Chemotherapy-induced febrile neutropenia (FN) is a major adverse event, which causes morbidity and mortality in cancer patients. Patients with neutropenia are more vulnerable to infection and can rapidly develop life-threatening complications such as sepsis and septic shock. Early manifestations of infection are often misleading in chemotherapy-induced FN patients and classic inflammatory markers, such as white blood cell (WBC) count, are not useful for assessing the severity of infection because inflammation may be severely influenced by the cancer itself and chemotherapy. The chronic, smoldering inflammation contributes to the development and progression of cancer and alters the innate and adaptive immune system (1). Moreover, sepsis is defined as a dysregulated host response to infection involving the early activation of both pro- and anti-inflammatory responses (2, 3). Therefore, it remains challenging to determine whether elevated inflammatory markers truly reflect the severity of infection in septic shock patients with chemotherapy-induced FN.
As a result of these limitations, several inflammatory markers, such as C-reactive protein (CRP) and procalcitonin, have been evaluated as indicators of diagnosis, prognosis, prediction, and therapeutic response in FN (4–6); however, the discriminating power has been challenging especially in critically ill patients (7–9). Recently, neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) have been suggested as potential inflammatory markers to differentiate acute inflammation from chronic inflammation (10, 11). Moreover, NLR and PLR are easily available and inexpensive markers without any additional laboratory test. However, no data for septic shock patients with chemotherapy-induced FN are available.
Although granulocyte colony-stimulating factor (G-CSF) administration has not been proven effective during episodes of FN (12), several studies have shown that G-CSF administration reduces the number of episodes of FN, documented infection rates, and hospitalization rates (13). The onset of action of G-CSF is generally within 24 h; however, which tests can predict the severity and recovery of infection after G-CSF administration in septic shock patients with chemotherapy-induced FN is currently unclear. In this study, we aimed to investigate the prognostic value of inflammatory markers, such as CRP level, immature granulocyte count, WBC count, absolute neutrophil count (ANC), NLR, and PLR, in septic shock patients with chemotherapy-induced FN at admission and after G-CSF administration.
MATERIALS AND METHODS
Study design and population
This single-center, observational, prospectively collected registry-based study included all adult patients who presented to the Emergency Department (ED) of Asan Medical Center, a tertiary care university-affiliated hospital in Seoul, Korea. Adult (≥18 years) patients admitted to the ED were enrolled in the septic shock registry when they showed evidence of refractory hypotension or hypoperfusion and suspected or confirmed infection (14). Refractory hypotension was defined as persistent hypotension (systolic blood pressure, <90 mmHg; mean arterial pressure, <70 mmHg; or systolic blood pressure decrease, >40 mmHg) after 20 to 30 mL/kg or more intravenous fluid challenge or requiring vasopressors to maintain a systolic blood pressure of ≥90 mmHg or mean arterial pressure of ≥70 mmHg (14). Hypoperfusion was defined as serum lactate levels of ≥4 mmol/L (15). Our septic shock registry did not include patients who refused intensive treatment and signed a “Do Not Attempt Resuscitation” order or refused to enroll in the registry. The institutional review board of Asan Medical Center approved the registry (IRB number: 2015-1253), and informed consent was obtained before data collection.
In this study, patients with chemotherapy-induced FN who were enrolled to the septic shock registry and treated with G-CSF between June 1, 2012 and June 30, 2017 were included. Chemotherapy-induced FN was defined as an oral temperature of >38.3°C or two consecutive readings of >38.0°C in 2 h and an ANC of 500/μL or expected to fall below 500/μL within 48 to 72 h in patients with chemotherapy before the episode (16). Patients were categorized into 1-month survivor and nonsurvivor groups. Clinical and serial laboratory data at admission and <24 h after G-CSF administration were compared between the two groups.
Management and data collection
All patients were treated in accordance with current guidelines and bundles of survival sepsis campaign, such as administration of crystalloid, acquisition of blood cultures before the administration of antibiotics, and administration of broad-spectrum antibiotics and vasopressor (14, 17, 18). Empirical broad-spectrum antibiotics, including piperacillin/tazobactam or cefepime as monotherapy, or ceftazidime and cefazolin in combination were administrated immediately after blood cultures and further antibiotic treatments were adjusted according to the guidelines of the Infectious Diseases Society of America (19, 20). G-CSF was administered after the initiation of antibiotics at a dose of 5 μg/kg/d until ANC reached 500/μL (21).
The demographic and clinical characteristics including age, sex, comorbidities, focus of infection, initial laboratory findings, sequential organ failure assessment (SOFA) and acute physiology and chronic health evaluation (APACHE) II scores, and 1-month mortality were retrieved from the septic shock registry. SOFA and APACHE II scores were calculated using the worst parameters during the initial 24 h after ED admission.
We additionally retrospectively reviewed the electrical medical records for the study patients. Blood samples for laboratory tests were collected at ED admission (before the administration of any antibiotics or G-CSF) and after administration of G-CSF within 24 h. NLR was calculated as the absolute count of neutrophils divided by the absolute count of lymphocytes. PLR was calculated as the absolute platelet count divided by the absolute count of lymphocytes. Primary outcome was 1-month survival.
Continuous variables are expressed as medians with interquartile ranges due to their nonnormal distribution by Kolmogorov–Smirnov tests. Categorical data are presented as absolute numbers and percent. Differences between medians were analyzed using Mann–Whitney U tests. Differences between categorical variables were analyzed using χ2 or Fisher exact tests, as appropriate. Variables with an entry-level significance of P <0.10 in univariate analysis were selected for multivariate logistic regression analysis with a backward elimination method to identify independent predictors for 1-month survival. The results were summarized by estimating the adjusted odds ratios (aORs) and 95% confidence intervals (CIs). Variables were tested for goodness-of-fit using the Hosmer–Lemeshow method. The prognostic value of the inflammatory markers and APACHE II scores to predict 1-month survival was analyzed using the receiver operating characteristic curve with the area under the cure (AUC). The optimal cutoff value of the scores was determined using the Youden's index. A two-tailed P < 0.05 was considered statistically significant. All statistical analyses were performed using IBM SPSS Statistics for Windows, version 20.0 (IBM Corp., Armonk, NY).
During the study period, 1,671 patients were enrolled in the septic shock registry, and 255 cancer patients were identified. A total of 97 patients were excluded due to their high ANC level (n = 90), and no prior chemotherapy (n = 7). Finally, 158 chemotherapy-induced FN patients were treated with G-CSF. These patients were categorized into 1-month survivor (n = 114, 72.2%) and nonsurvivor (n = 44, 27.8%) groups. The demographic and clinical characteristics of patients are summarized in Table 1. The median age of our cohort was 64 years, and the male-to-female ratio was close to 1:1. There was no significant difference in comorbidities and the focus of the infection between the two groups. Out of 158 patients, 124 (78.5%) had solid tumors and 34 (21.5%) hematological malignancies. The disease severity scores, including SOFA (median, 7.0 vs. 10.0, P < 0.001) and APACHE II scores (median, 20.0 vs. 31.5, P < 0.001) were significantly higher in the nonsurvivor group than in the survivor group. The patients were treated in accordance with current guidelines, and the rate of 3-h bundle achievement was not different between the survivor and nonsurvivor groups (64.9% vs. 59.1%, P = 0.496) (Supplemental Table 1, http://links.lww.com/SHK/A811). The majority of our study patients received broad-spectrum antibiotics, crystalloid, and vasopressor appropriately.
Serial laboratory findings are presented in Table 2. At ED admission, inflammatory markers, including WBC (median, 600 vs. 400/μL, P = 0.044), immature granulocyte count (median, 1.0% vs. 0.0%, P = 0.019), procalcitonin (median, 7.49 vs. 24.83 ng/mL, P = 0.008), showed significant differences between the survivor and nonsurvivor groups, whereas CRP levels (median, 14.9 vs. 18.2 mg/dL, P = 0.621) did not show any differences. The differences of inflammatory markers were more obvious after administration of G-CSF (Fig. 1). Nonsurvivors showed a higher degree of leukocytopenia (median, 900 vs. 350/μL, P = 0.037), neutropenia (median, 38.6% vs. 22.9%, P = 0.009), and thrombocytopenia (median, 65,000 vs. 36,500/μL, P < 0.001) compared with survivors after administration of G-CSF. Survivors had higher NLR (median, 1.16 vs. 0.42, P = 0.007) and PLR (median, 297.40 vs. 132.09, P = 0.002) compared to nonsurvivors after administration of G-CSF.
After adjusting for age, sex, APACHE II, and SOFA scores, no inflammatory markers at admission were independently associated with 1-month survival using multivariate logistic regression analysis. However, after administration of G-CSF, PLR (aOR, 1.002; 95% CI, 1.000–1.003, P = 0.033) and APACHE II (aOR, 0.897; 95% CI, 0.853–0.943, P < 0.001) were independent predictors for 1-month survival after adjusting for those clinical factors (Table 3). The discriminatory power of PLR after administration of G-CSF and APACHE II scores for 1-month survival was evaluated in terms of AUC, and it was 0.666 for PLR and 0.730 for APACHE II score. The optimal cutoff values for survival were 100 for PLR and 28 for APACHE II using the Youden's index. PLR after administration of G-CSF >100 (aOR, 9.394; 95% CI, 2.821–31.285, P < 0.001) and APACHE II <28 (aOR, 6.944; 95% CI, 2.351–20.511, P < 0.001) were independent predictors for 1-month survival using multivariate logistic regression analysis. PLR after administration of G-CSF >100 was predictive of 1-month survival with sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 89.4%, 46.2%, 82.9%, and 60.0%, respectively and APACHE II score <28 with sensitivity, specificity, PPV, and NPV of 86.8%, 63.6%, 86.1%, and 65.1%, respectively (Table 4).
In this study, we found that 27.8% (44/158) of septic shock patients with chemotherapy-induced FN died within 1 month. Inflammatory markers at admission were not independently associated with 1-month survival despite the significant differences observed between survivor and nonsurvivor groups. After administration of G-CSF, PLR was the only independent predictor for 1-month survival among WBC, ANC, and NLR. PLR after administration of G-CSF (aOR, 1.002; 95% CI, 1.000–1.003, P = 0.033) and APACHE II (aOR, 0.897; 95% CI, 0.853–0.943, P < 0.001) were independent predictors for 1-month survival with the AUC of 0.666 for PLR after G-CSF administration and of 0.730 for APACHE II score, respectively. The optimal cutoff values for survival were 100 for PLR after administration of G-CSF (aOR, 9.394; 95% CI, 2.821–31.285, P < 0.001) with sensitivity, specificity, positive predictive value, and negative predictive value of 89.4%, 46.2%, 82.9%, and 60.0%, respectively. These results imply that PLR after administration of G-CSF, an easily measurable and available laboratory marker, reflects the inflammatory response in septic shock patients with chemotherapy-induced FN.
The survival of septic shock patients with chemotherapy-induced FN has improved over the years; 1-month mortality rate has been reported to decrease from a maximum of 80.0% to approximately 25.0% (22–24). The 1-month mortality rate of our study patients was 27.8% (44/158), consistent with that reported in previous studies (23, 24). This improvement in the survival of septic shock patients was primarily due to improved, early, and aggressive management of critically ill cancer patients (22, 23, 25).
In our study, inflammatory markers including WBC, immature granulocyte count, and CRP at admission as well as after G-CSF administration were not significant predictors of 1-month survival after adjusting for age, sex, and severity scores. These results implied that septic shock patients with chemotherapy-induced FN who had chemotherapy-induced myelosuppression may show different inflammatory processes, and the inflammatory markers at admission could not reflect the patients’ status.
The immune response in sepsis involves both pro- and anti-inflammatory processes simultaneously, and the time course of the immune response in sepsis is generally divided in a primary cytokine-mediated hyperinflammatory phase and a subsequent immune-suppressive phase (2, 26). During the hyperinflammatory phase, numerous proinflammatory cytokines are secreted (26, 27) and induce neutrophilia, lymphopenia, and platelet production in the bone marrow, leading to an increase of PLR and NLR. Considering the complexity of innate and adaptive immune derangements, immune-modulatory therapy has been suggested as potential therapeutic interventions to improve the outcome of sepsis (28). G-CSF is a glycoprotein that stimulates bone marrow to enhance both neutrophil production and release (28). Despite no improvement in 28-day mortality rates in two randomized clinical trials, G-CSF is suggested as one of the most important agents for immune-modulatory therapy (28–30).
Survivors and nonsurvivors showed different responses to administration of G-CSF. Inflammatory markers after administration of G-CSF were significantly higher in the 1-month survivor group than in the nonsurvivor group. Among the inflammatory markers, PLR was the only independent predictor for survival (OR, 1.002; 95% CI, 1.000–1.003). PLR, easily available and inexpensive marker from complete blood count test, is considered to reflect the inflammatory status in other immune-mediated disease processes, such as cancer, chronic inflammatory disease, and autoimmune disease (11, 31–34). Generally, elevated PLR indicated the hyperinflammatory state, and many previous studies demonstrated that elevated PLR was significantly associated with poor outcome in many previous studies (11, 33, 34). In our study, in contrast to previous studies, elevated PLR levels were associated with better survival. This paradoxical result implied that PLR might reflect the early responses to administration of G-CSF and a recovery of the immune system. Therefore, dynamic changes in PLR may be useful for the evaluation of the inflammatory response, for the prediction of responses to administration of G-CSF and consequently for decision-making regarding further treatment.
In the present study, PLR after G-CSF administration and APACHE II score were the independent predictors for 1-month survival. SOFA score, another well-known clinical prediction tool in critically ill patients, was not significantly associated with 1-month survival in multivariate logistic analysis. The AUC was 0.666 for PLR after G-CSF administration and 0.730 for APACHE II score, indicating that APACHE II was superior to PLR for the prediction of 1-month outcome.
This study had several limitations. The retrospective design and relatively small study population impose inherent limitations. In addition, we did not consider the chemotherapy regimens before FN and time lapse after fever development, which influence the immune responses and inflammatory status. Although all the attending physicians treated the patients with septic shock according to the guidelines and there were no significant differences in the rate of 3-h bundle achievement, the possible differences in the treatment of septic shock care at intensive care unit could be potential confounding factors. This study was performed at the ED of single tertiary center and all the study patients admitted through ED, which compromises generalizability.
In this study, we found that inflammatory markers, including CRP, immature granulocyte count, WBC count, ANC, NLR, and PLR, showed dynamic changes in septic shock patients with chemotherapy-induced FN at admission and after administration of G-CSF. PLR after G-CSF administration and APACHE II score were the independent predictors for 1-month survival. Among those inflammatory markers, PLR after administration of G-CSF may be useful as an early marker to predict mortality without any additional cost.
1. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature
454 7203:436–444, 2008.
2. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, et al. The Third International Consensus Definitions for Sepsis and Septic Shock
315 8:801–810, 2016.
3. Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol
13 12:862–874, 2013.
4. Miedema KG, de Bont ES, Elferink RF, van Vliet MJ, Nijhuis CS, Kamps WA, Tissing WJ. The diagnostic value of CRP, IL-8, PCT, and sTREM-1 in the detection of bacterial infections in pediatric oncology patients with febrile neutropenia. Support Care Cancer
19 10:1593–1600, 2011.
5. Wu CW, Wu JY, Chen CK, Huang SL, Hsu SC, Lee MT, Chang SS, Lee CC. Does procalcitonin, C-reactive protein, or interleukin-6 test have a role in the diagnosis of severe infection in patients with febrile neutropenia? A systematic review and meta-analysis. Support Care Cancer
23 10:2863–2872, 2015.
6. Sakr Y, Sponholz C, Tuche F, Brunkhorst F, Reinhart K. The role of procalcitonin in febrile neutropenic patients: review of the literature. Infection
36 5:396–407, 2008.
7. Tang BM, Eslick GD, Craig JC, McLean AS. Accuracy of procalcitonin for sepsis diagnosis in critically ill patients: systematic review and meta-analysis. Lancet Infect Dis
7 3:210–217, 2007.
8. Prat C, Sancho JM, Dominguez J, Xicoy B, Gimenez M, Ferra C, Blanco S, Lacoma A, Ribera JM, Ausina V. Evaluation of procalcitonin, neopterin, C-reactive protein, IL-6 and IL-8 as a diagnostic marker of infection in patients with febrile neutropenia. Leuk Lymphoma
49 9:1752–1761, 2008.
9. Milcent K, Faesch S, Gras-Le Guen C, Dubos F, Poulalhon C, Badier I, Marc E, Laguille C, de Pontual L, Mosca A, et al. Use of procalcitonin assays to predict serious bacterial infection in young febrile infants. JAMA Pediatr
170 1:62–69, 2016.
10. de Jager CP, van Wijk PT, Mathoera RB, de Jongh-Leuvenink J, van der Poll T, Wever PC. Lymphocytopenia and neutrophil-lymphocyte count ratio predict bacteremia better than conventional infection markers in an emergency care unit. Crit Care
14 5:R192, 2010.
11. Qin B, Ma N, Tang Q, Wei T, Yang M, Fu H, Hu Z, Liang Y, Yang Z, Zhong R. Neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) were useful markers in assessment of inflammatory response and disease activity in SLE patients. Mod Rheumatol
26 3:372–376, 2016.
12. White L, Ybarra M. Neutropenic fever. Hematol Oncol Clin North Am
31 6:981–993, 2017.
13. de Souza Viana L, Serufo JC, da Costa Rocha MO, Costa RN, Duarte RC. Performance of a modified MASCC index score for identifying low-risk febrile neutropenic cancer patients. Support Care Cancer
16 7:841–846, 2008.
14. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock
, 2012. Intensive Care Med
39 2:165–228, 2013.
15. Casserly B, Phillips GS, Schorr C, Dellinger RP, Townsend SR, Osborn TM, Reinhart K, Selvakumar N, Levy MM. Lactate measurements in sepsis-induced tissue hypoperfusion: results from the Surviving Sepsis Campaign database. Crit Care Med
43 3:567–573, 2015.
16. Klastersky J, de Naurois J, Rolston K, Rapoport B, Maschmeyer G, Aapro M, Herrstedt J. Esmo Guidelines Committee: management of febrile neutropaenia: ESMO clinical practice guidelines. Ann Oncol
27 (Suppl. 5):v111–v118, 2016.
17. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock
: 2008. Crit Care Med
36 1:296–327, 2008.
18. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock
: 2016. Crit Care Med
45 3:486–552, 2017.
19. Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T, Feld R, Pizzo PA, Rolston KV, Shenep JL, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis
34 6:730–751, 2002.
20. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad II, Rolston KV, Young JA, Wingard JR, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis
52 4:e56–e93, 2011.
21. Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, Goldberg JM, Khatcheressian JL, Leighl NB, Perkins CL, et al. Recommendations for the use of wbc growth factors: American society of clinical oncology clinical practice guideline update. J Clin Oncol
33 28:3199–3212, 2015.
22. Larche J, Azoulay E, Fieux F, Mesnard L, Moreau D, Thiery G, Darmon M, Le Gall JR, Schlemmer B. Improved survival of critically ill cancer patients with septic shock
. Intensive Care Med
29 10:1688–1695, 2003.
23. Kuderer NM, Dale DC, Crawford J, Cosler LE, Lyman GH. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer
106 10:2258–2266, 2006.
24. Legrand M, Max A, Peigne V, Mariotte E, Canet E, Debrumetz A, Lemiale V, Seguin A, Darmon M, Schlemmer B, et al. Survival in neutropenic patients with severe sepsis or septic shock
. Crit Care Med
40 1:43–49, 2012.
25. Darmon M, Azoulay E. Critical care management of cancer patients: cause for optimism and need for objectivity. Curr Opin Oncol
21 4:318–326, 2009.
26. Boomer JS, Green JM, Hotchkiss RS. The changing immune system in sepsis: is individualized immuno-modulatory therapy the answer? Virulence
5 1:45–56, 2014.
27. Wiersinga WJ, Leopold SJ, Cranendonk DR, van der Poll T. Host innate immune responses to sepsis. Virulence
5 1:36–44, 2014.
28. Delano MJ, Ward PA. Sepsis-induced immune dysfunction: can immune therapies reduce mortality? J Clin Invest
126 1:23–31, 2016.
29. Nelson S, Belknap SM, Carlson RW, Dale D, DeBoisblanc B, Farkas S, Fotheringham N, Ho H, Marrie T, Movahhed H, et al. A randomized controlled trial of filgrastim as an adjunct to antibiotics for treatment of hospitalized patients with community-acquired pneumonia. CAP Study Group. J Infect Dis
178 4:1075–1080, 1998.
30. Root RK, Lodato RF, Patrick W, Cade JF, Fotheringham N, Milwee S, Vincent JL, Torres A, Rello J, Nelson S. Multicenter, double-blind, placebo-controlled study of the use of filgrastim in patients hospitalized with pneumonia and severe sepsis. Crit Care Med
31 2:367–373, 2003.
31. Yoldas H, Karagoz I, Ogun MN, Velioglu Y, Yildiz I, Bilgi M, Demirhan A. Novel mortality markers for critically ill patients. J Intensive Care Med
2018; [Epub ahead of print].
32. Le Tulzo Y, Pangault C, Gacouin A, Guilloux V, Tribut O, Amiot L, Tattevin P, Thomas R, Fauchet R, Drenou B. Early circulating lymphocyte apoptosis in human septic shock
is associated with poor outcome. Shock
18 6:487–494, 2002.
33. Meng X, Wei G, Chang Q, Peng R, Shi G, Zheng P, He F, Wang W, Ming L. The platelet-to-lymphocyte ratio, superior to the neutrophil-to-lymphocyte ratio, correlates with hepatitis C virus infection. Int J Infect Dis
34. Liu WY, Lin SG, Wang LR, Fang CC, Lin YQ, Braddock M, Zhu GQ, Zhang Z, Zheng MH, Shen FX. Platelet-to-lymphocyte ratio: a novel prognostic factor for prediction of 90-day outcomes in critically ill patients with diabetic ketoacidosis. Medicine (Baltimore)
95 4:e2596, 2016.