Evaluation of febrile neutropenic patients hospitalized in a hematology clinic

M¨ucahit G¨or¨uk，Mehmet Sinan Dal*，Tuba Dal，Abdullah Karakus，Recep Tekin，Nida¨Ozcan，Orhan AyyildizDepartment of Internal Medicine，Dicle University School of Medicine，Diyarbakιr，Turkey

2Department of Medical Microbiology，Yιldιrιm Beyazιt University School of Medicine，Ankara，Turkey

3Department of Clinical Microbiology and Infectious Diseases，Dicle University School of Medicine，Diyarbakιr，Turkey

4Department of Medical Microbiology，Dicle University School of Medicine，Diyarbakιr，Turkey

Evaluation of febrile neutropenic patients hospitalized in a hematology clinic

M¨ucahit G¨or¨uk1，Mehmet Sinan Dal1*，Tuba Dal2，Abdullah Karakus1，Recep Tekin3，Nida¨Ozcan4，Orhan Ayyildiz1
1Department of Internal Medicine，Dicle University School of Medicine，Diyarbakιr，Turkey

2Department of Medical Microbiology，Yιldιrιm Beyazιt University School of Medicine，Ankara，Turkey

3Department of Clinical Microbiology and Infectious Diseases，Dicle University School of Medicine，Diyarbakιr，Turkey

4Department of Medical Microbiology，Dicle University School of Medicine，Diyarbakιr，Turkey

ARTICLE INFO

Article history:

in revised form 4 Jul 2015

Accepted 4 Aug 2015

Available online 20 Oct 2015

Febrile neutropenia

Hematological malignancy

Leukemia

Multiple myeloma

Infections

Objective:To evaluate the febrile neutropenic patients with hematological malignancies hospitalized in hematology clinic with poor hygiene standards.

Methods:A total of 124 patients with hematological malignancies（69 male，55 female）hospitalized in hematology clinic with poor hygiene conditions depending on hospital conditions，between January 2007 and December 2010，were evaluated，retrospectively. Results:In this study，250 febrile neutropenia episodes developing in 124 hospitalized patients were evaluated.Of the patients，69 were men（56%）and 55 women（44%）.A total of 40 patients（32%）had acute myeloid leukemia，25（20%）acute lymphoblastic leukemia，19（15%）non-Hodgkin's lymphoma，10（8%）multiple myeloma，and 8（8%）chronic myeloid leukemia.In our study，56 patients（22%）were diagnosed as pneumonia，38（15%）invasive aspergillosis，38（15%）sepsis，16（6%）typhlitis，9（4%）mucormycosis，and 4（2%）urinary tract infection.Gram-positive cocci were isolated from 52%（n=20），while Gram-negative bacilli 42%（n=16）and yeasts from 6%（n=2）of the sepsis patients，respectively.The most frequently isolated Gram-positive bacteria were methicillin-resistant coagulase-negative staphylococci（n=18），while the most frequently isolated Gram-negative bacteria was Escherichia coli（n=10）.

Conclusions:Febrile neutropenia is still a problem in patients with hematological malignancies.The documentation of the flora and detection of causative agents of infections in each unit would help to decide appropriate empirical therapy.Infection control procedures should be applied for preventing infections and transmissions.

Clinical researchhttp://dx.doi.org/10.1016/j.apjtb.2015.09.014

1.Introduction

Febrile neutropenia is the most important cause of morbidity and mortality in patients with malignancies［1］.Intensive chemotherapy programs，successful applications of stem cell transplantation， platelettransfusions，usageofcolonystimulatingfactors，developingdiagnostictechniquesand broad spectrum antimicrobials have led to prolonged survival.A large number of infectious complications can lead to mortality and morbidity in hematologic malignancy patients.Iatrogenicmanipulations or damage of mucosal barriers due to chemotherapy or mucositis can cause opportunistic infections.In these patients，initiation of empirical antibiotic treatment within the first hour of the infection is life saving［1］.Other factors affecting mortalityonfebrileneutropenicpatientsareunderlying hematologic malignancy type，stage of disease，and comorbid diseases.The medical hygiene practises including isolation or quarantine of infectious persons，private rooms for each patientsormaterialstopreventspreadofinfection，sterilization of instruments used in surgical procedures，the use of protective clothing and barriers，such as masks，gowns，caps，eyewear and gloves，proper bandaging and dressing of injuries，and hand-washing are very important for the prevention of infections developed in these patients［1-4］.Therefore in this study，we aimed to evaluate the febrile neutropenic patientswith hematological malignancies hospitalized in hematology clinic with poor hygiene conditions depending on hospital conditions.

2.Materials and methods

2.1.Sample collections

A total of 124 patients with hematological malignancies（69 male，55 female）hospitalized in Department of Hematology，Faculty of Medicine，Dicle University，between January 2007and December 2010，were evaluated，retrospectively.Hematology Clinic of Dicle University Hospital had poor hospital infection control practices depending on hospital conditions（the lack of a private room for each patient）.Diagnosis of febrile neutropenia was based on axillary temperature measurement and peripheral blood neutrophil count.Measurement of oral or axillary temperature as≥38.3°C or of 38.0-38.2°C for 1 h were defined as fever.If the neutrophil count was lower than 500/mm3，or 500-1000/mm3but expected to fall＜500/mm3in 48 h were defined as neutropenia.Profound neutropenia was defined as neutrophilcountof＜100/mm3［1-4］.Patientsincludedinthestudy were divided into three groups:diagnosed microbiologically，clinically，and radiologically.The age，sex，admission date，length of stay，clinical diagnosis，duration of neutropenia，count of neutropenia，duration of fever，hemoglobin，leukocytes，platelets，prothrombintime/internationalnormalizedratio，alanine aminotransferase，aspartat aminotransferase，alkaline phosphatase，gamma-glutamyltransferase，total bilirubin，albumin，globulin，lactate dehydrogenase，C-reactive protein，erythrocyte sedimentation rate，blood culture，urine culture，sputum culture，blood smear，posteroanterior chest X-ray，thorax，upper and lower abdominal computed tomography results were recorded.In the diagnosis of invasive aspergillosis，European OrganizationforResearchandTreatmentofCancercriteriawereused［4］.

Outpatients with febrile neutropenia，patients with lung cancer，breast cancer，colorectal cancer and solid organ tumors，and febrile neutropenic patients hospitalized in hematology clinic but unclassified clinically，microbiologically and radiologically were excluded from the study.

2.2.Statistical analysis

SPSS program for Windows 7 was used in statistical evaluation of the data obtained in this study.Statistically，mean±SD，SE，minimum and maximum values were calculated.Odds and percentages were determined.Frequency distributions were created.Chi-square test was applied.Student's t-test was used in comparisons of the binary.Pearson correlation analysis was performed.Significance level was considered as P＜0.05.

3.Results

A total of 250 febrile neutropenia episodes of 124 hospitalized patients were evaluated.Of the patients，69 were men（56%）and 55 women（44%）.The mean age of the patients was（45.0±19.4）years.The average length of hospital stay was（22.7±15.8）days，average duration of fever was（11.1±6.8）days，while duration of neutropenia was（8.2±5.9）days.

A total of 40 patients（32%）were diagnosed as acute myeloid leukemia（AML），25（20%）acute lymphoblastic leukemia（ALL），19（15%）non-Hodgkin's lymphoma（NHL），10（8%）multiple myeloma，and 8 patients（8%）chronic myeloid leukemia.Among the patients 7 patients were defined as unclassified leukemia，6 patients were chronic lymphoblastic leukemia（Figure 1）.Gender，age and the number of attacks in AML，ALL and NHL patients were shown in Table 1.

Table 1 Gender，age and the number of attacks in AML，ALL and NHL patients.

In our study，56 patients（22%）were diagnosed as pneumonia，38（15%）invasive aspergillosis，38（15%）sepsis，16（6%）typhlitis，9（4%）mucormycosis，and 4（2%）urinary tract infection.

In 250 episodes of febrile neutropenia，129（51.6%）cases were diagnosed clinically，104（41.6%）radiologically and 71（28.4%）microbiologically.

Of 56 cases with pneumonia，42 cases had radiological diagnosis，25 clinical diagnosis and 9 microbiological diagnosis. Two of them died.Mean hospitalization duration of patients with pneumonia was（20.1±12.7）days，duration of fever was（9.9±4.7）days and neutropenia duration was（6.9±3.9）days.

Of 38 cases with invasive aspergillosis，35 had radiological diagnosis，10 clinical diagnosis and 5 microbiological diagnosis. The mortality was detected in 8 of 38 cases.Of cases with invasive aspergillosis，mean duration of hospitalization was（38.9±20.6）days，while of fever and neutropenia were（20.1±8.4）and（15.7±8.7）days，respectively.

Of 38 cases with sepsis，mean duration of hospitalization，fever and neutropenia were（26.6±17.6），（14.1±8.3）and（9.4±7.3）days，respectively.

Of 212 cases without sepsis，mean duration of hospitalization，fever and neutropenia were（22.0±15.4），（10.6±6.4）and（8.0±5.6）days，respectively.The mean age of sepsis cases was（43.6±16.6），while of cases without sepsis was（42.9±19.8）. No significant difference was found between the sepsis cases and non-sepsis cases in terms of the mean age（P=0.869），duration of hospitalization（P=0.098）and the duration ofneutropenia（P=0.191）.However，duration of fever（P=0.003）was higher in patients with sepsis，significantly.

Gram-positive cocci，Gram-negative bacilli，and yeasts were isolated 52%（n=20），42%（n=16），and 6%（n=2）of blood cultures of the sepsis patients，respectively.The most frequent isolated Gram-positive bacteria were methicillin-resistant coagulase-negative staphylococci（n=18），while the most frequently isolated Gram-negative bacteria was Escherichia coli（n=10）.

4.Discussion

Infections，type of underlying hematologic malignancy，stage of disease，and comorbid diseases are the significant factors affecting mortality in patients with febrile neutropenia.The most frequent underlying malignancies in patients with febrile neutropenia include AML，ALL，and lymphomas similar to our study［5］.

Studies conducted in the patients with febrile neutropenia showed lung infections were important source of the fever with the rates ranging from 20%to 24%［6，7］.Alterations of oropharyngealflora， damagesofgastrointestinaland respiratory mucosa due to chemotherapy and aspiration have important roles in the development of pneumonia.In crowded hospital rooms，pneumoniae agents can spread between the patients.Pneumonia were associated with a greater risk of mortality，and most types of infection were associated with a longer hospital length of stay and higher cost or radiation therapy［8，9］.Pneumonia rate in our patients was 22%，which is not higher than the rates mentioned in literature.However our results showed that to take measures to reduce the incidence of pneumonia was necessary for our clinic.

Incidence of invasive aspergillosis is higher in patients with hematological malignancies having prolonged and severe neutropenia.Development of invasive aspergillosis is associated with duration of neutropenic phase.Especially，after bone marrow transplantation，this risk varies between 4%and 6%［10］. Despite antifungal therapies，the mortality rate ranges from 50% to 80%in invasive aspergillosis.Early diagnosis and treatment greatlyaffecttheprognosis.Theclinicaldiagnosis，radiological findings，histopathological examination，culture andserologicalmethods（measurementofserumand bronchoalveolar lavage fluid galactomannan level），molecular methods are used for the diagnosis［4，11-16］.In our study，15% of patients had invasive aspergillosis.We suggested that medical hygiene practises including isolation or quarantine of infectious persons，private rooms for each patients should be immediately implemented in our clinic or a new hematology unit should be built in our hospital.

The risk factors for the development of bacteremia are age，type of transplantation，and type of malignancy，duration of neutropenia，presence of an indwelling central venous catheter were associated with bloodstream infection by multidrugresistant bacteria［17］.In a study that carried out to assess the isolation rate of bacterial and fungal causative agents in neutropenicadultswithhematologicalneoplasia， 120 consecutive episodes of febrile neutropenia during one year was evaluated.These episodes were observed in 630 patients discharged with diagnoses of leukemia or lymphoma，or after bone marrow transplantation.At least one pathogen was isolated in 42 of 120 episodes（35%），and was presented in 39 patients with AML（43%），ALL（23%），and in patients who underwent bone marrow transplantation（20%）.Primary bacteremia was the most frequent cause of fever（24 episodes，57%），followed by intravascular device-related infections（5 episodes，17%），and soft-tissue infections（5 episodes，15%）［18］.In our study，sepsis was observed in 15%of cases.This result was in substantial value.We suggested that our sepsis rate can be reduced with the use of effective antibiotics in early period.

Mortality rate was found to be 24.5%in febrile neutropenic patients developing bacteremia in the study of Velasco et al.［19］. In a different study，237 patients with febrile neutropenia were analyzed，and the mortality rate within 30 days was found to be 9%［20］.In our study，there was no difference in mortality between sepsis patients and non-sepsis patients.Differences between the distribution of patients'age groups，type of underlying disease，treatment regimens，isolated microorganism species may be responsible for the different results of the studies.

In the 1970s，the Gram-negative bacteria were the main microorganisms isolated from the infections.However，the incidenceofGram-positivemicroorganisminfectionshave gradually increased since the mid-1980s due to permanent use of indwellingvenouscatheters，previousempiricalantibiotic treatment regimens for Gram-positive microorganisms and increased use of chemotherapeutic agents［21-23］.In our study，Gram-positive cocci were isolated from 52%of the patients with sepsis，Gram-negative bacilli from 42%.Methicillinresistantcoagulase-negativestaphylococciwerethemost frequently isolated Gram-positive bacteria while Escherichia coli was the most frequently isolated Gram-negative bacteria.In our study，we did not determine the pattern of antibiotic susceptibility of microorganisms.However，we suggested that bacteria are the important cause of infections in febrile neutropenic patients and in order to select the most effective empirical therapy，each hospital should evaluate developing infections，and detect distribution of causative agents with their antimicrobial susceptibility pattern.The data obtained from this study will guide to appropriate empirical treatment policies and treatment success in febrile neutropenic patients of our clinic.On the other hand in a total of 250 episodes of febrile neutropenia，only 28.5%of the cases were diagnosed microbiologically.We suggested that evidence-based therapy was significant for reducing mortality and morbidity in febrile neutropenic patients. Shortcomings related with microbiological sampling and specimen transport shortcomings should be corrected，the hematology staffs should be in cooperation with the microbiology laboratory.

In conclusion，febrile neutropenia is still an important cause of mortality and morbidity in patients with hematological malignancies.The documentation of the flora，determination of causative agents of infections，and detection of antibiotic and antifungal susceptibility profiles in each unit would help to decide appropriate empirical therapy.In addition to these it should be kept in mind that infection control procedures including hand hygiene，standard barrier precautions，private rooms，and don't allow plants and dried or fresh flowers into patient rooms may be effective means for preventing infections and transmissions.

Conflict of interest statement

We declare that we have no conflict of interest.

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25 May 2015

Mehmet Sinan Dal，Department of Internal medicine，Faculty of Medicine，Dicle University，Diyarbakir，Turkey.

Tel:+90 506 3572438

E-mail:dr.sinandal@hotmail.com

Peer review under responsibility of Hainan Medical University.