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Rinnakkaistallenteet Terveystieteiden tiedekunta
2020
Febrile neutropenia in patients with acute myeloid leukemia: outcome in relation to qSOFA score, C-reactive protein and blood culture findings
Lappalainen, Marika
Wiley
Tieteelliset aikakauslehtiartikkelit
© 2020 John Wiley & Sons A/S All rights reserved
http://dx.doi.org/10.1111/ejh.13500
https://erepo.uef.fi/handle/123456789/24344
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This article has been accepted for publication and undergone full peer review but has DR. AUNI JUUTILAINEN (Orcid ID : 0000-0003-0271-4368)
Article type : Original Article
Febrile neutropenia in patients with acute myeloid leukemia: outcome in relation to qSOFA score, C-reactive protein and blood culture findings
Original article
Marika Lappalainen1,2, Sari Hämäläinen1, Tuomo Romppanen2, Kari Pulkki3,4, Marja Pyörälä1, Irma Koivula1, Esa Jantunen1,2,5, Auni Juutilainen1,2
1Department of Medicine, Kuopio University Hospital, Kuopio, Finland.
2Institute of Clinical Medicine/Internal Medicine, Faculty of Medicine, University of Eastern Finland, Kuopio, Finland
3Laboratory Division, Turku University Hospital, and Clinical Chemistry, Faculty of Medicine, University of Turku, Turku, Finland
4Eastern Finland Laboratory Centre, Kuopio, Finland
5Department of Medicine, North Carelia Central Hospital, Joensuu, Finland Running head: Quick SOFA and outcome in AML
Abstract word count: 182
Word count: main text 33973695 Number of references: 44
Tables and figures: 4 tables, 21 figure Corresponding author: Marika Lappalainen
Department of Medicine, Kuopio University Hospital Kuopio, Finland
Mailing address: Kuopion yliopistollinen sairaala, PL 100, 70029 KYS
E-mail: marika.lappalainen@kuh.fi
Phone number: +35817173311
Fax number: +35817173599
ORCID iD: 0000-0002-8182-4452
NOVELTY STATEMENT
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1. What is the new aspect of your work? There are only a few preliminary studies on the usefulness of quick Sequential Organ Failure Assessment (qSOFA) score during febrile neutropenia in adult patients receiving intensive chemotherapy for acute myeloid leukemia (AML).
2. What is the central finding of your work? qSOFA score was found to be valuable in distinguishing life-threatening sepsis from non-severe infection in AML patients, being a strong predictor of ICU admissions and infectious mortality.
3. What is (or could be) the specific clinical relevance of your work? qSOFA score, possibly combined with biomarkers, would provide a tool for prompt upgrading of treatment intensity in case of rapid deterioration of clinical condition in febrile neutropenia of AML patients.
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Abstract
Objectives: To evaluate quick Sequential Organ Failure Assessment (qSOFA) score during febrile neutropenia (FN) in adult patients receiving intensive chemotherapy for acute myeloid leukemia (AML).
Methods: qSOFA score, as well as the association of qSOFA score with ICU admission, infectious mortality, blood culture findings and C-reactive protein (CRP) measurements during FN were assessed among 125 adult AML patients with 355 FN periods receiving intensive chemotherapy in a tertiary care hospital from November 2006 to December 2018.
Results: The multivariate model for qSOFA score ≥ 2 included CRP ≥ 150 mg/L on d0- 2 [OR 2.9 (95% CI 1.1-7.3), P = 0.026], Gram-negative bacteremia [OR 2.7 (95% CI 1.1-6.9), P = 0.034], and treatment according to AML-2003 vs. more recent protocols [OR 2.7 (95% CI 1.0-7.4), P = 0.047]. Age or gender did not gain significance in the model. qSOFA score ≥ 2 was associated with ICU treatment and infectious mortality during FN with sensitivity and specificity of 0.700 and 0.979, and 1.000 and 0.971, respectively.
Conclusion: qSOFA offers a useful tool to evaluate the risk of serious complications in AML patients during FN.
Keywords: acute myeloid leukemia; febrile neutropenia; quick Sequential Sepsis- related Organ Failure Assessment score;
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1. INTRODUCTION
Intensive chemotherapy for adult patients with acute myeloid leukemia (AML) is associated with a high incidence of febrile neutropenia (FN) and bacteremia (1). A significant proportion of these patients develop infectious complications associated with substantial mortality (1, 2).
In a previous AML cohort treated in Kuopio University Hospital, Finland, from 1996 to 2005, FN was observed in almost all neutropenic periods. In that cohort, 5% of the patients died due to infectious complications during the induction therapy, and altogether 11% due to septic complications during induction and consolidation courses (1). Severe sepsis (3) was observed in 13% of the neutropenic periods, intensive care unit (ICU) admission was needed in 5% of FN periods, and 62% of the patients admitted to ICU died due to severe sepsis (1). In a recent study, 26.1% of AML patients, who were admitted to the hospital for the therapy of AML or its complications, required admission to ICU with a mortality rate of 46.1% (4). Overall, ICU mortality for sepsis or septic shock is known to be high among AML patients, but also a decreasing trend has been observed (5, 6).
Quick Sequential (Sepsis-related) Organ Failure Assessment (qSOFA) score was introduced along with Sepsis-3 criteria to recognize high-risk patients outside ICU (7).
The score was found to be associated with increased infectious mortality in several studies among non-neutropenic patients (8-10). There are only a few preliminary studies on implementation of qSOFA in FN of AML patients (11, 12). We therefore postulated
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in AML patients after intensive chemotherapy. In the current study, we assessed the factors for increased qSOFA score and the association of qSOFA score with the risk of ICU admission and infectious mortality during FN in AML patients.
2. PATIENTS AND METHODS
2.1 Study design and patients
At the end of 2006, we started a prospective study aiming to improve the supportive care at the hematology ward during FN (1, 13). This specific study population consisted of adult AML patients treated with intensive chemotherapy at the hematology ward of the Department of Medicine, Kuopio University Hospital, Finland, from November 2006 to December 2018. Patients of age ≥ 18 years with FN after intensive chemotherapy for AML (de novo or secondary) were included. Exclusion criteria were acute promyelocytic leukemia, treatment with azacytidine, or a relapse. Altogether 125 adult AML patients (57 females, 68 males) participated in the study with 396 intensive treatment courses. The age of the patients ranged from 18 to 79 years with a median of 59 years. Forty-one treatment courses (13 induction and 28 consolidation courses) did not meet the study criteria for FN (see 2.5.) and were thus excluded. Finally, 125 adult AML patients with 355 episodes of FN were included. qSOFA scores during FN were assessed retrospectively from electronic patient documents by a single investigation (ML).
2.2 Chemotherapy
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The patients received chemotherapy according to the Finnish Leukaemia Group protocols, which are presented in the Table 1. Until 2012, the AML-2003 protocol (14) was applied, in which the patients were randomized to receive the first induction course either including idarubicin, cytarabine, and thioguanine (IAT) or intermediate-dose cytarabine plus idarubicin (IdAraC-Ida). The protocol used during 2012-2017 was AML-2012 (15), in which the first induction course comprised idarubicin and cytarabine (IA) and the second one mitoxantrone and high-dose cytarabine (Mito- HDAraC) followed by consolidation courses, which all were cytarabine-based. In the most recent AML-protocol (AML-2018) (16), induction was intensified by increasing the dose of cytarabine and fludarabine-cytarabine regimen was applied for low risk patients as consolidation, instead of conventional cytarabine-based regimens.
Overall, the therapy for AML has remained quite constant in recent years, with the exception of acute promyelocytic leukemia, consisting of induction including anthracycline and cytosine arabinoside, followed by consolidation courses based on high-dose cytarabine and allogeneic stem cell transplantation in eligible patients. More recently, intensive chemotherapy has also been applied to elderly patients if considered feasible, contrasting the previous strict upper age limit of 65-70 years.
2.3 Supportive care
All study patients were carefully observed at the hematology ward until recovery from neutropenia. Blood pressure, oxygen saturation, respiratory frequency, heart rate, skin
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temperature, urine output, fluid intake, and alterations in cognitive functions were monitored three times a day but even hourly if necessary from the start of FN. Each patient was daily examined thoroughly for clinical signs and sources of infection.
Attention was paid to features indicating the development of sepsis or septic shock.
2.4 Antimicrobial treatment
Following blood culture sampling, broad-spectrum antibiotics (third-generation cephalosporin and tobramycin or piperacillin-tazobactam and tobramycin) were started for all patients. 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 the microbiological, radiological and clinical findings. New blood cultures were taken if fever persisted for 3-5 days. At the onset of neutropenia, earlier oral fluconazole and from 2009 onwards posaconazole was started for antifungal prophylaxis. In case of persistent fever, caspofungin was empirically started to cover a possible fungal infection.
2.5 Definitions
FN was defined using the criteria from Infectious Diseases Society of America (IDSA) 2002 (17). Neutropenia was defined as neutrophil count < 0.5 x 109/L or with predicted decrease to < 0.5 x 109/L during the next 48 h. Fever was defined as a single oral temperature of ≥ 38.3°C or a temperature of ≥ 38.0°C sustained over 1-hour period.
Sepsis was defined according to the third international consensus definitions for sepsis
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and septic shock (Sepsis-3) as a life-threatening organ dysfunction caused by dysregulated host response to infection (18). qSOFA score (7) was defined when the clinical situation was as its worst during FN by assessing organ dysfunction: 1) respiratory rate ≥ 22/min, 2) altered mental status (Glasgow-Coma-Scale < 15) and 3) systolic blood pressure ≤ 100 mmHg; one point for each dysfunction, maximum 3 points. Septic shock was regarded as a subset of sepsis, in which underlying circulatory, cellular and metabolic abnormalities are profound enough to substantially increase mortality (18). Patients with septic shock were identified with a clinical construct of sepsis with persisting hypotension requiring vasopressors to maintain mean arterial pressure ≥ 65 mmHg and with a serum lactate level ˃ 2 mmol/L despite adequate volume resuscitation. Mean arterial pressure was based on calculation at ward but on invasive measurement at ICU. Serum lactate was not routinely measured but was analyzed in specific situations including complicated course of FN, e.g. hypotension or need for ICU admission.
2.6 Laboratory measurements
Serum C-reactive protein (CRP) was analyzed daily during FN on day 0 (d0), day 1 (d1) and day 2 (d2). CRP was measured with a Konelab60i Clinical Chemistry Analyzer (Lab systems CLD, Konelab, Helsinki, Finland) or Cobas 6000-analyzer (Hitachi, Tokyo, Japan). The run variations were between 2.3–4.3%. The upper reference limit of serum or plasma CRP to a healthy reference population is 3 mg/L.
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Plasma lactate was measured using an amperometric method and ABL735 blood-gas analyzer (Radiometer Medical A/S; Copenhagen, Denmark) or Rapidlab 1265 blood- gas analyzer (Bayer HealthCare LLC, NY, USA). The ABL735 glood-gas analyzer was calibrated against Li-salt of lactate (Sigma L-2250, Sigma-Aldrich Corp., St.Louis, MO, USA) and the Rapidlab 1265 against commercial calibrators using a manual spectrophotometric method. The reference range of plasma lactate was 0.63-2.44 mmol/L.
2.7 Blood cultures
Samples for blood cultures (two sets including two bottles/set for both aerobic and anaerobic cultures) were collected from antecubital veins immediately at the beginning of FN on d0, and additional samples were taken if fever persisted for 3–5 days. Fungal blood samples were collected to three bottles per set in case of persistent or recurrent fever. The samples were processed using the automated blood culture system Bactec 9240 (Becton Dickinson, Sparks, NV, USA) and Bactec Myco F/Lytic in 2006-2016.
After 2017 they were processed by BacT/ALERT VirtuO (BioMérieux, Durham, NC, USA). The incubation episode for aerobic and anaerobic bottles was 7 days and for MYCO F/Lytic bottles 42 days. A single positive blood culture finding was considered as a true positive only if regarded as a clinically relevant cause of infection. If the pathogen was a common skin contaminant, blood culture finding was considered relevant only if found in two successive cultures or if there was an ongoing skin or catheter infection.
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2.8 Statistical analysis
Continuous variables were expressed as medians and interquartile ranges due to the skewed distribution. Kruskal-Wallis test and Mann-Whitney U-test were used to detect differences between the groups in continuous variables. Differences in frequencies were evaluated by Chi-Square for four-fold tables or by Fisher’s exact test. Chi-Square test for trend was used for testing trends over qSOFA categories. Univariate regression analysis was performed for qSOFA score 1 and score 2, admission to ICU, and infectious cause of death during FN as dependent variables, using Wald test statistics.
The test was performed for variables age ≥ 50 years, age ≥ 60 years, gender, AML treatment protocol, Gram-negative bacteremias vs. others, Gram-positive bacteremias vs. others, positive blood culture finding vs. negative, polymicrobial bacteremias vs. no, induction vs. consolidation course, CRP max ≥ 100 mg/L on d0-d2, CRP max ≥ 150 mg/L on d0-d2, qSOFA ≥ 1, qSOFA ≥ 2, and qSOFA ≥ 3. Multivariate regression analysis, using backward stepwise logistic regression model, was performed for qSOFA
≥ 2 as the dependent variable with the statistically significant variables from the univariate regression analysis as the offered covariates. Moreover, the sensitivity and specificity for qSOFA ≥ 2 in association with ICU treatment and with infectious mortality during FN were calculated.
The data analyses were conducted with SPSS 25.0 software (SPSS Inc. Chicago, Illinois, USA). P-values less than 0.05 were considered significant.
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2.9 Ethical approval
This study was conducted according to the principles expressed in the Declaration of Helsinki (19) and approved by the local ethics committee (the Research Ethics Committee of the Northern Savo Hospital District; 100/2006; 369/2015). All patients gave a written informed consent at the enrollment.
3. RESULTS
3.1 qSOFA scores during febrile neutropenia periods
The patient characteristics are described in Table 2. The time elapsed from the start of the fever to qSOFA score estimation (when the clinical situation was at its worst) is illustrated in Figure 1 and the was longer in regard to qSOFA score 3 than in regard to qSOFA scores 1 and 2 (mean 7 vs. 2 days). qSOFA scores 0, 1, 2 and 3 were observed in 290 (81.7%), 44 (12.4%), nine (2.5%) and twelve (3.4%) out of all 355 FN episodes included in the study, respectively (Table 3). There was a trend towards high qSOFA score among FNs with Gram-negative bacteremias and among FNs with candidemias, and a trend towards low qSOFA score in blood culture negative FNs. Hypotension was the most common reason for qSOFA score 1. Six out of nine FN periods with qSOFA score 2 were treated at the hematology ward and three at ICU, and all except one (11/12) episodes with qSOFA score 3 were treated at ICU. Both ICU treatment and death of infectious cause during FN were strongly associated with qSOFA score (Table 3). The sensitivity and specificity of qSOFA score ≥ 2 in predicting ICU treatment were
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0.700 and 0.979, respectively, and in predicting infectious death during FN 1.000 and 0.971, respectively.
3.2 Outcome according to treatment protocols
There were 15/167 (9.0%), 5/151 (3.3%) and 1/37 (2.7%) FN episodes with qSOFA score ≥2 during AML-2003, AML-2012 and AML-2018 protocols, respectively (P = 0.024 for the difference between the AML-2003 vs. more recent protocols). ICU treatment was needed in twelve (7.2%), seven (4.6%) and two (5.4%) FN periods during AML-2003, AML-2012 and AML-2018 protocols, respectively (P = 0.649). Eight patients (8/59, 13.6%) treated according to AML-2003 protocol and four patients (4/51, 7.8%) treated according to AML-2012 protocol died due to complications of FN. None (0/15, 0%) of the patients treated according to AML-2018 protocol died due to complications of FN. The differences according to treatment protocols were not statistically significant (P = 0.242). In all, treatment at ICU was needed in 21 out of 355 FN episodes (5.9%) and twelve AML patients (12/125, 9.6%) with FN died.
3.3 Outcome according to treatment courses
There were altogether 150 induction courses (113 first, 36 second, and one third induction course) and 205 consolidation courses with FN, respectively. There was no difference in the occurrence of FN episodes graded to qSOFA score ≥2 between induction and consolidation courses (11/150, 7.3% vs. 10/205, 4.9%, P = 0.368). ICU treatment was needed in nine FN periods of the first induction course (9/113, 7.9%), in
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six FN episodes of the second induction course (6/36, 17%), and in six FN periods of consolidation courses (6/205, 2.9%) (P = 0.003). FN periods after the induction courses were more likely to lead to ICU admission than FN periods after consolidation courses (P = 0.006). Four patients died in the first induction (4/113, 3.5%), four in the second induction (4/36, 11.1%) and four during the consolidation courses (4/205, 2.0%) (P = 0.020).
3.4 The associations of blood culture findings with chemotherapy courses and outcome
Blood cultures were positive in 49% (174/355) episodes of FN, and the proportion of Gram-positive bacteremia was 51% (89/174). The most frequent bacteremia was caused by Enterococcus faecium, including one vancomycin-resistant strain. The proportion of Gram-negative bacteremia was 45% (79/174), and among those, Escherichia coli, Klebsiella sp. and Pseudomonas aeruginosa were the most frequent causes for bacteremias (Table 3). Fourteen of the bacteremias were polymicrobial (8.0%).
Candidemia was observed in four episodes of FN (2.3%). Patients with FN accompanied by any bacteremia needed more frequently ICU treatment than FN patients with negative blood cultures (15/174, 8.6% vs. 6/181, 3.3%; P = 0.042).
Especially, P. aeruginosa bacteremia was associated with high mortality (4/8, 50%).
Gram-positive bacteremia occurred more frequently during induction than during consolidation courses (34/113, 30%, during the first induction and 15/36, 42%, during the second induction vs. 40/205, 20%, during consolidation courses; P = 0.006). Gram-
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negative bacteremia was more frequent during consolidation than during induction courses (50/205, 24%, vs. 15/150, 10%; P < 0.001). Polymicrobial bacteremias did not occur significantly more often during induction than during consolidation courses (9/150, 6.0% vs. 5/205, 2.4%; P = 0.103).
3.5 The association of C-reactive protein with qSOFA score and blood culture findings
Those FN episodes, which led to the deterioration of the clinical condition to qSOFA score 3, represented higher d0, d1 and d2 CRP values than those periods without clinical deterioration (P = 0.001, P = 0.003, and P = 0.010, respectively) (Figure 1). The differences in d0-d2 CRP levels between qSOFA score 0, qSOFA score 1 and qSOFA score 2 were less substantial. CRP was higher in blood culture positive than in blood culture negative FN episodes on d1 (96 mg/L vs. 71 mg/L) and on d2 (110 mg/L vs. 91 mg/L) (P < 0.001 and P = 0.001, respectively), and higher in Gram-negative than in Gram-positive FN episodes on d1 (108 mg/L vs. 82 mg/L, P = 0.012), and also higher in polymicrobial bacteremia than in monomicrobial Gram-negative bacteremia on d2 (158 mg/L vs. 106 mg/L, P = 0.024).
3.6 The results of logistic regression analyses
The results of univariate logistic regression analysis for qSOFA score ≥ 1, qSOFA score
≥ 2, ICU treatment, and infectious death during FN as the dependent variables are shown in Table 4. The qSOFA scores showed the highest odds ratio (OR) and Wald test
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statistics values for both ICU treatment and infectious mortality. In a multivariate backward stepwise logistic regression model for qSOFA score ≥ 2, the variables included were CRP ≥ 150 mg/L [OR 2.9 (95% CI 1.1-7.3), P = 0.026], Gram-negative bacteremia [OR 2.7 (95% CI 1.1-6.9), P = 0.034], and treatment according to AML- 2003 vs. more recent protocols [OR 2.7 (95% CI 1.0-7.4), P = 0.047]. Age and gender were not significant in the model.
4. DISCUSSION AND CONCLUSION
In this study, we evaluated the utility and usefulness of qSOFA score to identify the AML patients at risk for septic complications in FN. We found that Gram-negative bacteremia and CRP > 150 mg/L on d0-2 were independent factors for increased qSOFA ≥ 2 in this patient group, as did the AML-treatment protocol by comparing AML-treatment protocol 2003 with more recent ones. Age was not an explanatory factor for increased qSOFA score. Further, qSOFA ≥ 2 predicted need for ICU treatment during FN with a sensitivity of 0.700 and specificity of 0.979, and death of infectious cause during FN with a sensitivity of 1.000 and specificity of 0.971.
In our study, qSOFA score grade 3 recognized 11 out of 12 fatal courses of sepsis.
Among patients who received treatment at ICU, two thirds had qSOFA score ≥ 2. We agree with Lee et al. (20), who concluded that qSOFA score was one of the independent predictors of ICU admission and of in-hospital mortality in cancer patients with FN. We also agree with Kim et al. (21), who evaluated qSOFA in patients with chemotherapy- induced FN and concluded that qSOFA could rather be regarded as a warning sign of
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increased risk of deterioration for patients with suspected infection. The absence of qSOFA score 0 did not exclude sepsis especially in hematological patients (22), and the sepsis mortality in patients with hematological malignancies did not differ between patients qSOFA score ≥ 2 or < 2 in a previous study (23). In our study, there were some severe infectious complications without septic shock, like a lung abscess and peritonitis, which did not yield any qSOFA points, even though the clinical situation was life- threatening.
Our study showed that Gram-negative bacteremia is an explanatory factor of qSOFA score ≥2. According to previous reports, treatment courses might influence the incidence of bacteremias in AML patients (24, 25). Gram-negative bacteremias occur especially during the consolidation treatments probably due to the prolonged exposure to broad-spectrum antimicrobials and the resulting prominent changes in gut microbiota (26). In the present study, induction treatments were more commonly associated with Gram-positive bacteremias and consolidation treatments with Gram-negative bacteremias. Of interest, polymicrobial bacteremias were frequent during the second induction course, and seemed to be associated with prominent increase in plasma level of CRP. However, without the finding of Gram-negative bacteria bacteremias they were not significantly associated with qSOFA score ≥ 2.
Compared to the earlier series of AML patients treated at the same institution (1), the incidence of Gram-negative bacteremia was similar (25% in the earlier series vs. 22% in the current series). Among Gram-negative pathogens, P. aeruginosa represents a major cause of an infectious complication in patients with hematologic malignancies (27). In
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the present study, half of P. aeruginosa bacteremias were fatal and responsible for one third of all infectious deaths raising this pathogen as the most severe threat for AML patients receiving intensive chemotherapy.
The incidence of positive blood culture findings was lower in the present than in the previous series (1). However, a significantly growing incidence of Enterococcus faecium was observed. Our finding is in line with the results of a European multicenter cohort study of neutropenic patients demonstrating an increasing proportion of difficult to treat pathogens such as E. faecium, S. maltophilia, and Candida spp. in neutropenic patients (28).
A Major limitations of this study were the study design as a single center investigation and the retrospective evaluation of qSOFA score from patient documents. The comparison of diagnostic or prognostic biomarkers with clinical qSOFA scoring is limited by the differences in the time span elapsed from biomarker measurements to the actual occasion of the clinical deterioration leading to qSOFA grading.(Figure 1). Long delays from the start of the fever are known to be associated to secondary infections and significant clinical consequences (29, 30), consistent with the result of our study showing a long delay with regard to qSOFA score 3.
The combination of serum procalcitonin and qSOFA has been found to predict sepsis mortality up to a sensitivity of 90% in non-neutropenic patients (31). Combining the diagnostic capacity of FN biomarkers (32) and routine use of early warning score might result in improvement of prognosis in FN of AML patients. In comparison to qSOFA,
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other early warning scores, e.g. the National Early Warning Score (NEWS) (11, 12, 33), should be further evaluated in AML populations with FN.
Sepsis mortality in adult AML patients with FN has not significantly decreased from the period 1996-2005 to this study period from 11/2006 to 12/2018. Nowadays, older patients are treated with intensive chemotherapy than previously, but age was not an explanatory factor for increased qSOFA score in multivariate analysis. In accordance, a Swedish registry study showed that most unselected patients up to 80 years with AML benefitted from intensive treatment (34, 35).
The frequency of Gram-negative bacteremia, e.g., Escherichia coli, known to be associated with substantial mortality, has increased as a cause of sepsis (36, 37). The need for fluoroquinolone prophylaxis also in AML patients has been considered (26, 38, 39). In the study by Castañón et al., fluoroquinolone prophylaxis reduced the incidence of Gram-negative bacterial infections during the consolidation treatments (40). The other side of the coin is the threat of multidrug resistance, which has even been reported to influence the clinical course of AML (41, 42). P. aeruginosa is still relatively sensitive to fluoroquinolones in Finland (43) suggesting possibility to consider prophylaxis.
There is limited possibility to further intensify cytotoxic treatments for adult AML, because the benefit could be lost due to an increase of infection-related deaths. A preferable policy might be to continue pursuing towards more targeted but less toxic treatment choices (44-48). Combination of venetoclax with azacytidine or decitabine
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has shown promising results among elderly patients with secondary AML and poor cytogenetics (49).
In this study, qSOFA score appeared valuable in distinguishing life-threatening sepsis from non-severe infection in patients with AML. Combining biomarkers at the onset of FN to daily qSOFA assessment could improve early identification of infectious complications, as reported in some studies on non-neutropenic patient groups (31, 50).
In FN, qSOFA score in routine use would provide a tool for prompt upgrading of treatment intensity in case of rapid deterioration of clinical condition. There is clearly a need for further studies on the implementation of qSOFA into clinical practice among AML patients with fever and neutropenia. Our study emphasizes the importance of vigorous, continuous clinical evaluations of AML patients with FN.
Conflict of interest statement
The authors declare that they have no conflict of interest.
Acknowledgements
The authors acknowledge the technical assistance of Ms Raija Isomäki and Ms Anu Holopainen, MSc.
Funding
The work was supported by Matti and Vappu Maukonen Foundation scholarship to Marika Lappalainen.
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Accepted Article
Figure legends:
Figure 1. Days from the onset of neutropenic fever to clinical deterioration leading to quick Sequential Organ Failure Assessment (qSOFA) grading. C–reactive protein (CRP) was measured in each febrile neutropenia period from d0 to d2. Y-axis: number of periods of febrile neutropenia according to qSOFA scoring. X-axis: Number of days from the start of fever to qSOFA scoring.
Figure 1. C-reactive protein (CRP) medians with interquartile ranges from day 0 (d0) to day 2 (d2) from the beginning of febrile neutropenia episode (N = 355) after intensive treatment according to the quick Sequential Organ Failure Assessment (qSOFA) score of 125 patients with acute myeloid leukemia.
Accepted Article
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Table 1. Finnish Leukaemia Group protocols for acute myeloid leukemia AML-2003, AML-2012, and AML-2018 First induction Second induction
(if needed) First consolidation Second consolidation Third consolidation
Fourth consolidation (only for high risk
patients)
AML-2003 IAT or IdAraC-Ida MEA+/- GO HDAraC-Ida Mito-IDAraC +/- GO MACE +/- GO ICE +/- GO
AML-2012 IA Mito-HDAraC HDAraC-Ida HDAraC HDAraC-Mito
AML-2018
Low risk IA FA-Ida FA/ HDAraC-Ida† FA FA
Intermediate or high risk IA Mito-HDAraC HDAraC-Ida‡ HDAraC HDAraC-Mito‡
Abbreviations:
FA, fludarabin and high-dose cytarabine
FA-Ida, fludarabin, high-dose cytarabine, and idarubicin
GO, gemtuzumab ozogamicin, if no possibility for allogeneic stem cell transplantation HDAraC, high-dose cytarabine
HDAraC-Ida, high-dose cytarabine and idarubicin
HDAraC-Mito, high-dose cytarabine, idarubicin, and mitoxantrone IA, idarubicin and cytarabine
IAT, idarubicin, cytarabine, and thioguanine ICE, idarubicin, cytarabine, and etoposide
IdAraC-Ida, intermediate-dose cytarabine, and idarubicin MACE, amsacrine, cytarabine, and etoposide
MEA, mitoxantrone, etoposide, and cytarabine
Mito-IDAraC, mitoxantrone and intermediate-dose cytarabine
† FA for core-binding factor AML and HDAraC-Ida for other low risk AML
‡ HDAraC without anthracycline/ mitoxantrone for patients proceeding to allogeneic hematopoietic stem cell transplantation
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Table 2. Characteristics of the acute myeloid leukemia study population with febrile neutropenia after intensive chemotherapy.
Patients Periods of febrile neutropenia
All (N) 125 355
Gender [N (%)]
Female 57 (45.6%)
Male 68 (54.4%)
Age [N (%)]
< 50 years 27 (21.6%)
50-59 years 36 (28.8%)
≥ 60 years 62 (49.6%)
White blood cell count (x 109/L)
Median 0.2
Range < 0.1 – 0.8
Site of infection [N (%)]
Unknown site of infection but positive blood culture
93 (26.2%)
Gastrointestinal or abdominal 57 (16.1%)
Pulmonary 51 (14.4%)
Skin /Perineum 47 (13.2%)
Central venous catheter 29 (8.2%)
Upper respiratory tract 18 (5.0%)
Spondylodiscitis 1 (0.3%)
qSOFA score [N (%)]
qSOFA score 0 290 (81.7%)
qSOFA score 1 44 (12.4%)
qSOFA score 2 9 (2.5%)
qSOFA score 3 12 (3.4%)
Number of days from the onset of fever to the clinical deterioration leading to qSOFA scoring (mean; median)
qSOFA score 1 2.1; 0.5
qSOFA score 2 2.2; 0.0
qSOFA score 3 7.2; 6.0
Comorbidity [N (%)]
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Hypertension 43 (34.4%)
TIA or stroke 5 (4.0%)
Other cardiovascular diseases 19 (15.2%)
Diabetes 9 (7.2%)
Previous hematological disease 29 (23.2%)
Other malignancies 11 (8.8%)
Treatment program [N (%)]
AML-2003 59 (47.2%) 167 (47.0%)
AML-2012 51 (40.8%) 151 (42.5%)
AML-2018 15 (12.0%) 37 (10.4%)
Treatment course [N (%)]
Induction 150 (42.3%)
Consolidation 205 (57.7%)
Treatment at intensive care unit needed [N (%)] 21 (5.9%)
Fatal outcome of febrile neutropenia [N (%)] 12 (9.6%)
qSOFA, Quick Sequential (Sepsis-related) Organ Failure Assessment; FN, febrile neutropenia; AML, acute myeloid leukemia; TIA, transient ischemic attack;
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Table 3. Quick Sequential (Sepsis-related) Organ Failure Assessment (qSOFA) scores (%) cross-tabulated with blood culture findings, intensive care treatment and infectious mortality during febrile neutropenia (FN) in 355 FN periods of 125 patients with acute myeloid leukemia from November 2006 to December 2018.
qSOFA 0 qSOFA 1 qSOFA 2 qSOFA 3 Total Chi-square;
df
P for trend†
Blood culture findings
Blood culture negative 164 (91%) 10 (5.5%) 3 (1.7%) 4 (2.2%) 181 12.00; 1 < 0.001
Gram-negative †, ¶ 47 (59%) 23 (29%) 4 (5.1%) 5 (6.3%) 79 21.02; 1 < 0.001
Gram-positive § 75 (84%) 11 (12%) 1 (1.1%) 2 (2.2%) 89 1.026; 1 0.311
Polymicrobial ¶ 10 (71%) 3 (21%) 1 (7.1%) - 14 0.2114; 1 0.646
Anaerobic 2 (100%) - - - 2 0.3381; 1 0.561
Yeast 2 (50%) - 1 (25%) 1 (25%) 4 8.464; 1 0.004
Total 290 (82%) 44 (12%) 9 (2.5%) 12 (3.4%) 355
Treatment at intensive care unit due to FN 2/290 (0.69%) 5/44 (11%) 3/9 (33%) 11/12 (92%) 21 173.0; 1 < 0.001 Infectious cause of death during FN 1/290 (0.34%) 0/44 (0%) 2/9 (22%) 9/12 (75%) 12 161.8; 1 < 0.001
†P for trend of qSOFA score according to the microbiological findings: blood culture negative vs. not negative, Gram-negative vs. not Gram-negative, Gram- positive vs. not Gram-positive, polymicrobial vs. not polymicrobial, anaerobic vs. not anaerobic, yeast vs. not yeast.
‡ Klebsiella sp. (n=19); Escherichia coli (n=20); Enterobacter sp. (n= 11); Pseudomonas aeruginosa (n=8); Other Gram-negative (n=7);
§ Coagulase-negative staphylococci (n=37); Viridans group streptococci (n=22); Enterococcus faecium (n=24); Other Gram-positive (n=6);
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¶ Klebsiella sp. (n=4); Escherichia coli (n=4); Enterobacter sp. (n= 1); Other Gram-negative (n=7); Viridans group streptococci (n=9); Enterococcus faecium (n=5); Other Gram-positive (n=2);
Accepted Article
Table 4. Factors affecting Sequential (Sepsis-related) Organ Failure Assessment (qSOFA) score (qSOFA score
≥1 and qSOFA score ≥2), and predictors for intensive care unit (ICU) admission and infectious mortality during FN in 355 febrile neutropenia periods of 125 AML patients.
Dependent variable Factor OR (95% CI) Wald P
qSOFA score ≥ 1
Age ≥ 60 years 1.8 (1.0-3.1) 4.4 0.036
Induction vs. consolidation 1.9 (1.1-3.3) 5.5 0.019
CRP max ≥ 100 mg/L on d0-d2 2.1 (1.2-3.7) 6.8 0.009
Positive blood culture finding vs. negative 3.7 (2.0-6.7) 18 <0.001 Gram-negative blood culture finding vs. no 5.0 (2.8-8.49) 30 <0.001
qSOFA score ≥ 2
AML-2003 vs. more recent treatment protocol 3.0 (1.1-7.9) 4.9 0.027 Gram-negative bacteremia blood culture finding
vs. no 2.8 (1.1-7.0) 5.1 0.024
CRP max ≥ 150 mg/L on d0-d2 3.6 (1.4-8.9) 7.5 0.006
ICU admission
Positive vs. negative blood culture finding 2.8 (1.0-7.3) 4.2 0.041
CRP max ≥ 150 mg/L on d0-d2 3.6 (1.4-8.9) 6.7 0.006
Induction vs. consolidation 3.7 (1.4-9.7) 6.9 0.009
CRP max ≥ 100 mg/L on d0-d2 4.4 (1.4-13) 7.5 0.009
Polymicrobial blood culture findingbacteremia 6.9 (2.0-24) 9.3 0.002
qSOFA ≥ 1 59 (13-260) 29 <0.001
qSOFA ≥ 2 93 (28-300) 57 <0.001
qSOFA ≥ 3 366 (43.0-3119) 29 <0.001
Infectious mortality
Polymicrobial blood culture findingbacteremia 5.1 (1.0-26) 3.9 0.049
CRP max ≥ 100 mg/L on d0-d2 11 (1.4-87) 5.2 0.022
CRP max ≥ 150 mg/L on d0-d2 4.3 (1.3-14.4) 5.4 0.020
qSOFA score ≥ 1 59 (7.4-465) 15 <0.001
qSOFA score ≥ 2 366 (43-3100) 29 <0.001
qSOFA score ≥ 3 340 (60-1900) 44 <0.001
