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ORIGINAL ARTICLE
Year : 2014  |  Volume : 51  |  Issue : 4  |  Page : 470-474
 

Pattern of infection, therapy, outcome and risk stratification of patients with febrile neutropenia in a tertiary care oncology hospital in India


1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Microbiology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication1-Feb-2016

Correspondence Address:
K Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.175306

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 » Abstract 

Context: Indian febrile neutropenia (FN) data are limited, especially in adult solid tumor patients. AIMS: The aim was to study patterns of presentation, source of infection, management and outcome and to evaluate the factors which may correlate with outcome. Materials And Methods: A retrospective analysis of prospective data of FN patients at a tertiary care oncology teaching hospital in India between 2007 and 2012. A standardized form was filled for each patient. Patient management was at the discretion of the treating physician. Multinational Association for Supportive Care in Cancer (MASCC) score was retrospectively calculated. Failure of therapy was defined as death, organ failure, shifting from outpatient to inpatient or requirement of intensive care support. SPSS version 16 was used for analysis. Results: A total of 388 FN episodes were included: 256 in hematolymphoid and 132 in solid tumor patients. 156 episodes were high-risk by MASCC score. Focus of infection was clinical in 45% and radiologic in 16%. Blood cultures were positive in 18% cases, most commonly Gram-negative organisms (72%). 93% patients were treated with an antibiotic combination of third-generation cephalosporin/beta-lactamase inhibitor, with aminoglycoside or fluoroquinolone. Antibiotic sensitivity to ceftriaxone was low at 38% while sensitivity to cefoperazone/sulbactam and piperacillin/tazobactam ranged between 50% and 55% and for carbapenems 75%. Failure of therapy occurred in 156 episodes, most commonly due to the need for second line antibiotics. Mortality was 5.5%. On univariate analysis, MASCC score, age, type of malignancy, prophylactic growth factors, presence of focus of infection, hemoglobin and nadir platelet count correlated with FN complications. Conclusion: Gram-negative bacteremia continues to be the predominant cause of FN in our setup.


Keywords: Chemotherapy, febrile neutropenia, India, infections, Multinational Association for Supportive Care in Cancer, validate


How to cite this article:
Noronha V, Joshi A, Patil V M, Bhosale B, Muddu V K, Banavali S, Kelkar R, Prabhash K. Pattern of infection, therapy, outcome and risk stratification of patients with febrile neutropenia in a tertiary care oncology hospital in India. Indian J Cancer 2014;51:470-4

How to cite this URL:
Noronha V, Joshi A, Patil V M, Bhosale B, Muddu V K, Banavali S, Kelkar R, Prabhash K. Pattern of infection, therapy, outcome and risk stratification of patients with febrile neutropenia in a tertiary care oncology hospital in India. Indian J Cancer [serial online] 2014 [cited 2019 Aug 23];51:470-4. Available from: http://www.indianjcancer.com/text.asp?2014/51/4/470/175306



 » Introduction Top


Febrile neutropenia (FN) continues to be the major toxicity of intensive chemotherapy regimens and contributes to overall mortality and morbidity. The management of patients with FN traditionally consists of inpatient admission and intravenous antibiotics. This approach is resource-intensive and may not be feasible for all FN patients in developing countries like India. Outpatient management has been found to be possible in patients with low-risk FN.[1] Home-based intravenous therapy has also been successfully used in select patients.[2] The criteria for classifying low-risk and high-risk FN have been discussed previously and validated in studies in the west. The best known is the Multinational Association for Supportive Care in Cancer (MASCC) score, which stratifies patients on the basis of seven factors including the burden of illness, clinical factors such as age, dehydration, and blood pressure, whether the patient has had a prior fungal infection and whether the patient presents with FN in the outpatient setting.[3]

There have been some studies on FN from India. However, these studies have either been conducted in high-risk patients with hematological malignancies and stem cell transplants or have focused on specific patient subsets like the pediatric population.[4],[5],[6],[7] There are other studies, including from our center on the profile of infections and the antibiotic sensitivity patterns.[8],[9] There are limited data on FN in patients with solid organ malignancies in adults, and very few studies have attempted to validate a risk scoring system in South Asia. To address these concerns, we undertook a retrospective analysis of patients presenting with FN to our center to look at the patterns of presentation, the sources of infection, management of patients and their outcomes. We attempted to validate the MASCC scoring system in our setup and to identify factors other than the MASCC score, which may correlate with outcome.


 » Materials and Methods Top


We conducted a retrospective audit of prospectively collected data of patients with malignancy undergoing chemotherapy who were admitted to the FN ward of Tata Memorial Hospital, Mumbai, a tertiary care hospital between January 2007 and December 2010; and outpatients with FN or patients who presented to the emergency department with FN between September 2011 and November 2012. Standard definitions were used for FN, that is, a single oral temperature of 38.3°C (101°F), in the absence of obvious environmental causes, or two temperature readings of 38.0°C (100.4°F) in 1 h. Neutropenia was defined as an absolute neutrophil count (ANC) of ≤500 cells/µL or ≤1000 cells/µL with a predicted decrease to ≤500 cells/µl.[10] Patients undergoing hematopoietic stem cell transplantation were excluded. At presentation, a detailed history was recorded and clinical evaluation was undertaken, with special attention to commonly infected sites, according to a standardized form [Appendices 1 and 2]. For the inpatients, the data were collected in the hospital at the time of admission while, for outpatients, the form was filled in the outpatient or emergency department at the initial visit and at subsquent visits. The MASCC score was calculated retrospectively in all patients. Since the MASCC score was calculated retrospectively, it was not used for clinical decision making. Inpatients were followed-up daily. The decision to admit patients for therapy, initiation of intravenous antibiotics, choice of the initial antibiotic, change in antibiotic therapy, addition of antifungal therapy, use of growth factors, length of hospitalization and all management decisions were at the treating physician's discretion. Reevaluation was done at 48–72 h or earlier depending on the response. Patients responding to the initial therapy were continued on the same antibiotics. Modification was done according to the culture reports or any clinical deterioration. In patients responding to therapy, the antibiotics were continued for at least 7 days. In some patients with early resolution of neutropenia, the antibiotics were switched to oral antibiotics. In other patients, antibiotics were continued for 10–14 days until complete resolution of neutropenia and fever. The patients were followed-up daily till complete recovery of the febrile episode. An attempt was made to check for delays in chemotherapy due to the FN episode. Failure of therapy was defined as death, failure of first-line antibiotics, organ failure, shifting from outpatient to inpatient department for the patients who were initially treated on an outpatient basis or requirement of intensive care support due to complications related to the infection.

Statistical analysis

All statistical analysis was done with the Statistical Package for the Social Sciences (SPSS), software version 16 (IBM Corporation). Descriptive analysis was done for the clinical features and presentation of the patients. The end point was taken to be a failure of therapy as defined earlier. In addition to the MASCC score, we attempted to assess whether the following clinical and laboratory parameters impacted the outcome of FN:

  • Patient's age (<60 years vs. ≥60 years)
  • Gender (male vs. female)
  • Type of malignancy (hematolymphoid vs. solid tumors)
  • Use of prophylactic growth factors (yes vs. no)
  • Day of onset of FN (within 7 days vs. after 7 days of chemotherapy)
  • Nadir hemoglobin during FN episode (<8 g/dl vs. ≥8 g/dl)
  • Nadir platelet count during FN episode (> or <50,000/µL)
  • Nadir ANC (< or >100/µL)
  • Renal dysfunction (serum creatinine >2 g/dL)
  • Liver dysfunction (serum glutamic oxaloacetic transaminase-SGOT or serum glutamic pyruvic transaminase-SGPT >2 times elevated)
  • Serum albumin during FN episode (<3 g/dL).


Predictive factors were sought by univariate and multivariate analysis. Univariate analysis was performed by log-rank test, and multivariate analysis was then done by regression analysis.


 » Results Top


A total of 388 FN episodes were evaluated. 256 of these episodes occurred in patients with hematolymphoid malignancies, and 132 were in patients with solid organ malignancy. Among the patients with hematolymphoid malignancies, acute myeloid leukemia (113/256) was the commonest while osteogenic sarcoma (39/132) was the commonest diagnosis among solid tumors. [Table 1] enumerates the various malignancies.
Table 1: Type of malignancy


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The clinical and laboratory parameters of the patients are shown in [Table 2].
Table 2: Clinical and laboratory parameters of the patients, with the outcome


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A total of 156 FN episodes were high risk according to the MASCC score, primarily among patients with hematolymphoid malignancies (128/256 with hematolymphoid malignancies and 28/132 in solid malignancies).

Details of the source of infection are given in [Table 3]. The focus of infection was clinical, based on symptoms, in 174 patients (44.8%) and radiologically documented in 62 patients (16%). 145 cultures were positive including blood/stool/bronchoalveolar lavage/urine/pus. Blood culture was positive in 69 (17.7%) cases; majority of isolates were Gram-negative organisms (50 cases, 72%). The most prevalent organism was Escherichia coli followed by Pseudomonas, Acinetobacter, and Klebsiella. Gram-positive organisms were isolated in 18 episodes, most commonly Staphylococcus aureus in 14 out of 18.
Table 3: Source of infection


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First-line antibiotic therapy was at the discretion of the treating physician and consisted typically of an aminoglycoside or a fluoroquinolone combined with a third-generation cephalosporin/beta-lactamase inhibitor. 93% of the patients were treated with a combination of antibiotics, most commonly cefoperazone/sulbactam, which was started in 241 patients; piperacillin/tazobactam was used in 93 patients. Additional first-line Gram-positive coverage was used in only 35 patients: Vancomycin in 13 patients and teicoplanin in 22 patients. 17 of the 24 patients treated with first-line single agent antibiotics received imipenem/cilastatin[Table 4].
Table 4: Bacterial isolates identified in blood


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The antibiotic sensitivity pattern [Table 5] showed that the 3rd-generation cephalosporin, ceftriaxone had low sensitivity of 38%. In contrast, the combination of beta-lactam/beta-lactamase inhibitors such as cefoperazone-sulbactam and piperacillin-tazobactam had sensitivity of 50–55%. The carbapenems had high sensitivity of approximately 75%.

Of all the episodes, failure as per our definition was seen in 156 episodes. 131 patients required second line antimicrobials, 22 died (21 related to FN complication, 1 unrelated to FN), 1 patient required admission (OPD to inpatient) and the remaining 2 patients had a very poor prognosis and took a discharge against medical advice. A switch to second-line antimicrobials was mostly seen in patients with hematolymphoid malignancies, that is, 105/131. Antifungal therapy was also required primarily among patients with hematolymphoid malignancies, that is, 90/104. The mortality rate in our FN patients was 5.5%.

On univariate analysis, apart from the MASCC score, age, type of malignancy, prophylactic use of growth factors, presence of focus of infection, hemoglobin and nadir platelet count were significantly associated with development of complications after FN. All these factors except age and haemoglobin remained significant on multivariate analysis.


 » Discussion Top


We evaluated patients with FN in our center over an approximately 5 year period in an attempt to analyze the pattern of infections, to evaluate the clinical outcome, to assess if the MASCC scoring system can reliably predict outcomes for our patients, and to determine if any other specific factors correlate with outcome. About 1/3rd of the patients in our dataset had solid tumors and received intensive chemotherapy protocols. Usually, the risk of developing FN depends upon the type of malignancy, in addition to other factors including the intensity of the chemotherapy protocol and patient-related factors such as age, comorbidities, etc., In general, approximately 85% of patients with leukemia develop FN while, in patients with lymphomas and solid tumors, the risk varies.[11] 80% of our patients with solid tumors (104/132) had low-risk FN according to the MASCC score, as compared to half of the patients with hematolymphoid malignancies. Failure of therapy was higher in the patients with hematolymphoid malignancies (49%) as compared to the patients with solid organ malignancies (23%). Thus, it appears that our patients with hematolymphoid malignancies more commonly developed high-risk FN and were more likely to experience failure of therapy.

We found that 37% of all cultures were positive; blood cultures were positive in 17.7%. Of the positive blood cultures, 72% were Gram-negative organisms (most commonly E. coli, followed by Pseudomonas). Thus, the major cause of FN in our patients was Gram-negative infection, as compared to the Western population, in which Gram-positive infections are now the predominant cause.[12],[13],[14] We have previously reported the infection profile in our center.[8],[9],[15] Gram-negative bacilli were the most common isolates with a high level of resistance to 3rd-generation cephalosporins. Since the combination of beta-lactam/beta-lactamase inhibitor was previously noted to have good in vitro activity, the combination of a beta-lactam/beta-lactamase inhibitor (most commonly cefoperazone/sulbactam) with either an aminoglycoside (most commonly amikacin) or a fluoroquinolone was routinely used as our first line antibiotic regimen for FN. Reports from other authors in India have also suggested that Gram-negative infections continue to be the predominant cause of FN in Indian patients.[16],[17],[18]{Table 4}

Overall, 40% of our patients had high-risk FN according to the MASCC score. This is consistent with the world literature in which approximately one-third patients have high-risk FN.[19] We found that our patients with an MASCC score of 21 or less had a poor clinical outcome. The MASCC score was originally developed in 2000 by Klastersky et al. on behalf of the Study Section on Infections of MASCC to help predict patients at low risk for febrile neutropenic complications.[3] This score has been accepted and recommended by the Infectious Disease Society of America (IDSA)[14] as well as the European Society of medical oncology (ESMO).[13] This scoring system has been internationally validated in many countries,[20] including South Africa,[21] China [22] and Brazil.[23] The MASCC score has been previously found to be useful in Indian patients as well.[24] We found that apart from the MASCC score, various clinical factors like the patient's age, type of malignancy, identification of a focus of infection, use of prophylactic granulocyte colony-stimulating factors, low hemoglobin and a low platelet count predicted for a poorer outcome. Our patients had low median hemoglobin, and we found that a low hemoglobin correlated independently with poorer outcomes, although this did not remain significant on multivariate analysis. Ammann et al. have also reported that the hemoglobin level is related to the level of adverse events from FN.[25]

Regarding outcomes, we used a composite measure including failure of first-line antibiotics, death, necessity of shifting from outpatient to inpatient and organ failure. 40% of our patients had failure of therapy, 34% required second-line antibiotics and 27% required antifungals. Thus, the commonest reason for failure of therapy was persistent infection and requirement of second line antibiotics. The mortality rate in our FN patients was 5.5%. This mortality rate is similar to that described in other FN publications, including the ESMO guidelines that report a mortality rate of 5% in solid tumor patients, and a mortality of 11% in hematolymphoid patients [13] and the group from All India Institute of Medical Sciences, which reported a mortality of 8%.[6]

The weaknesses of our findings include the general drawbacks relating to a retrospective audit. Although we tried to include all patients with FN, it is conceivable that a few patients were inadvertently not included. The investigations were not standardized and differed in patients according to the clinical presentation. We could not estimate the true incidence of FN among various chemotherapy regimens as the information regarding the total number of patients undergoing chemotherapy during the time period was not available. There was no single standard antibiotic policy followed and the decision of change of antibiotics and requirement for inpatient admission were at the discretion of the individual treating physicians.

Despite these weaknesses, our dataset gives important information on general presentation and management of FN in a tertiary care center in India. The significant proportion of patients with solid organ malignancy and FN and the discovery of factors other than the MASCC score influencing the outcomes are other highlights of the present study. Our dataset includes a large number of patients with FN being treated in the real-world situation as opposed to a specific trial where patients are more homogenous and monitored more stringently.

To conclude, FN continues to be a serious concern in the management of cancer, with Gram-negative infections still being a major problem in India. Understanding the local microbiologic milieu and appropriately tailoring antibiotic therapy leads to outcomes that are similar to those described in the worldwide literature. Patients should be risk-stratified using the MASCC score and various clinical features.

 
 » References Top

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Talcott JA, Yeap BY, Clark JA, Siegel RD, Loggers ET, Lu C, et al. Safety of early discharge for low-risk patients with febrile neutropenia: A multicenter randomized controlled trial. J Clin Oncol 2011;29:3977-83.  Back to cited text no. 1
    
2.
Hendricks AM, Loggers ET, Talcott JA. Costs of home versus inpatient treatment for fever and neutropenia: Analysis of a multicenter randomized trial. J Clin Oncol 2011;29:3984-9.  Back to cited text no. 2
    
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Klastersky J, Paesmans M, Rubenstein EB, Boyer M, Elting L, Feld R, et al. The Multinational Association for Supportive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 2000;18:3038-51.  Back to cited text no. 3
    
4.
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 2010;27:1037-45.  Back to cited text no. 4
    
5.
Biswal S, Godnaik C. Incidence and management of infections in patients with acute leukemia following chemotherapy in general wards. Ecancermedicalscience 2013;7:310.  Back to cited text no. 5
    
6.
Ghosh I, Raina V, Kumar L, Sharma A, Bakhshi S, Thulkar S, et al. Profile of infections and outcome in high-risk febrile neutropenia: Experience from a tertiary care cancer center in India. Med Oncol 2012;29:1354-60.  Back to cited text no. 6
    
7.
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. 7
    
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Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002;34:730-51.  Back to cited text no. 10
    
11.
Aoun M. Febrile neutropenia. Infectious disease and antimicrobial agents. Available from: http://www.antimicrobe.org/new/e49.asp. [Last accessed on 2015 Jan 16].  Back to cited text no. 11
    
12.
Flowers CR, Seidenfeld J, Bow EJ, Karten C, Gleason C, Hawley DK, et al. Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2013;31:794-810.  Back to cited text no. 12
    
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De Naurois J, Novitzky-Basso I, Gill MJ, Marti FM, Cullen MH, Roila F, et al. Management of febrile neutropenia: ESMO Clinical Practice Guidelines. Ann Oncol 2010;21 Suppl 5:v252-6.  Back to cited text no. 13
    
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Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, 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 2011;52:e56-93.  Back to cited text no. 14
    
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Kumar P, Medhekar A, Ghadyalpatil NS, Noronha V, Biswas S, Kurkure P, et al. The effect of age on the bacteria isolated and the antibiotic-sensitivity pattern in infections among cancer patients. Indian J Cancer 2010;47:391-6.  Back to cited text no. 15
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Lakshmaiah KC, Abhayakumar SM, Shetty R, Loknath D, Jayashree RS, Govindbabu K. Management of febrile neutropenia in solid organ malignancies following chemotherapy. J Cancer Res Ther 2014;10:540-3.  Back to cited text no. 17
    
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Mandal PK, Maji SK, Dolai TK, De R, Dutta S, Saha S, et al. Micro-organisms Associated with Febrile Neutropenia in Patients with Haematological Malignancies in a Tertiary Care Hospital in Eastern India. Indian J Hematol Blood Transfus 2015;31:46-50.  Back to cited text no. 18
    
19.
Klastersky J, Awada A, Paesmans M, Aoun M. Febrile neutropenia: A critical review of the initial management. Crit Rev Oncol Hematol 2011;78:185-94.  Back to cited text no. 19
    
20.
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21.
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Hui EP, Leung LK, Poon TC, Mo F, Chan VT, Ma AT, et al. Prediction of outcome in cancer patients with febrile neutropenia: A prospective validation of the Multinational Association for Supportive Care in Cancer risk index in a Chinese population and comparison with the Talcott model and artificial neural network. Support Care Cancer 2011;19:1625-35.  Back to cited text no. 22
    
23.
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 2008;16:841-6.  Back to cited text no. 23
    
24.
Bengre ML, Prabhu MK, Arun S, Prasad K, Bhat KG. Evaluation of the multinational association for supportive care in cancer (MASCC) score for identifying low risk febrile neutropenia patients at a South Indian tertiary care centre. J Clin Diagn Res 2012;6:839-43.  Back to cited text no. 24
    
25.
Ammann RA, Niggli FK, Leibundgut K, Teuffel O, Bodmer N. Exploring the association of hemoglobin level and adverse events in children with cancer presenting with fever in neutropenia. PLoS One 2014;9:e101696.  Back to cited text no. 25
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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