Archives of Academic Emergency Medicine. 2019; 7 (1): e39 OR I G I N A L RE S E A RC H Clinical Characteristics and Associated Factors of Mortal- ity in Febrile Neutropenia Patients; a Cross Sectional Study Hamidreza Hatamabadi1, Ali Arhami Dolatabadi2, Ayda Akhavan2∗, Saeed Safari3 1. Safety Promotion and Injury Prevention Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2. Emergency Department, Imam Hossein Hospital, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 3. Emergency Department, Shohadaye Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Received: May 2019; Accepted: June 2019; Published online: 27 July 2019 Abstract: Introduction: The duration and severity of neutropenia directly correlate with the incidence of life-threatening infections. This study aimed to evaluate the clinical characteristics and associated factors of mortality in febrile neutropenia patients. Methods: This retrospective cross sectional study was conducted on all febrile neutrope- nia patients who were admitted to oncology department of two educational hospitals, Tehran, Iran, from 2011 to 2016. Available patients’ data regarding baseline characteristics, treatment, and outcome were collected and an- alyzed using SPSS 21. Results: 357 patients with the mean age of 50.9 ± 17.7 years were studied (59.7% female). Mean white blood cell count of the studied patients was 715.1 ± 270.4 (100 – 1400) cells/mm3. The absolute neutrophil count (ANC) of all patients was < 500 cells/mm3. The most frequent sources of malignancy in stud- ied patients were gastrointestinal (35.9%), breast (22.4%), and sarcoma (15.7%), respectively. The mean time interval between initiation of treatment in ED and increase of ANC to > 500 cells/mm3 was 2.45 ± 2.1 (1 – 16) days. 186 (52.1%) subjects reached ANC > 500 cells/ mm3 after 2-5 days of hospitalization. The rate of hospital mortality was 5.3% (338 (94.7%) survived). The correlation between gender (p = 0.11), temperature (p = 0.123), number of ED visits (p = 0.765), presenting clinical manifestation (p = 0.201), source of malignancy (p = 0.328), presence of metastasis (p = 0.69), positive urine culture (p = 0.45), positive blood culture (p = 0.62), time from last chemotherapy (p = 0.677), and time to reach ANC > 500 cells/mm3 (p = 0.739) with mortality was not sig- nificant. Conclusion: Based on the findings of the present study, the rate of hospital mortality in patients with febrile neutropenia was 5.3%. Older age and lower white blood cell count were among the significant associated factors of mortality in this series. Keywords: Chemotherapy-induced febrile neutropenia; infection; mortality; risk factors Cite this article as: Hatamabadi H, Arhami Dolatabadi A, Akhavan A, Safari S. Clinical Characteristics and Associated Factors of Mortality in Febrile Neutropenia Patients; a Cross Sectional Study. Arch Acad Emerg Med. 2019; 7(1): e39. 1. Introduction The occurrence of fever in patients with cancer and re- duced immune status is one of their subsequent problems. The lowest normal limit for circulating neutrophils is 1500 cells/mm3. The duration and severity of neutropenia di- rectly correlate with the incidence of infections including those that are life-threatening. The incidence of infection finds a significant increase at the critical level of less than 500 cells/mm3 (1, 2). Neutropenia can be acquired or inherited. ∗Corresponding Author: Ayda Akhavan; Emergency Department, Imam Hos- sein Hospital, Madani Avenue, Imam Hossein Square, Tehran, Iran. Email: ay- daakhavan@yahoo.com Its acquired type is common and is associated with different malignant conditions, radiotherapy and chemotherapy, and also idiosyncratic response to drugs such as phenothiazines, sulfonamides, penicillins, cephalosporins, and vancomycin (3). Neutropenia is the most prominent factor in the inci- dence of infection in patients undergoing chemotherapy or bone marrow transplantation, and fever is the most common symptom in these patients. About twenty years ago, gram- negative microorganisms were the most commonly isolated pathogens in patients with fever and neutropenia, but in recent years, gram-positive microorganisms have become more common and are found in about 60-50% of infections (4, 5). Today, fever in patients with a reduced level of immunity has become a major problem in hospitals. Due to the medical ad- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem H. Hatamabadi et al. 2 vances in the use of immunosuppressive drugs for the trans- plantation of various organs, the number of patients with fever and neutropenia has increased significantly (6). Those with persistent fever may be at risk for complications and need rapid medical treatment with antibiotics. Individuals with ANC > 500 cells/µl do not require treatment with Gran- ulocyte - colony stimulating factor (G-CSF), but do require close monitoring for inflammation (7, 8). The mortality rate of febrile neutropenia has been reported from 5.4% to 15% in different studies (9-11). Patient characteristics, type of malig- nancy, age, race, prolonged neutropenia and infectious com- plications are stated as contributing factors of death in stud- ies (12-14). We are faced with an increasing number of febrile neutropenia patients in our emergency departments and this study aimed to evaluate the clinical characteristics and asso- ciated factors of mortality in these patients. 2. Methods 2.1. Study design and setting This retrospective cross sectional study was conducted on all febrile neutropenia patients who were admitted to on- cology departments of Imam Hossein and Shohadaye Tajr- ish Hospitals, Tehran, Iran, from 2011 to 2016. Available pa- tients’ data regarding baseline characteristics, treatment, and outcome were collected and analyzed using SPSS 21. The study group adhered to the principles of medical ethics in- troduced by the Ministry of Health and the Declaration of Helsinki and legislation in the medical ethics committee of Shahid Beheshti University of Medical Sciences. In addition, the ethics committee of Shahid Beheshti University of Medi- cal Sciences approved the protocol of the study (Ethics code: IR.SBMU.MSP.REC.1395.141). 2.2. Participants Data of all ≥ 15 years old febrile neutropenia patients who were admitted to the oncology departments of motioned hospitals were collected using census sampling method. Subjects with incomplete medical records were excluded. 2.3. Data gathering Data were recorded using a predesigned checklist containing demographic variables (gender, age), malignancy type, clin- ical presentation, time from last chemotherapy, type of re- ceived antibiotics, blood culture, urinary culture, cell blood count, neutrophil count, presenting temperature, number of ED visits, as well as outcome (survival, death). A trained third year emergency medicine resident was responsible for data gathering under direct supervision of an emergency medicine specialist. 2.4. Definitions One time oral temperature of 38.3◦ C (101◦ F) or a persistent oral temperature > 38.0◦ C (100.4◦ F) for > 1 hour was defined as fever and ANC ≤ 500 cell/mm3 was defined as neutropenia in this study. 2.5. Statistical Analysis Data were analyzed using SPSS version 21 and P<0.05 was considered significant. Findings were presented as mean ± standard deviation or frequency and percentage. T-test was used for comparing quantitative variables and chi-square or Fisher’s exact test for qualitative ones. 3. Results 3.1. Baseline characteristics of febrile neutrope- nia patients 357 patients with the mean age of 50.9 ± 17.7 (16 – 88) years were studied (59.7% female). Mean temperature at the time of presentation to ED was 38.7 ± 0.4 (38.1 – 40) Celsius. Mean white blood cell count of the studied patients was 715.1 ± 270.4 (100 – 1400) cell/mm3. The ANC of all patients was < 500 cell/mm3. Table 1 shows the baseline characteristics of the studied patients. The most frequent sources of malig- nancy in the studied patients were gastrointestinal (35.9%), breast (22.4%), and sarcoma (15.7%), respectively. 327 (91.7) cases had visited ED for the first time and 262 (73.4%) cases had presented 6-10 days from last chemotherapy. 43 (12.0%) cases with positive blood culture and 18 (5.0%) cases with positive urine culture were detected. 3.2. Outcome The mean time interval between initiation of treatment in ED and ANC increasing to > 500 cells/mm3 was 2.45 ± 2.1 (1 – 16) days. 186 (52.1%) subjects reached ANC > 500 cells/ mm3 after 2-5 days of hospitalization. The rate of hospital mor- tality was 5.3% (338 (94.7%) survived). Table 3 compares dif- ferent baseline characteristics of survived and non-survived subjects. The correlation between gender (p = 0.11), tem- perature (p = 0.123), number of ED visits (p = 0.765), pre- senting clinical manifestation (p = 0.201), source of malig- nancy (p= 0.328), presence of metastasis (p = 0.69), positive urine culture (p = 0.45), positive blood culture (p = 0.62), time from last chemotherapy (p = 0.677), and time to reach ANC > 500 cell/mm3 (p = 0.739) with mortality was not significant. Mean white blood cell count of survived and non-survived patients was 725.7 ± 268.7 and 526.3 ± 232.9 cell/mm3, re- spectively (p = 0.002). The mean age of those who survived was significantly lower (table 3; p = 0.005). This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2019; 7 (1): e39 Table 1: Baseline characteristics of studied patients Variables Number (%) Gender Male 144 (40.3) Female 213 (59.7) Age ( Year) < 20 27 (7.5) 21-40 80 (22.4) 41-60 126 (35.3) > 61 124 (34.7) Source of malignancy Lung 20 (5.6) Gastrointestinal 128 (35.9) Breast 80 (22.4) Sarcoma 56 (15.7) Genitourinary 35 (8.8) Gynecology 17 (4.8.2) Endocrine 13 (5.1) Blood 8 (2.2) Clinical Manifestations Dyspnea 27 (7.5) Vomiting 58 (16.2) Diarrhea 122 (34.2) Cough 17 (4.8) Weakness 54 (5.1) Urinary symptoms 10 (2.9) Abdominal pain 24 (6.7) Others 23 (6.4) Time from last chemotherapy (day) 1-5 46 (12.9) 6-10 262 (73.4) > 11 49 (13.7) Metastasis Positive 93 (26) Negative 264 (74) Number of ED visits 1 327 (91.7) 2 22 (6.1) 3 5 (1.4) ≥4 3 (0.8) 4. Discussion Based on the findings of the present study, the rate of hos- pital mortality in patients with febrile neutropenia was 5.3%. Older age and lower white blood cell count were among the significant associated factors of mortality in this series. There was not any significant relationship between mortality and gender, temperature, number of ED visit, clinical manifes- tation, source of malignancy, presence of metastasis, pos- itive urine culture, positive blood culture, time from last chemotherapy, or time to reach ANC > 500 cell/mm3. The mean age of patients in this study was 50.9 years and about 60% of cases were female. This finding is in line with Amini et al. study, which reported the mean age and gender distri- bution of neutropenia fever patients as 46 years and 52%, re- spectively (15) and also Fotokian et al. findings, which calcu- Table 2: Cultures and antibiotic therapy Variables Number (%) Antibiotics Meropenem 201 (56.3) Meropenem and Vancomycin 85 (23.8) Imipenem 45 (12.6) Imipenem and Vancomycin 5 (1.4) Vancomycin 1 (0.2) Tazocin 1 (0.2) Ceftazidime 8 (2.2) Others 11 (3.1) Blood Culture Positive 43 (12.0) Negative 314 (88.0) Urine Culture Positive 18 (5.0) Negative 339 (95.0) lated the mentioned measures as 43 years and 50%, respec- tively (16). The most common sources of malignancy were gastrointesti- nal and breast, respectively; and diarrhea and vomiting were among the most frequent symptoms of patients in this series. In the study by Lakshmaiah et al. the most common sources of malignancy were lymphoma, leukemia, and germ cell tu- mors (17). In Hosseini et al. study, the majority of patients had lymphatic cancers (18). Hakim et al. reported blood- lymphatic cancers (16%) as the most common type of can- cers, followed by solid tumors (19). Tamai et al. reported blood cancers and respiratory symptoms as the most com- mon source of malignancy and patients’ complaint, respec- tively, in their series (20). These differences among the stud- ies regarding the source of malignancy may be due to differ- ent distribution of malignancy types among countries and regions. We observed that almost 50% of individuals reached ANC > 500 cells/mm3 after 2-5 days of treatment. Consistent with our finding, Cortes el al. revealed that the ANC of 56% of cases had improved and reached more than 500 cells/mm3 after four days (21). Another study showed that more than 80% of patients improve after a course of treatment (22). In this study, we observed that antibiotic type did not signifi- cantly influence patient outcome. Malik et al. found that use of the combination of ceftazidime and amikacin did not have any advantages over ceftriaxone monotherapy (23). These findings are also consistent with the results of the studies by Walsh et al., Ben et al., and Malik et al., because they concluded that single-agent regimens of ceftazidime and imipenem were equally effective in controlling neutropenic fever in patients with cancer (23-25). In our study, 11.2% and 3.9% of patients had positive blood and urine cultures, respectively. In many studies, bacteremia was reported in about 100% of patients (26, 27). In Hosseini’s study, 13.7% This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem H. Hatamabadi et al. 4 Table 3: Comparison of different variables between survived and non-survived patients Variables Survived P value Yes (n = 338) No (n = 19) Gender Male 136 (97.7) 5 (2.3) 0.11 Female 208 (94.4) 8 (5.6) Age ( Year) Mean ± SD 50.3 ± 17.6 62.1 ± 12.7 0.005 Temperature Mean ± SD 38.7 ± 0.4 38.5 ± 0.2 0.123 Metastasis Positive 89 (95.7) 4 (4.3) 0.69 Negative 255 (96.6) 9 (3.4) Urine Culture Positive 14 (100) 0 (0) 0.45 Negative 330 (96.2) 13 (3.8) Blood Culture Positive 38 (95) 2 (5) 0.62 Negative 306 (96.5) 11 (3.5) WBC count (cell/mm3 ) Mean ± SD 725.7 ± 268.7 526.3 ± 232.9 0.002 Time to ANC>500 cell/mm3 (Days) Mean ± SD 2.4 ± 2.1 2.7 ± 1.2 0.736 Time from last chemotherapy (Days) Mean ± SD 7.8 ± 2.7 8.1 ± 4.0 0.677 Data are presented as mean ± standard deviation (SD) or number (%). WBC: white blood cell; ANC: absolute neutrophil count. of patients had a positive blood culture, and 13.7% had posi- tive urine culture (18). In Soroush et al. study, the prevalence of positive blood culture and urine culture was 8% and 5%, respectively (28). In a study on mortality of cancer patients with febrile neutropenia, Gray et al. concluded that adjusted risk of mortality increased 15% in cases experiencing febrile neutropenia (9). Chen et al., reported the death rate of neu- tropenia fever patients as 5.7% (10). Furthermore, Ahn et al. reported that 5.4% of patients admitted to hospital with neu- tropenia fever died (11). Patient characteristics, type of malignancy, comorbidities, and infectious complications were among the most impor- tant associated factors of mortality in adult cancer patients with febrile neutropenia in one study (12). In the study by Swati et al. race, age, year of discharge, associated compli- cations, and cancer type were significantly associated with higher mortality of these patients (13). In another study prolonged neutropenia, acute renal failure, nosocomial bac- teremia, age > 55 years, and monomicrobial bacteremia were among the significant predictive factors of mortality in hematologic patients with bacteremia (14). It is clear that the risk factors of mortality in febrile neutrope- nia are different among studies. This could be due to differ- ent economic, social, health, and case mix of these studies. It seems that each country or even each hospital should try to explore their own contributing factors of mortality and plan to reduce its rate via controlling the modifiable factors. 5. Limitation It should be noted that in the current study due to lack of ac- cess to patients, it was not possible to find other infectious sites. 6. Conclusion Based on findings of the present study, the rate of hospi- tal mortality in patients with febrile neutropenia was 5.3%. Older age and lower white blood cell count were among the significant associated factors of mortality in this series. 7. Appendix 7.1. Acknowledgements This study is derived from Dr. Aida Akhavan’s thesis for achieving her specialist degree in emergency medicine. 7.2. Author contribution The author met the standard criteria for authorship based on the recommendations of the international committee of medical journal editors. Authors ORCIDs Hamidreza Hatamabadi: 0000-0002-9085-8806 Ali Arhami Dolatabadi: 0000-0001-9492-9520 Saeed Safari: 0000-0002-7407-1739 This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 5 Archives of Academic Emergency Medicine. 2019; 7 (1): e39 7.3. Funding/Support No funding to declare. 7.4. Conflict of interest The authors declared no competing interests. References 1. 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