2016, 20(1):222.
4. Palomo J, Dietrich D, Martin P, Palmer G, Gabay C. The interleukin (IL)-1 cytokine family--Balance between agonists and antagonists in inflammatory diseases. Cytokine 2015, 76(1):25-37.
5. Arend WP, Guthridge CJ. Biological role of interleukin 1 receptor antagonist isoforms.
Ann Rheum Dis 2000, 59 Suppl 1:i60-64.
6. van Deuren M, van der Ven-Jongekrijg J, Vannier E, van Dalen R, Pesman G, Bartelink AK, Dinarello CA, van der Meer JW. The pattern of interleukin-1beta (IL- 1beta) and its modulating agents IL-1 receptor antagonist and IL-1 soluble receptor type II in acute meningococcal infections. Blood 1997, 90(3):1101-1108.
7. de Vries-Bouwstra JK, Goekoop-Ruiterman YP, Wesoly J, Hulsmans HJ, de Craen AJ, Breedveld FC, Dijkmans BA, Allaart CF, Huizinga TW. Ex vivo interleukin 1 receptor antagonist production on lipopolysaccharide stimulation is associated with rheumatoid arthritis and with joint damage. Ann Rheum Dis 2007, 66(8):1033-1037.
8. Andus T, Daig R, Vogl D, Aschenbrenner E, Lock G, Hollerbach S, Köllinger M, Schölmerich J, Gross V. Imbalance of the interleukin 1 system in colonic mucosa-- association with intestinal inflammation and interleukin 1 receptor antagonist [corrected] genotype 2. Gut 1997, 41(5):651-657.
9. Arend WP, Malyak M, Guthridge CJ, Gabay C. Interleukin-1 receptor antagonist: role in biology. Annu Rev Immunol 1998, 16:27-55.
10. Iannitti RG, Napolioni V, Oikonomou V, De Luca A, Galosi C, Pariano M, Massi- Benedetti C, Borghi M, Puccetti M, Lucidi V, Colombo C, Fiscarelli E, Lass-Flörl C,
Accepted Article
Majo F, Cariani L, Russo M, Porcaro L, Ricciotti G, Ellemunter H, Ratclif L, De Benedictis FM, Talesa VN, Dinarello CA, van de Veerdonk FL, Romani L. IL-1 receptor antagonist ameliorates inflammasome-dependent inflammation in murine and human cystic fibrosis. Nat Commun 2016, 7:10791.
11. Sekiyama KD, Yoshiba M, Thomson AW. Circulating proinflammatory cytokines (IL-1 beta, TNF-alpha, and IL-6) and IL-1 receptor antagonist (IL-1Ra) in fulminant hepatic failure and acute hepatitis. Clin Exp Immunol 1994, 98(1):71-77.
12. Pihlajamäki J, Kuulasmaa T, Kaminska D, Simonen M, Kärjä V, Grönlund S, Käkelä P, Pääkkonen M, Kainulainen S, Punnonen K, Kuusisto J, Gylling H, Laakso M. Serum interleukin 1 receptor antagonist as an independent marker of non-alcoholic steatohepatitis in humans. J Hepatol 2012, 56(3):663-670.
13. Arnold N, Gori T, Schnabel RB, Schulz A, Prochaska JH, Zeller T, Binder H, Pfeiffer N, Beutel M, Espinola-Klein C, Lackner KJ, Blankenberg S, Münzel T, Wild PS. Relation between arterial stiffness and markers of inflammation and hemostasis - data from the population-based Gutenberg Health Study. Sci Rep 2017, 7(1):6346.
14. Herder C, de Las Heras Gala T, Carstensen-Kirberg M, Huth C, Zierer A, Wahl S, Sudduth-Klinger J, Kuulasmaa K, Peretz D, Ligthart S, Bongaerts BWC, Dehghan A, Ikram MA, Jula A, Kee F, Pietilä A, Saarela O, Zeller T, Blankenberg S, Meisinger C, Peters A, Roden M, Salomaa V, Koenig W, Thorand B. Circulating levels of interleukin 1-receptor antagonist and risk of cardiovascular disease: meta-analysis of six population-based cohorts. Arterioscler Thromb Vasc Biol 2017, 37(6):1222-1227.
15. Fizelova M, Jauhiainen R, Kangas AJ, Soininen P, Ala-Korpela M, Kuusisto J, Laakso M, Stancáková A. Differential associations of inflammatory markers with insulin sensitivity and secretion: the prospective METSIM study. J Clin Endocrinol Metab 2017, 102(9):3600-3609.
16. Arnalich F, Garcia-Palomero E, López J, Jiménez M, Madero R, Renart J, Vázquez JJ, Montiel C. Predictive value of nuclear factor κB activity and plasma cytokine levels in patients with sepsis. Infect Immun 2000, 68(4):1942-1945.
17. Schönbohn H, Schuler M, Kolbe K, Peschel C, Huber C, Bemb W, Aulitzky WE.
Plasma levels of IL-1, TNF alpha, IL-6, IL-8, G-CSF, and IL1-RA during febrile neutropenia: results of a prospective study in patients undergoing chemotherapy for acute myelogenous leukemia. Ann Hematol 1995, 71(4):161-168.
18. Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T, Feld R, Pizzo PA, Rolston KV, Shenep JL, Young LS. 2002 guidelines for the use of antimicrobial
Accepted Article
19. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med 2003, 29(4):530-538.
20. Hanley JA, McNeil BJ. A method of comparing the areas under receiver operating characteristic curves derived from the same cases. Radiology 1983, 148(3):839-843.
21. Shan G. Improved confidence intervals for the Youden index. PLoS One 2015, 10(7):e0127272.
22. Hämäläinen S, Juutilainen A, Matinlauri I, Kuittinen T, Ruokonen E, Koivula I, Jantunen E. Serum vascular endothelial growth factor in adult haematological patients with neutropenic fever: a comparison with C-reactive protein. Eur J Haematol 2009, 83(3):251-257.
23. Hämäläinen S, Juutilainen A, Kuittinen T, Nousiainen T, Matinlauri I, Pulkki K, Koivula I, Jantunen E. Serum amino-terminal pro-brain natriuretic peptide in hematological patients with neutropenic fever: a prospective comparison with C-reactive protein. Leuk Lymphoma 2010, 51(6):1040-1046.
24. Juutilainen A, Hämäläinen S, Pulkki K, Kuittinen T, Nousiainen T, Jantunen E, Koivula I. Biomarkers for bacteremia and severe sepsis in hematological patients with neutropenic fever: multivariate logistic regression analysis and factor analysis. Leuk Lymphoma 2011, 52(12):2349-2355.
25. Juutilainen A, Vänskä M, Pulkki K, Hämäläinen S, Nousiainen T, Jantunen E, Koivula I.
Pentraxin 3 predicts complicated course of febrile neutropenia in haematological patients, but the decision level depends on the underlying malignancy. Eur J Haematol 2011, 87(5):441-447.
26. Vänskä M, Koivula I, Hämäläinen S, Pulkki K, Nousiainen T, Jantunen E, Juutilainen A.
High pentraxin 3 level predicts septic shock and bacteremia at the onset of febrile neutropenia after intensive chemotherapy of hematologic patients. Haematologica 2011, 96(9):1385-1389.
27. Purhonen AK, Vänskä M, Hämäläinen S, Pulkki K, Lehtikangas M, Kuittinen T, Nousiainen T, Koivula I, Jantunen E, Juutilainen A. Plasma copeptin in the assessment of febrile neutropenia. Peptides 2012, 36(1):129-132.
28. Korpelainen S, Intke C, Hämäläinen S, Jantunen E, Juutilainen A, Pulkki K. Soluble CD14 as a diagnostic and prognostic biomarker in hematological patients with febrile neutropenia. Dis Markers 2017, 2017:9805609.
Accepted Article
29. Vänskä M, Koivula I, Jantunen E, Hämäläinen S, Purhonen AK, Pulkki K, Juutilainen A.
IL-10 combined with procalcitonin improves early prediction of complications of febrile neutropenia in hematological patients. Cytokine 2012, 60(3):787-792.
30. Vänskä M, Purhonen AK, Koivula I, Jantunen E, Hämäläinen S, Pulkki K, Juutilainen A.
Soluble form of urokinase-type plasminogen activator receptor as a diagnostic and prognostic marker in hematological patients with neutropenic fever. Leuk Lymphoma 2014, 55(3):718-721.
31. Purhonen AK, Juutilainen A, Vänskä M, Lehtikangas M, Lakkisto P, Hämäläinen S, Koivula I, Jantunen E, Pulkki K. Human plasma cell-free DNA as a predictor of infectious complications of neutropenic fever in hematological patients. Infect Dis (Lond) 2015, 47(4):255-259.
32. Manian FA. A prospective study of daily measurement of C-reactive protein in serum of adults with neutropenia. Clin Infect Dis 1995, 21(1):114-121.
33. van der Velden WJ, Herbers AH, Feuth T, Schaap NP, Donnelly JP, Blijlevens NM.
Intestinal damage determines the inflammatory response and early complications in patients receiving conditioning for a stem cell transplantation. PLoS One 2010, 5(12):e15156.
34. Sakr Y, Sponholz C, Tuche F, Brunkhorst F, Reinhart K. The role of procalcitonin in febrile neutropenic patients: review of the literature. Infection 2008, 36(5):396-407.
35. Suberviola B, Márquez-López A, Castellanos-Ortega A, Fernandez-Mazarrasa C, Santibáñez M, Martinez LM. Microbiological diagnosis of sepsis: polymerase chain reaction system versus blood cultures. Am J Crit Care 2016, 25(1):68-75.
36. Meidani M, Khorvash F, Abolghasemi H, Jamali B. Procalcitonin and quantitative C- reactive protein role in the early diagnosis of sepsis in patients with febrile neutropenia.
South Asian J Cancer 2013, 2(4):216-219.
37. Zou Q, Wen W, Zhang XC: Presepsin as a novel sepsis biomarker. World J Emerg Med 2014, 5(1):16-19.
38. Endo S, Suzuki Y, Takahashi G, Shozushima T, Ishikura H, Murai A, Nishida T, Irie Y, Miura M, Iguchi H, Fukui Y, Tanaka K, Nojima T, Okamura Y. Presepsin as a powerful monitoring tool for the prognosis and treatment of sepsis: a multicenter prospective study. J Infect Chemother 2014, 20(1):30-34.
Accepted Article
39. Nagata T, Yasuda Y, Ando M, Abe T, Katsuno T, Kato S, Tsuboi N, Matsuo S, Maruyama S. Clinical impact of kidney function on presepsin levels. PLoS One 2015, 10(6):e0129159.
40. Koh H, Aimoto M, Katayama T, Hashiba M, Sato A, Kuno M, Makuuchi Y, Takakuwa T, Okamura H, Hirose A, Nakamae M, Hino M, Nakamae H. Diagnostic value of levels of presepsin (soluble CD14-subtype) in febrile neutropenia in patients with haematological disorders. J Infect Chemother 2016, 22(7):466-71.
41. Urbonas V, Eidukaitė A, Tamulienė I. The predictive value of soluble biomarkers (CD14 subtype, interleukin-2 receptor, human leucocyte antigen-G) and procalcitonin in the detection of bacteremia and sepsis in pediatric oncology patients with chemotherapy- induced febrile neutropenia. Cytokine 2013, 62(1):34-37.
42. Korpelainen S, Intke C, Hämäläinen S, Jantunen E, Juutilainen A, Pulkki K. Soluble CD14 as a diagnostic and prognostic biomarker in hematological patients with febrile Neutropenia. Dis Markers 2017:9805609. doi: 10.1155/2017/9805609.
43. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The third international consensus definitions for sepsis and septic shock (Sepsis- 3). JAMA 2016, 315(8):801-810.
44. Seymour CW, Liu VX, Iwashyna TJ, Brunkhorst FM, Rea TD, Scherag A, Rubenfeld G, Kahn JM, Shankar-Hari M, Singer M, Deutschman CS, Escobar GJ, Angus DC.
Assessment of clinical criteria for sepsis: for the third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016, 315(8):762-774.
45. Schiff MH. Role of interleukin 1 and interleukin 1 receptor antagonist in the mediation of rheumatoid arthritis. Ann Rheum Dis 2000, 59 Suppl 1:i103-108.
46. Fisher CJ, Jr., Slotman GJ, Opal SM, Pribble JP, Bone RC, Emmanuel G, Ng D, Bloedow DC, Catalano MA. Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial. Crit Care Med 1994, 22(1):12-21.
47. Opal SM, Fisher CJ, Jr., Dhainaut JF, Vincent JL, Brase R, Lowry SF, Sadoff JC, Slotman GJ, Levy H, Balk RA, Shelly MP, Pribble JP, LaBrecque JF, Lookabaugh J, Donovan H, Dubin H, Baughman R, Norman J, DeMaria E, Matzel K, Abraham E, Seneff M. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Crit Care Med 1997, 25(7):1115-1124.
Accepted Article
48. Shakoory B, Carcillo JA, Chatham WW, Amdur RL, Zhao H, Dinarello CA, Cron RQ, Opal SM. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial. Crit Care Med 2016, 44(2):275-281.
49. Meyer NJ, Reilly JP, Anderson BJ, Palakshappa JA, Jones TK, Dunn TG, Shashaty MGS, Feng R, Christie JD, Opal SM. Mortality benefit of recombinant human interleukin-1 receptor antagonist for sepsis varies by initial interleukin-1 receptor antagonist plasma concentration. Crit Care Med 2018, 46(1):21-28.
50. Arnalich F, López-Maderuelo D, Codoceo R, López J, Solis-Garrido LM, Capiscol C, Fernandez-Cápitan C, Madero R, Montiel C. Interleukin-1 receptor antagonist gene polymorphism and mortality in patients with severe sepsis. Clin Exp Immunol 2002, 127(2):331-336.
Accepted Article
Table 1 Baseline characteristics (N, %, min-max or SD)
Sex
Male 55 (64%)
Female 31 (36%)
Age
Median (min, max) 61 (18-70)
Mean (SD) 58 (10.2)
Over age of 60 years 48 (56%)
Absolute leukocyte count on day 0
Leukocyte count < 0.1 x 109/L 53 (62%)
Acute myeloid leukemia 23 (27%)
Autologous stem cell transplantation 63 (73%)
Non-Hodgkin lymphoma 41 (65%)
Multiple myeloma 19 (30%)
Hodgkin lymphoma 3 (5%)
Chemotherapy regimen
BEAM 41 (48%)
HD-MEL 19 (22%)
IdAraC-Ida 9 (10%)
IAT 7 (8%)
MEA 4 (5%)
Carmustine-thiotepa 3 (4%)
Mito-HDAraC 2 (2%)
HDAraC-Ida 1 (1%)
BEAM: carmustine, etoposide, cytarabine, and melphalan; HD-MEL: high-dose melphalan, IdAraC- Ida: intermediate-dose cytarabine, and idarubicin; IAT: idarubicin, cytarabine, and thioguanine; MEA:
mitoxantrone, etoposide, and cytarabine; Mito-HDAraC: mitoxantrone, and high-dose cytarabin;
HDAraC-Ida: high-dose cytarabine and idarubicin
Accepted Article
Table 2 Receiver operating characteristics curve (ROC) analysis of interleukin-1 receptor antagonist (IL-1Ra), C-reactive protein (CRP) and procalcitonin (PCT) as early biomarkers of severe sepsis from day 0 to day 2 from the onset of febrile neutropenia. AUC, area under the curve; CI, confidence interval
AUC (95% CI) P-value
IL-1Ra
Day 0 0.768 (0.593 – 0.944) 0.013
Day 1 0.822 (0.631 – 1.000) 0.003
Day 2 0.772 (0.536 – 1.000) 0.018
C-reactive protein
Day 0 0.637 (0.436 – 0.837) 0.208
Day 1 0.767 (0.610 – 0.925) 0.014
Day 2 0.832 (0.703 – 0.961) 0.004
Procalcitonin
Day 0 0.679 (0.473 – 0.886) 0.096
Day 1 0.733 (0.521 – 0.944) 0.031
Day 2 0.720 (0.481 – 0.958) 0.055
Accepted Article
Table 3 The diagnostic characteristics of IL-1 Ra, CRP and procalcitonin on d0-d2 from the onset of febrile neutropenia by optimal cut-off values (ng/L) for severe sepsis in patients with neutropenic fever with Youden’s indices and their 95% confidence intervals.
Optimal cut-off
Sensitivity Specificity Positive predictive
value
Negative predictive
value
Youden’s index (95% CI)
Interleukin 1 receptor antagonist
Day 0 362 ng/L 0.875 0.692 0.226 0.982 0.57 (0.20 − 0.71)
Day 1 511 ng/L 0.875 0.773 0.292 0.983 0.65 (0.28 − 0.78)
Day 2 438 ng/L 0.857 0.740 0.231 0.983 0.60 (0.21 − 0.74)
C-reactive protein
Day 0 51 mg/L 0.750 0.657 0.200 0.958 0.41 (0.04 − 0.61)
Day 1 97 mg/L 0.750 0.722 0.230 0.963 0.47 (0.11 − 0.67)
Day 2 126 mg/L 1 0.618 0.194 1 0.62 (0.24 − 0.72)
Procalcitonin
Day 0 0.14 µg/L 0.875 0.519 0.159 0.976 0.39 (0.05 − 0.66) Day 1 0.89 µg/L 0.625 0.893 0.385 0.957 0.52 (0.18 − 0.76)
Day 2 1.28 µg/L 0.571 0.934 0.444 0.959 0.51 (0.17− 0.78)
Accepted Article
Table 4 Medians (interquartile range) of interleukin-1 receptor antagonist (IL-1Ra), C-reactive protein and procalcitonin in patients with febrile neutropenia according to the blood culture positivity from day 0 to day 2 from the onset of febrile neutropenia.
Positive blood culture finding
(N = 18)
Negative blood culture finding
(N = 68)
P-value
IL-1Ra (ng/L)
Day 0 445 (238 – 863) 237 (154 – 413) 0.003
Day 1 492 (240 – 4649) 275 (178 – 473) 0.011
Day 2 309 (231 – 773) 256 (162 – 499) 0.114
C-reactive protein (mg/L)
Day 0 47 (22 – 115) 37 (18 – 67) 0.337
Day 1 98 (53 – 227) 68 (37 – 100) 0.039
Day 2 129 (73 – 257) 87 (44 – 169) 0.108
Procalcitonin (µg/L)
Day 0 0.18 (0.12 – 0.32) 0.12 (0.08 – 0.19) 0.043 Day 1 0.52 (0.20 – 2.24) 0.16 (0.10 – 0.32) 0.001 Day 2 0.41 (0.18 – 5.38) 0.17 (0.10 – 0.44) 0.005
