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ORIGINAL ARTICLE
Year : 2021  |  Volume : 19  |  Issue : 4  |  Page : 253-257

Febrile neutropenia in the emergency department


1 Department of Pulmonary Medicine, MNR Medical College, Fasalwadi, Telangana, India
2 Department of Emergency Medicine, Christian Medical College, Vellore, Tamil Nadu, India

Date of Submission20-Mar-2020
Date of Decision13-Apr-2020
Date of Acceptance27-May-2020
Date of Web Publication07-Dec-2021

Correspondence Address:
Dr. Malle Simeon
Department of Pulmonary Medicine, MNR Medical College and Hospital, Fasalwadi, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cmi.cmi_37_20

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  Abstract 


Introduction: Febrile neutropenia is one of the most common presentations to the emergency department. Identification and empirical antibiotic therapy improve the outcome of these patients. The objectives of the study are to collect prospective data on febrile neutropenic patients and describe their clinical profile. Materials and Methods: The study was conducted at the Emergency Department, Christian Medical College and Hospital, Vellore, from July 2017 to February 2018. After obtaining informed consent, all adult patients who presented with fever and neutropenia were included in the study. Results: Of 3778 patients with fever, 101 patients had febrile neutropenia and were included in the study. Males comprised 55.5%. Moderate neutropenia was seen in 30 patients and severe neutropenia was seen in 71 patients. Among the various comorbidities, diabetic patients were more at risk of developing febrile neutropenia (17. 82%). The common organisms isolated were Gram-negative organisms (62. 5%). Coagulase-negative staphylococci and Escherichia coli were the most common organisms. Aplastic anemia was the main diagnosis among those patients with febrile neutropenia (43.76%). The mortality of the febrile neutropenic patients was 1.98%. Overall survival was 96.04%. Conclusion: Empirical antibiotic therapy covering the most common organisms should be started early in febrile neutropenia patients.

Keywords: Emergency department, empirical antibiotic therapy, febrile neutropenia


How to cite this article:
Simeon M, Paul P N, Abhilash KP. Febrile neutropenia in the emergency department. Curr Med Issues 2021;19:253-7

How to cite this URL:
Simeon M, Paul P N, Abhilash KP. Febrile neutropenia in the emergency department. Curr Med Issues [serial online] 2021 [cited 2022 May 21];19:253-7. Available from: https://www.cmijournal.org/text.asp?2021/19/4/253/331827




  Introduction Top


Febrile neutropenia is one of the common conditions presenting to the emergency department (ED). Fever is the principle symptom in these patients. Febrile neutropenia is the most common risk factor for severe infections during malignancies. The duration of hospital stay is influenced by the severity of neutropenia.[1] It also leads to increase the cost of treatment, morbidity, and mortality. The initial management of febrile neutropenia is very important in the ED. Febrile neutropenia is clinically evident in patients receiving chemotherapy caused due to the myelosuppressive effects of treatments with high-dose anticancer agents. Hence, there is a rapid deterioration of patient's health responses of the patients. These patients are susceptible to various infections if not treated in due time leads to complications such as septic shock and refractory shock, and it is fatal.[2] Those at the highest risk for infections are patients with hematological malignancies who undergo hematopoietic stem cell transplantation (HSCT). Majority of these infections are bacterial. This risk is doubled in those people HSCT recipients who develop hypogammaglobulinemia. Many studies published in this decade show that 45%–94% of hematological malignancies develop febrile neutropenia.[3] It is estimated that there is an established or occult infection in at least one-half of all patients with fever and neutropenia. The foremost usually known explanation for infection in such patients is bacterial bloodstream infection (BSI), occurring in about 11%–35% of cases. It has also been found that mortality rates for patients with BSI and hematologic malignancy vary between 5% and 38% and this depends on the patient population and the causative organism which again is higher in Gram-negative organisms. Other common bacterial infectious complications of hematologic malignancies include skin and soft-tissue infections, community- and healthcare-associated pneumonia, neutropenic enterocolitis, sinusitis, and genitourinary infections. In majority of patients receiving chemotherapy, the culture does not grow any microorganism and the causative organism remains unknown. Empirical antibiotic therapy has led to a decrease in mortality due to febrile neutropenia. However, infectious complications remain the most complication of chemotherapy-induced febrile neutropenia. An increasing trend has been noticed in infections due to Gram-negative bacteria which have higher rates of resistance for a variety of reasons.[4] Oral antibiotic treatment seems to be appropriate in low-risk patients. Monotherapy is the most common option in moderate- or high-risk patients.

Aim

The aim was to study the clinical profile of patients presenting to the ED with febrile neutropenia.

Objectives

  1. To determine the prevalence of febrile neutropenia among patients presenting with fever to ED
  2. To identify the etiology in patients with febrile neutropenia
  3. To correlate the time of administration of the first dose of antibiotics with the outcome of the patients (mortality of the patient at the end of 1 week or follow-up of admitted patients for 1 week with febrile neutropenia).



  Materials and Methods Top


Study setting

The study was conducted in the ED of Christian Medical College Hospital (CMC), Vellore, which is a tertiary medical care center, with more than a hundred years of teaching experience since it was established in the year 1900. The ED is a 47-bed department and tends to about 200 patients per day.

Study design

This is a prospective observational study.

Subjects

The study recruited all patients with fever who were 18 years and above who presented to the ED of CMC, Vellore, during the study period.

Inclusion criteria

  1. All patients aged 18 years and above
  2. All hematological patients with fever and neutropenia.


Exclusion criteria

  1. All patients below 18 years of age
  2. Patients who refused to give consent
  3. Patients with solid-organ malignancy.


Treatment protocol

After obtaining informed consent, all patients who were older than 18 years and diagnosed as febrile neutropenia, who had a single oral temperature of ≥38.3°C (101°F) or 38.0°C (100.4°F) for more than 1 h along with an absolute neutrophil count (ANC) ≤500/μl or ≤1500/μl with predicted rapid decline during next 48 h, were evaluated from the study. The evaluation included a relevant history, physical examination, complete hem gram, liver function test, renal function test, serum electrolytes, and chest X-ray. Blood cultures from the peripheral vein or central line if present and urine cultures were conducted routinely for all febrile episodes. Sputum, stool, and/or pus cultures were done according to the clinical indication. Blood culture (two sets of blood culture, 10 ml each, one from the central line and the other from the peripheral line) was repeated every 48 h if fever persisted. A single blood culture was obtained from all enrolled patients in an aerobic BacT/Alert 3D (bioMerieux, Hazelwood, MO, USA) bottle and incubated for up to 7 days in the BacT/Alert blood culture system. Chest X-ray was done if there was clinical suspicion of fungal infection.

These patients were categorized as severe if ANC <500/and mild to moderate group if ANC was ≤1000/μl, with predicted rapid decline during the next 48 h and associated with fever.

Most of the febrile neutropenic patients, with fever presenting to ED, were given empirical antibiotics after blood culture was done. Our patients were given broad-spectrum antibiotics to cover both Gram-positive and Gram-negative organisms (piperacillin/tazobactam for hemodynamically stable patients and meropenem/ertapenem for hemodynamically unstable patients). Once a microbiological culture report was available, antibiotics were modified accordingly. However, if the culture was negative, the same antibiotics were continued. Vancomycin was administered additionally to the patients who had persistent fever, hypotension, redness, or tenderness at the central line insertion site and pneumonia. Bacterial pathogens in all samples yielding a positive culture were identified and their antibiogram was recorded. Polymerase chain reaction for viral pathogens was done to confirm viral etiology and fungal culture was done on Sabouraud Dextrose agar to confirm fungal etiology. Diagnosis, clinical features, time lapsed for the administration of antibiotic, culture positivity, and outcome of febrile neutropenia were recorded.

Statistical methods

Categorical variables were summarized using counts and percentages. Quantitative variables were summarized using mean and standard deviation or median and interquartile range (IQR). All the statistical analyses were done using the Statistical Package for the Social Sciences for Windows (SPSS Inc., Released 2007, version 16.0. Chicago, Illinois, United States of America).

Ethics committee approval

Patient confidentiality was maintained using identifiers, and a password-protected access to the data for a limited number of individuals was maintained to ensure the protection of privacy. The study was approved by the institutional review board and ethics committee (IRB Min no: 9919 dated February 5th, 2016).


  Results Top


A total of 3778 patients with fever presented to our ED during the period of 8 months from July 2016 to February 2017, which 101 (2.67%) patients presented with febrile neutropenia, and these patients were included into the study [Figure 1]. The median age of the patients was 42 years (IQR: 23–55 years). The mean value for hemoglobin was 7.2. The median value for total white blood count was 1900 cells per cubic millimeter of blood. In our study, the majority of the subjects belonged to the category of ANC <500 (37.62%) and 100–500 (32.67%) and the rest of the febrile neutropenic patients had ANC between 500 and 1500 (29.70%) [Table 1]. The median value for platelet count was 15,500/μl of blood. Various comorbidities included diabetes mellitus (17.82%), ischemic heart disease (2.97%), chronic liver disease (2.97%), human immunodeficiency virus (0.99%), hypothyroidism (1.98%), chronic kidney disease (1.98%), and hypertension (7.92%) [Table 2]. One-third of the febrile neutropenic patients received the first dose of antibiotic within 1–4 h (33.66%) [Figure 1]. After 1 week, 97.02% of the patients survived, while 2% passed away [Table 3]. Majority of the patients (56.44%) had no growth on blood culture, while others grew coagulase-negative staphylococci (2.97%), Escherichia coli (l. 98), Klebsiella (1.98%), Gram-negative bacilli (0.99%), Enterococcus (0.99%), Pseudomonas (0.99%), nonhemolytic streptococci (0.99%), Streptococcus pneumoniae (0.99%), multiple growth with carbapenem-resistant organisms and E. coli (0.99%), and multiple growth with Klebsiella and E. coli (0.99%). Culture was not done in 29.71% of the patients. Majority of the bacteria were Gram-negative organisms (60%) and Gram-positive organisms (40%) (n = 14). A large proportion of the patients who had febrile neutropenia presenting to our ED had aplastic anemia (43.76%) and acute leukemia (23.76%) [Figure 2].
Figure 1: Strobe diagram showing the flow of the study.

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Table 1: Correlation between absolute neutrophil count and antibiotic delivery

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Table 2: Baseline characteristics (n=101)

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Table 3: Correlation between the 1-week patients' outcome with antibiotic administration

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Figure 2: Time duration for the administration of antibiotics to febrile neutropenia patients presenting to the emergency department.

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Majority of the patients with febrile neutropenia in patients had bacterial etiology (16.83%), viral etiology (2.97%), and fungal etiology (4.95%) [Figure 3]. Fifty-five percent of the patients with ANC count <100 received the first dose of antibiotic within 4 h [Table 1]. The median hospital stay for our patients with febrile neutropenia was 3 days. The overall survival in febrile patients was 96.04%. Two patients were lost to follow-up.
Figure 3: Final diagnosis of patients with febrile neutropenia.

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  Discussion Top


Febrile neutropenia is one of the common conditions presenting to the ED. It is a global burden among oncology patients. Most of these patients received cytotoxic chemotherapy as a part of treatment. The medications that increase the risk of infection in neutropenic patients are mainly monoclonal antibodies directed against cell receptors on B- and T-cell precursors used to treat lymphoma and acute leukemia. Our study stresses on the outcomes and targets at improving the management of patients who come to the ED with febrile neutropenia. In India, there are minimal data regarding the prevalence of febrile neutropenia in patients. The prevalence of febrile neutropenia in hematological patients among all fever patients coming to our ED was found to be 2.67% as compared to 2% in oncology patients in the United Kingdom.[5]

The most common presentation of febrile neutropenic patients in our study was consistent with previous studies. The median hospital stay for our patients with febrile neutropenia was less as compared to previous studies.[5] Decreased hospital stay may be attributed to the early delivery of antibiotics; however, we did not have enough sample size to confirm the same.

Guidelines recommend the Multinational Association of Supportive Care in Cancer (MASCC) to determine which adult patients with cancer should be hospitalized. In our hospital, most of the febrile neutropenic patients coming to the ED could be sicker as compared to those admitted in the hematological wards or who are outside the hospital during the time when fever starts. Thus, the positive predictive value of the MASCC risk-index is lower in this population, and false positives (complications in the low-risk group) are higher. Furthermore, the MASCC score itself is insufficiently accurate, with a negative predictive value for complications of only 83%. Even though initiating antibiotics promptly is recommended in febrile neutropenia, initiating it too early may interfere with the choice of adequate antibiotics. This assumption is in accordance with a study published recently by the Infectious Diseases Society of America (IDSA) about the last Surviving Sepsis Campaign Guidelines. Despite these conflicts, the IDSA recommended initiating antibiotics within 60 min of presenting with febrile neutropenia such that broad-spectrum antibiotics will be given more frequently without waiting for laboratory results.[6],[7]

Even in the blood cultures done for patients in our study, there are chances of contamination by various organisms.[8] Empirical antibiotics should be broad-spectrum covering Gram-negative organisms predominantly. Either a cephalosporin or a carbapenem was administered intravenously for uncomplicated cases. In case of complicated cases and drug resistance, two-drug combinations may be used. Later, based on blood culture and sensitivity reports, microbe-specific antibiotics should be started.[9] The overall mortality was 26% in Asian countries based on previous studies.[10] In our study, when compared with previous recent studies, mortality rates had decreased to 1.98% due to the early administration of antibiotics to febrile neutropenic patients. In one of the studies conducted in South Korea, febrile neutropenic patients presenting with hypotension had a poor outcome.[11]

Understanding febrile neutropenia and role in immediate diagnosis and management of febrile neutropenic patients is an important step toward improving the overall outcome.

Limitations of the study

We did not have information regarding the onset of fever and the delay in presenting to the ED. A few patients were lost to follow-up because they were followed up telephonically. This study is also a tertiary hospital center-based study, so it would not represent the true population. Our sample size calculation assuming a 10% prevalence of febrile neutropenia was 385; however, due to time constraints, we were only able to recruit 101 patients.


  Conclusions Top


In our study, we noticed that diabetes mellitus was more prevalent among the febrile neutropenic patients than any other comorbidities. Majority of the patients did not have any growth in blood cultures, and of the positive cultures, coagulase-negative staphylococci were the most common microbe. Aplastic anemia was the predominant diagnosis among those patients with febrile neutropenia. Most of our patients received their first dose of antibiotics in the first few hours of presentation with febrile neutropenia. It is important to follow standard protocols for early antibiotic administration for hematology patients with febrile neutropenia.

Research quality and ethics statement

The authors of this manuscript declare that this scientific work complies with reporting quality, formatting, and reproducibility guidelines set forth by the EQUATOR Network. The authors also attest that this clinical investigation was determined to require Institutional Review Board/Ethics Committee review, and the corresponding protocol/approval number is IRB Min. No. 9919 dated 05.02.2016. We also certify that we have not plagiarized the contents in this submission and have done a plagiarism check.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Kuderer NM, Dale DC, Crawford J, Cosler LE, Lyman GH. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer 2006;106:2258-66.  Back to cited text no. 1
    
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Yoshida M. Infections in patients with hematological diseases: Recent advances in serological diagnosis and empiric therapy. Int J Hematol 1997;66:279-89.  Back to cited text no. 2
    
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Klastersky J, Paesmans M, Aoun M, Georgala A, Loizidou A, Lalami Y, et al. Clinical research in febrile neutropenia in cancer patients: Past achievements and perspectives for the future. World J Clin Infect Dis 2016;6:37-60.  Back to cited text no. 3
    
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Cullen M, Steven N, Billingham L, Gaunt C, Hastings M, Simmonds P, et al. Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas. N Engl J Med 2005;353:988-98.  Back to cited text no. 4
    
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Schelenz S, Giles D, Abdullah S. Epidemology, management and economic impact of febrile neutropenia in oncology patients receiving routine care at a regional UK cancer centre. Ann Oncol Off J Eur Soc Med OnctllESM0 2012;23:1889 93.  Back to cited text no. 5
    
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Peyrony O, Gerlier C, Barla I, Ellouze S, Legay L, Azoulay E, et al. Antibiotic prescribing and outcomes in cancer patients with febrile neutropenia in the emergency department. PLoS One 2020;15:e0229828.  Back to cited text no. 6
    
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Alison G, Eric J, Kent A, Michael J, James I, Craig A, 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. 7
    
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Kumar P, Hazra D, Nekkanti AC, Madhiyazhagan M, Sundarshanam T, Balaji VR, et al. A prospective study on the comparison of contamination rate and risk factors of blood culture done in the emergency department and medical high-dependency unit/medicine intensive care units. Curr Med Issues 2020;18:7-13.  Back to cited text no. 8
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9.
Trecarichi EM, Pagano L, Candoni A, Pastore D, Cattaneo C, Fanci R, et al. Current epidiomology and antimicrobial resistance data for bacterial bloodstream infections in patients with haematological malignancies: An Italian multicentre prospective survery. Clin Microbiol Infec 2015;21:337-43.  Back to cited text no. 9
    
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Osmani AH, Jabbar AA, Gangwani MK, Hassan B. Outcomes of high risk patients with febrile neutropenia at a tertiary care center. Asian Pac J Cancer Prev 2017;18:2741-5.  Back to cited text no. 10
    
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Ahn S, Lee YS, Chun YH, Kwon IH, Kim W, Lim KS, et al. Predictive factors of poor prognosis in cancer patients with chemotherapy-induced febrile neutropenia. Support Care Cancer 2011;19:1151-8.  Back to cited text no. 11
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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