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  Table of Contents  
Year : 2014  |  Volume : 51  |  Issue : 4  |  Page : 481-486

Factors predicting outcome in high risk febrile neutropenia in patients receiving intensive chemotherapy for acute sleukemia: A prospective, observational study from South India

1 Department of Medical Oncology, Cancer Institute (WIA)Adyar, Chennai, Tamil Nadu, India
2 Department of Microbiology, Cancer Institute (WIA)Adyar, Chennai, Tamil Nadu, India

Date of Web Publication1-Feb-2016

Correspondence Address:
R Rajendranath
Department of Medical Oncology, Cancer Institute (WIA)Adyar, Chennai, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-509X.175303

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 » Abstract 

Background: Outcome of febrile neutropenia (FN) in acute leukemia patients undergoing intensive chemotherapy from India is scanty. Materials and Methods: A prospective, observational, single institutional study was conducted to evaluate the clinical features, microbiological aspects, risk factors influencing the outcome of high risk FN during intensive therapy in acute leukemia. Results: Among 115 febrile episodes, though 94 (81.7%) had indwelling central venous catheter (CVC) at the time of diagnosis of FN, infective foci clinically were identified in 70.4% of episodes, with lung as the major site (25.2%) followed by CVC (17.4%). Microbiological documentation was possible in 33% (n = 40) episodes. Gram-negative bacteria isolates were 58.3% and Gram-positive isolates were 41.7% of which Pseudomonas was the predominant Gram-negative and Staphylococcus aureus was the most common Gram-positive isolate. Piperacillin-tazobactam + amikacin were used as first line antibiotic in 93% episodes and second line antibiotics were necessary in 73% episodes. Granulocyte colony stimulating factor was used in 60.9% episodes of high risk FN mostly in acute myeloid leukemia consolidation patients. Eighteen episodes (15.7%) were assigned to have invasive fungal disease. Eleven (9.6%) out of 115 high risk FN had a fatal outcome. Presence of pulmonary infection predicted for fatal outcome (P = 0.02). Conclusion: This study reports the outcome of high risk FN in patients with acute leukemia undergoing intensive chemotherapy. Gram-negative isolates are highly sensitive to piperacillin-tazobactum and hence in a cost restraint scenario, carbapenems needs to be judiciously used. Focus of Infection in lungs during FN predicted higher fatal outcomes.

Keywords: Acute leukemia, catheter related infections, febrile neutropenia, high risk

How to cite this article:
Rajendranath R, Balasubramaniyum V, Vijayakumar V, Ganesan P, Tenali G S. Factors predicting outcome in high risk febrile neutropenia in patients receiving intensive chemotherapy for acute sleukemia: A prospective, observational study from South India. Indian J Cancer 2014;51:481-6

How to cite this URL:
Rajendranath R, Balasubramaniyum V, Vijayakumar V, Ganesan P, Tenali G S. Factors predicting outcome in high risk febrile neutropenia in patients receiving intensive chemotherapy for acute sleukemia: A prospective, observational study from South India. Indian J Cancer [serial online] 2014 [cited 2021 Jul 24];51:481-6. Available from: https://www.indianjcancer.com/text.asp?2014/51/4/481/175303

 » Introduction Top

Infections are an important complication during the intensive phases of treatment of acute leukemia's and accounts for 50-80% of morbidity and mortality in these patients.[1],[2],[3],[4],[5] Importance of prolonged and deep neutropenia as a pre-disposing factor for infections is clearly recognized. The risk of developing infections in this group of patients is influenced by factors like intensity and phase of chemotherapy regimen, indwelling central venous catheters (CVCs), endemicity of the pathogenic organisms and duration of hospital stay.[6] CVC's followed by respiratory tract contribute to the majority of the sites.

Indian data on high risk febrile neutropenia (FN) show that Gram-negative bacteria were the predominant organism and use of the first line antibiotics was non-uniform in some of the reports.[7] Many reports combined FN and non-neutropenic fever. Impact of granulocyte colony stimulating factor (G-CSF) usage and catheter related infections have not been described in patients receiving intensive chemotherapy regimens. With this above background, defined parameters, a uniform antimicrobial policy, the present study was conducted to generate data to guide therapeutic decisions and for updating our clinical practice and patient outcome.

 » Materials and Methods Top

Objectives of current study

Primary objective

To evaluate the clinical features, risk factors, microbiological aspects and outcome of high risk FN in acute leukemia patients treated at the Medical Oncology Department.

Secondary objective

To assess the factors influencing the outcome of high risk FN and profile of catheter related infections in this subset of patients.

The study was designed as prospective, observational, single institutional study under Medical Oncology Department at our Institute from January 2011 to December 2011.

Definition of neutropenia and FN

Neutropenia is defined as neutrophil count <500 cells/mm 3 or a neutrophil count of <1000 cells/mm 3, which is predicted to decrease to <500 cells/mm 3 within the next 48-72 h. High risk FN was defined as inpatient status at the time of development of fever, significant medical comorbidity or clinically unstable, anticipated absolute neutrophil count (ANC) <100 for >7 days, hepatic or renal insufficiency, pneumonia or other complex infection and Grade 3 or 4 mucositis.

Phase of treatment

In-patients of all age groups with high risk FN during intensive therapy of acute leukemia including acute myeloid leukemia (AML) during all phases of treatment (induction and consolidation) and acute lymphoblastic leukemia (ALL) during induction, consolidation and re-induction were included in the study. The protocol used for ALL was Berlin Frankfurt Munster 95 protocol (BFM 95) at our institute

Exclusion criteria

Patients with low risk FN, patients who were already on intravenous (IV) antibiotics for greater than 24 h prior to the development of FN and patients with high risk FN with underlying diagnosis other than acute leukemia were excluded from the study.

CVC care policy

Central venous access devices were inserted under strict aseptic precautions in minor theater and occasionally at the bed side if patient was sick. Chlorhexidine wash was given prior to insertion. CVC and peripheral blood cultures were done with automated BacTalert method. Patient was considered to have catheter related infection if same organism with same susceptibility pattern were grown on catheter tip and peripheral blood culture or if culture from the catheter and peripheral blood had same organism and culture from catheter became positive 2 h before peripheral blood culture.

Evaluation during FN

Patients were evaluated for complete blood cell count and manual differential count, serum biochemistry including liver function tests, renal function tests and electrolytes, blood cultures from each lumen of the CVC and urine culture and chest radiograph. Computed tomography scan of the chest was frequently performed as per clinical situation. The day of prior chemotherapy cycle at the onset of FN, NC at fever onset, nadir ANC and duration of fever was documented for all FN episodes.

Antibiotic policy

Treatment was carried out with the first line dual antibiotics piperacillin + tazobactam 100 mg/kg/dose IV, 6-8 hourly and amikacin 15 mg/kg IV, once daily and second line antibiotics like imipenem 60 mg/kg/day IV every 6 hourly or meropenem 60 mg/kg/day IV every 8 hourly. Cefoperazone-sulbactum was given drug holiday so as to prevent the development of resistance during the study period as per the local Antibiotic policy. As per existing departmental policy, antibacterial prophylaxis was not routinely used.

Antifungal policy

Conventional IV amphotericin B was used as the predominant first line antifungal at a dose of 1 mg/kg/day. Second line antifungals were used in case of unresponsiveness/toxicity to the first line therapy. All patients of AML received fluconazole prophylaxis during all protocol chemotherapy cycles. No antifungal prophylaxis was used in patients of ALL.

Response assessment

As part of an ongoing process, after the first line empiric therapy, overall response was evaluated in 3 days. The entire course of FN in a patient during or following a single cycle of chemotherapy was considered as one episode. Febrile episode was considered responding if there was a decreasing fever trend, signs and symptoms of infection were stable or improving and patient was hemodynamically stable. Febrile episode was considered non-responding if patient was persistently or intermittently febrile, signs and symptoms of infection were not improving, patient was hemodynamically unstable and with persistent positive blood culture.


Endpoints of the study were recovery from FN and resolution of infective foci and/or death.

Data analysis and statistical methods

Descriptive statistics was used for clinical and microbiological profile of FN. Success rate of various antibiotics were assessed and descriptive statistics was used for clinical and microbiological profile of FN. Chi-square analysis and Student's t-test were used to look for association between FN outcomes and various parameters studied. The results were considered significant if was P < 0.05 and all the statistical analysis was performed by Statistical Package for the Social Sciences (SPSS) IBM Corporation version 13.0.

 » Results Top

Baseline characteristics

A total of 115 febrile episodes in 66 acute leukemia patients were studied. Treatment settings and frequency of enrolled FN episodes in each phase of protocol chemotherapy are shown in [Table 1]. FN episode is maximum during AML induction phase followed by AML consolidation, ALL induction, ALL re-induction and ALL consolidation phases.
Table 1: Treatment settings and frequency of enrolled FN episodes (n=115)

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Patient characteristics

Age of patients enrolled in the study were between 2 years and 75 years, among which 2-year-old child who had ALL received high risk arm of BFM 95 protocol and 75-year-old gentleman who had AML received standard protocol chemotherapy. Patient characteristics are shown in [Table 2].
Table 2: Patient characteristics

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Day of fever onset during after developing neutropenia is shown in [Figure 1] and the median duration of neutropenia at fever onset was found to be 3 days.
Figure 1: Frequency of fever onset during neutropenia

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The median day of chemotherapy cycle at the onset of fever was day 10. The median nadir ANC was 30 cells/mm 3 and 87.8% of the febrile episodes had ANC <100 cells/mm 3 indicating that the majority of FN had profound neutropenia.

The median ANC at the onset of FN was 80 cells/mm 3 and the average number of days for which fever lasted during FN episode was 7.

Central venous catheterization characteristics during FN

Out of 115 FN episodes, 94 (81.7%) had indwelling CVC at the time of diagnosis of FN. Peripherally inserted central catheter was present in 60 FN episodes, followed by subclavian vein catheter in 31 episodes, Hickman catheter in 2 episodes and PORT in 1 episode.

Profile of infections

All potential sites of infective foci during FN were meticulously examined and documented with infective foci identified clinically in 81 episodes (70.4%). Lung was found to be the major foci of infection. The clinical foci of infection are shown in [Figure 2].
Figure 2: Clinical foci of infection (n = 115)

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Microbiological documentation was possible in 38 FN episodes with a total of 40 isolates and the different source of microbiological isolates are shown in [Table 3] with catheter blood culture contributing to the majority of culture with 19 isolates.
Table 3: Source of microbiological isolates (n=40)

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Spectrum of microbiological isolates

Out of the total 40 isolates, 36 were identified as bacterial isolates, Gram-negative organisms constituted 21 isolates (58.3%) and Gram-positive organisms constituted 15 isolates (41.7). The frequency of microbiological isolates is shown in [Table 4].
Table 4: Spectrum of microbiological isolates (n=40)

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Among the catheter blood cultures, there were 10 Pseudomonas isolates followed by 5 Staphylococcus isolates, 2 Candida species, 1 Acinetobacter species and 1 Klebsiella pneumonia species.

Antibiotic usage and antibiotic sensitivity pattern

The first line and second line antibiotics usage frequency is shown in [Table 5]. Escalation to the second line antibiotics was not necessary in 31 FN episodes (27%), whereas in 84 episodes (73%), second line antibiotics were used. The median number of days of antibiotic treatment was found to be 4 and 8 for first line antibiotics without escalation and second line antibiotics respectively. The antibiotic sensitivity pattern of antimicrobials toward Gram-negative bacteria and Staphylococcus aureus is shown in [Figure 3].
Table 5: First line and second line antibiotics usage frequency

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Figure 3: Sensitivity pattern of antimicrobials toward Gram-negative bacteria and staphylococcus aureus

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There were no extended spectrum beta lactamase (ESBL) isolates. Methicillin resistant S. aureus (MRSA) was identified in 1 episode. All Enterococcus isolates were resistant to beta-lactam antibiotics as well as carbapenems. All Gram-positive isolates were 100% sensitive to glycopeptides and linezolid.

Antifungal usage

Fifty five episodes of FN (47.8%) required antifungal treatment. Empirical antifungal therapy was started in 41 FN episodes. Out of 55 episodes requiring antifungal usage, amphotericin B was used in 31 episodes (56.4%) followed by voriconazole in 22 episodes, caspofungin and posaconazole in 1 episode. Average number of days for which first line antifungals were used was 11 days. Sixteen episodes required change of the first line antifungal therapy to the second line antifungals either due to inadequate response or toxicity concerns. Voriconazole was used in 11 of these episodes and caspofungin in 5 episodes.

Invasive fungal disease

As per European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) guidelines,[8] 18 episodes were assigned as invasive fungal disease (IFD). Invasive candidemia (blood culture positivity) was documented in 2 FN episodes, one during ALL induction and another during AML consolidation. One case of AML induction was proven to have sino-nasal aspergillosis by histopathological demonstration of Aspergillus hyphae from sino-nasal specimen biopsy. Frequency of IFD is shown in [Table 6].
Table 6: Frequency of IFD

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G-CSF usage

G-CSF was used in 70 episodes of FN (60.9%) and the frequency of G-CSF usage is shown in [Table 7].
Table 7: Frequency of G-CSF usage

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Outcome and potential factors influencing outcome

Among 115 high risk FN, 11 (9.6%) had a fatal outcome while the rest 104 FN episodes (90.4%) had resolution of FN and were discharged or continued on further management. The potential factors influencing the outcome of high-risk FN is shown in [Table 8]. Age, gender, remission status, duration of neutropenia, day of chemotherapy cycle at fever onset, nadir ANC, ANC at fever onset, G-CSF usage did not influence the outcome of FN. The development of lung infection during FN significantly influenced the outcome.
Table 8: Potential factors influencing the outcome of high risk FN

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 » Discussion Top

The present study was an attempt to study the clinical features, risk factors, microbiological aspects and outcome of high risk FN in acute leukemia patients. The predominance of Gram-negative bacteria and Gram-positive bacteria has varied significantly during the past 20-30 years and depending on the local isolates and sensitivity pattern, choice of antimicrobials is varied for the management of high risk FN. A series of well-conducted studies have been generated to reduce the incidence, severity and mortality of FN.

In our study, the median duration of day of chemotherapy cycle at fever onset was 10 days and the median duration of neutropenia at fever onset was 3 days. Park et al. reported median time lag with the onset of fever and neutropenia as 4.3 days.[9] Louw et al. reported that the median duration between delivery of chemotherapy and onset of FN episode was 14 days and that FN episode occurred at a median of 3 days from the onset of neutropenia.[10]

The nadir ANC was 30 cells/mm 3 in our study, which was higher than those reported by Louw et al. as 10 cells/mm 3.[10] The baseline characteristics of FN vary among the studies with the median duration of fever per FN episode being 7 days in our study and 10 days as reported by Park et al.[9]

In our study, lung was the most common site of identifiable infective foci (25.2%), which was in agreement with Kumar et al. (37.9%) and Gupta et al.[11],[12] Jagarlamudi et al. and Bakhshi et al. reported chest as clinical foci of infection in 35.7% and 27.3% of FN episodes respectively.[13],[14]

In this study, 33% of FN episode has documented microbiological data. However, Kumar et al. had reported as 58.2% of FN episode.[11] The predominant site of microbial isolate in this study (47.5%) and that reported by Bakhshi et al. was the blood.[14] In this study, Gram-negative bacteria constituted 58.3% of bacterial isolates, which correlates with the reports of Baskaran et al. as well as Santa et al.[15],[16] Bakhshi et al. (67%), Prabhash et al. (68.18%) and Gupta et al. reported the predominant bacterial isolates as Gram-negative bacteria.[12],[14],[17]

The most common Gram-negative bacteria isolated in this study was Pseudomonas, which was similar to those reported by Raje et al. and Prabhash et al. and the most common Gram-positive isolate was S. aureus.[17],[18] Prabhash et al. reported that S. aureus constituted 72.3% of isolates in his study.[17]Pseudomonas was the most common isolate from CVC blood culture in this study whereas coagulase negative S. aureus, was the most common isolate from CVC blood as reported by Sherertz et al.[19]

In our study, Gram-negative isolates were 100% sensitive to carbapenem, 95.2% sensitive to amikacin, cefoperzone-sulbactum and piperacillin-tazobactum, whereas sensitivity tocefoperazone-sulbactumwas 58.5% and 48.8% to piperacillin-tazobactumin a study by Prabhash et al.[17] Ghosh et al. had reported that Gram-negative isolates were 84.1% sensitive to cefoperazone-sulbactum, 65.9% sensitive to piperacillin-tazobactum, 63.7% sensitive to imipenem and 48.8% sensitive to amikacin. The Gram-negative isolates in our study were sensitive to ceftazidime by 33.3% as against 15.9%.[20] The low incidence of ESBL and carbapenem resistance in our study may be attributed to our strict and uniform antibiotic policy and also the fact that Ghosh et al. study was from a multispecialty hospital with likely variable pathogens from various specialties while ours is a stand-alone cancer center.

The prevalence of MRSA among S. aureus in our study was 10%, whereas it was 20% as reported by Ghosh et al.[20] There was no resistance tovancomycin and teicoplanin among Gram-positive isolates including Enterococcus species in our study. However, Ghosh et al. had reported that the prevalence of vancomycin resistant Enterococcus (25%) in his study.[20] This may be due to epidemiology of microbial organisms are dynamic and can vary between centers depending on local antibiotic policy, prudent use of antimicrobial therapy.

Guidelines on choice of empiric therapy in FN are varied. National Comprehensive Cancer Network recommends monotherapy with carbapenem or aminoglycoside with antipseudomonal cephalosporin as first line empiric therapy for high risk FN.[21] In our study, carbapenem was used only in 54.7% of high risk FN and underscores the fact that routine first line usage of carbapenem in high risk FN may not be necessary and should be tailored to needs of individual patients. This could again explain the low incidence of carbapenem resistance in our isolates.

The routine practice as per Infectious Diseases Society of America (IDSA) Fever and Neutropenia Guidelines 2010 Update is to initiate on empiric antifungal therapy in high risk FN.[22] In our study 47.8% of FN episodes required therapeutic antifungal agent which is almost same to that reported by Ghosh et al. (41.5%) and Gupta et al. (51%).[12],[20]

The mortality rate of 9.6% in our study is comparable to other published data.[23] Age, gender, remission status, nadir ANC, ANC at fever onset, G-CSF usage did not influence outcome in this study and clinical focus of lung infection was significantly associated with fatal outcome. However, other studies revealed that sex, duration of neutropenia and ANC at fever onset failed to influence the outcome in FN.[9] Ghosh et al. reported that nadir Total Leucocyte Count (TLC) <200/μl and abnormal chest radiograph were associated with a fatal outcome.[20]

 » Conclusion Top

It could be said that lung was the most common site of clinical focus of infection that was significantly associated with mortality. Gram-negative isolates were found to be the most common isolates with Pseudomonas being the predominant one that is highly sensitive to cefoperazone-sulbactum and piperacillin-tazobactum. Carbapenems needs to be judiciously used in a resource limited setting.

 » References Top

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Pizzo PA. Evaluation of fever in the patient with cancer. Eur J Cancer Clin Oncol 1989;25 Suppl 2:S9-16.  Back to cited text no. 3
Feld R, Bodey GP. Infections in patients with malignant lymphoma treated with combination chemotherapy. Cancer 1977;39:1018-25.  Back to cited text no. 4
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Louw VJ, Westhuizen J, Rautenbach W, van der BE, Wamelink M, Joubert G. The antibiotic susceptibility of bacteria isolated from blood cultures during episodes of neutropenic fever in patients with acute myeloid leukaemia. South Afr J Epidemiol Infect 2010;25:09-11.  Back to cited text no. 10
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Gupta A, Singh M, Singh H, Kumar L, Sharma A, Bakhshi S, et al. Infections in acute myeloid leukemia: An analysis of 382 febrile episodes. Med Oncol 2009;27:1037-45.  Back to cited text no. 12
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Bakhshi S, Padmanjali KS, Arya LS. Infections in childhood acute lymphoblastic leukemia: An analysis of 222 febrile neutropenic episodes. Pediatr Hematol Oncol 2008;25:385-92.  Back to cited text no. 14
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Santa A. Infectious complications in children and young adults with acute lymphoblastic leukemia in Southern India [dissertation]. T N Dr. MGR Medical University; 2007.  Back to cited text no. 16
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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]


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