Nosocomial infections and fever of unknown

origin in pediatric hematology/oncology unit:

a retrospective annual study

Youssef A Al-Tonbary, Othman E Soliman, Mohammed M Sarhan, Moustafa A Hegazi,

Rasha A El-Ashry, Ashraf A El-Sharkawy, Osama S Salama, Raida Yahya

Mansoura, Egypt

Author Affiliations: Mansoura University Children's Hospital, Hematology and Oncology Unit (Al-Tonbary YA, Sarhan MM, El-Ashry RA, El-Sharkawy AA), Unit of Infectious Diseases (Soliman OE, Hegazi MA), Clinical Pathology Department (Salama OS, Yahya R), Mansoura University, Egypt

Corresponding Author: Prof. Youssef Al-Tonbary, Mansoura University Children's Hospital, Mansoura, Egypt (Tel: +20123165302; Fax: +20502262307; Email: ytonbary@gmail.com)

Background: Pediatric hematology/oncology patients are faced with an increased risk of nosocomial infections (NIs) that vary in different populations and different institutions with considerable morbidity and mortality. This study was undertaken to assess the frequency and patterns of NIs in 1564 pediatric patients and to determine the prevalence of causative organisms and their antimicrobial sensitivity.

Methods: A retrospective analysis was made in the patients admitted between January 2007 and January 2008 to the pediatric hematoloy/oncology unit of Mansoura University, Egypt. The 1564 patients showed 2084 admissions and 27 092 inpatient days. The Centers for Disease Control and Prevention criteria were used as a standard definition for NI.

Results: The overall rate of NIs in all patients and neutropenic patients was 8.6 and 25.3 per 1000 patient-days respectively. The frequent sites of NIs were blood stream (42.7%), the respiratory system (25.3%), the urinary system (22.2%) and the central nervous system (9.8%), whereas nosocomial fever of unknown origin constituted 52.9% of cases. The incidence of NIs was significantly higher during neutropenic days (P<0.001). Gram-positive organisms represented 64.5% of pathogens (Staphylococci 71.5%, Streptococci 16%, and pneumococci 7%), and Gram-negative organisms represented 30% (E. coli 48.6%, Klebsiella 15.7%, Pseudomonas 35.7%, and C. albicans 5.5%). Positive cultures were more frequent in summer (July to September). Susceptibility of isolated organisms was relatively low (cefoperazone/sulbactam 49.9%, amikacin 35.9%, imipenem/cilastin 34.4%, cefoperazone 33.6%, and vancomycin 36.5%). Methicillin-resistant S. aureus, extended spectrum beta lactamase and vancomycin resistant enterococci represented 30%, 45% and 75% of isolated S. aureus, Gram-negative organisms and Enterococci, respectively.

Conclusions: Blood stream infection and fever of unknown origin are the most common nosocomial infections in pediatric hematology/oncology patients with a higher risk during neutropenic days. Isolated organisms are multi-drug resistant, predominantly Gram-positive pathogens with a high incidence of methicillin-resistant S. aureus, extended spectrum beta lactamase and vancomycin resistant enterococci organisms.

Key words: fever of unknown origin; hematology/oncology; nosocomial infections;  pediatric

World J Pediatr 2011;7(1):60-64

Introduction

The occurrence of NIs differs in different patient populations and different hospitals. However, there are few studies on the incidence of nosocomial infections in pediatric patients and comparative data from pediatric hematology/oncology units are rarely reported.^[1,6,7]

This study was designed to evaluate the frequency of NIs in pediatric hematology/oncolgy patients in relation to different risks and to determine the main sites of infections, common microorganisms and their antimicrobial susceptibilities.

Methods

A retrospective study was carried out in pediatric hematology/oncology unit, Mansoura University, Egypt from January 2007 to January 2008. The hematology/oncology unit has 4 high efficiency particulate absorbing filtered rooms with single beds in addition to other 10 naturally-ventilated rooms each having 2 beds. The unit has 6 staff members, 3 registrars and one nurse for every 3 patients. The unit follows the standard recommendations of infection control measures.

During the surveillance period, 1564 patients (256 oncology patients, 1293 beta thalassemia patients and 15 patients with other hematologic disorders) were included. The beta thalassemia patients were included because they were maintained on the oral chelating agent, deferiprone, which may be complicated by neutropenia or agranulocytosis in addition to leukopenia that may be caused also by hypersplenism. These patients were also managed in the same unit and expected to be exposed to the same environmental risks.

The criteria of Centers for Disease Control and Prevention (CDC) were used as the standard definition for NI. Infections were regarded as NI if they appeared 48 hours after admission or within 48 hours of discharge.^[8-11]

Demographic and clinical data including discharge diagnosis, date of onset, site of infections, results of microbiologic cultures from peripheral blood, body fluids and any suspected focus of infection and the antibiotics used were recorded. Cultures were done using Dade Behring automated Microscan (Sacramento, California, USA). Antimicrobial sensitivity was recorded for organisms isolated from sterile sites. The number of days during which patients were at increased risk as a result of leukopenia (leukocytic count <1×10³/µL) or severe neutropenia (neutrophil count <0.5×10³/µL) were calculated.^[7,10]

Nosocomial fever of unknown origin (nFUO) was defined as fever of at least 38ºC for more than 4 hours occurring on several occasions in a hospitalized patient in whom neither fever nor infection was present on admission and for which a cause cannot be determined after 3 days of investigation, including 2 days of cultures.^[7,12,13]

As to antibiotic prophylaxis, all of our oncologic patients were subjected to pneumocystis jiroveci prophylaxis with trimethoprim/sulfamethoxazole three times weekly. Prophylaxis with colistin and itraconazole was given to those patients with expected prolonged neutropenia (>10 days).^[14]

Statistical analysis

Infection rates were calculated as overall infection rate (per 100 admissions) and incidence density rate (per 1000 patient-days and per 1000 patient-days at risk). The Chi-square test was used to compare the frequency of infections between neutropenic and non-neutropenic days.Data were analyzed using SPSS version 16 for windows.

Results

During 27 092 days of inpatient surveillance, 497 NIs and nFUO were registered in 1564 patients (2084 admissions with a mean length of hospital stay of 13 days) (Table 1). Of these, 234 (47.1%) were documented NIs, and 263 (52.9%) nFUO. The overall rates for NIs and nFUO were 8.6 and 9.7 per 1000 patient-days (25.3 and 15.4 per 1000 patient-days at risk), respectively.

A total of 497 cultures were collected (160 blood samples, 151 urine, 109 respiratory secretions, and 77 cerebrospinal fluid); 234 of the 497 cultures were positive (47.1%). Blood stream infection was detected in 100 of 234 positive cultures (42.7%), followed by respiratory tract infections (25.3%), urinary tract infections (22.2%), and lastly central nervous system infections (9.8%). nFUO accounted for 263 episodes (52.9% of defined patients).

Gram-positive cocci represented 64.5% of isolated organisms (151/234), followed by Gram-negative bacilli that were isolated in 30% of the organisms (70/234). Staphylococci were the most common Gram-positive bacterial isolates (71.5%), of which coagulase negative Staphylococci constituted 20%. E. coli were responsible for 48.6% of isolated Gram-negative bacilli (34/70). Fungal infections caused by candida albicans were detected in 13 patients (5.5%) (Table 2).

The highest sensitivity of isolated organisms was recorded for cefoperazone/sulbactam with a percent sensitivity of 49.9%, followed by amikacin, imipenem/cilastin, and cefoperazone with percent sensitivities of 35.9%, 34.4%, and 33.6% respectively. Vancomycin had a sensitivity of 36.5%, and the lowest sensitivities were recorded for erytheromycin (24.5%), gentamicin (24.1%), and tobramycin (12.5%) (Fig.). Methicillin-resistant S. aureus (MRSA), extended spectrum beta lactamase (ESBL) and vancomycin resistant Enterococci (VRE) represented 30%, 45% and 75% of isolated Staphylococcus aureus, Gram-negative organisms and Enterococci respectively.

The risks for NIs and nFUO were significantly higher during neutropenic days compared to non-neutropenic days, with 184 of 234 NIs (78.6%) and 198 of 263 nFUO (75.3%) occurring during 10 865 patient-days at risk (P<0.001) (Table 3). 

Discussion

In this study, the overall incidence rate of NIs was 8.6 per 1000 patient-days (11.2 per 100 admissions). A similar incidence was reported by Wang et al.^[6] However, higher incidences were found in other studies.^[1,10,15] The sample size, the length of study, and the inclusion criteria together with the epidemiological data in different institutions may affect the rate of NIs in different studies. In our study, the inclusion of thalassemic patients who were at lower risk than oncologic patients (incidence rate 2.5 per 1000 patient-days) affected the overall NI incidence. The multi-center European study of Raymond and Aujard^[5] supports this explanation with an overall incidence of 2.5%, ranging from 1% in general pediatric wards to 23.6% in pediatric intensive care units.

The rate of NIs was significantly higher in neutropenic patients (patients at-risk) than in non-neutropenic patients. This finding is consistent with that reported by Engelhart et al^[10] who reported a significant risk of NI during neutropenic days with a rate of 25 per 1000 patient-days. Other studies have shown a higher incidence of NIs among cancer patients with neutropenia.^[4,16,17] This supports the role of neutropenia as a risk factor predisposing to NI and necessitates more careful management with strict application of infection control measures for this group of patients.^[1]

nFUO represented 52.9% of defined nosocomial infection cases. It is in agreement with several other studies which reported a high incidence of FUO reaching up to 50% in hematology/oncology and neutropenic patients.^[1,10,18,19] Viral infections may be among the pathogens responsible for FUO in these patients, but we did not screen for viruses because of lack of resources. However, viruses accounted for 6%-22% of NIs in different studies.^[5,16] Fungal as well as bacterial infections may also underlie this problem as evidenced by response to empiric antifungal agents and antibiotics.^[20,21]

With regard to the frequency of clinically or microbiologically documented sites of infections in our study, blood stream infection was responsible for the majority of cases, which is similar to the findings in other studies.^[1,7,15,22] Interestingly, bacteremia was even observed in asymptomatic neutropenic patients.^[23] This finding may raise the argument about the benefit of prophylactic antibiotics to prevent bacteremia in oncologic patients especially during neutropenia. Although this approach may reduce the incidence of fever, probable infection and the rate of hospitalization, it may interfere with culture results and may predispose to microbial resistance.^[24]

Infections of the central nervous system and urinary tract represented 9.8% and 22.2% of documented infections respectively, which are relatively high. However, the reported incidence of central nervous system infections in immunocompromised patients ranged from 0.6% to 14% with an expected mortality of 42%-77%.^[25] Similarly the incidence of urinary tract infections in oncologic patients was also reported to be as high as 25.6%.^[4] Environmental and non-environmental factors could explain this wide variation of incidence in different localities. In addition to the immunocompromised state in studied patients, other factors such as intrathecal therapy, catheters placement, overcrowding and unhealthy hygienic habits of some patients may underlie this problem in our series as well as in those of other developing countries. However we could not document any predictors in such patients.

Most of the isolated organisms in this study were Gram-positive (64.5%), a finding that support the reported trend of Gram-positive predominance since the 1980s.^[1,7,19] Several reasons were postulated to explain this predominance of Gram-positive pathogens in hematology/oncology patients. Generally, treatment of cancer has been intensified and it is associated with severe mucositis predisposing to Strept viridans bacteremia. In addition, partially or totally implantable intravenous catheters form a risk of Staphylococcal infection. The selection pressure of antibiotics that are more sensitive against Gram-negative organisms may play a role.^[26,27]

In the present study, the highest sensitivity of isolated organisms was recorded for cefoperazone/sulbactam (49.9%) followed by amikacin, imipenem/cilastin, and cefoperazone. This finding confirmed the growing antimicrobial resistance, especially induced by Staphylococci, Enterococci and Klebsiella.^[5,7,28,29] Unfortunately, vancomycin had a low in vitro sensitivity of only 36.5% against Gram-positive organisms in our study. Despite numerous reports of vancomycin resistance, the frequency of this resistance was found to be low.^[30] Froggatt et al^[31] however, observed that 42% of cases of Staphylococcal haemolyticus were intermediately resistant to vancomycin. This low susceptibility to vancomycin may be due to the frequent use of the agent leading to the appearance of resistant strains. The sensitive technique used to detect drug resistance that adds intermediate sensitivity to resistant organisms may be an additional factor. Anyhow, this should represent a serious problem of emerging or increasing resistance of Gram-positive bacteria to this antibiotic.

MRSA constitutes 30% of S. aureus isolates and 45% of Gram-negative bacteria showed an ESBL phenotype. These findings are in agreement with previous studies that the incidence of MRSA was 30%-38.5% from Staphylococcus species and that 30%-44% of enterobacteria were ESBL.^[32-34] VRE represented 75% of the few enterococcus faceum isolates. Our results indicated the increased VRE colonization of patients. Colonization with VRE was recorded in 38%-50% of pediatric hematology/oncology patients.^[35,36] This high frequency of resistant pathogens necessitates meticulous implementation of infection control measures with targeted MRSA control programs together with restrictive use of gylcopeptide antibiotics.

In conclusion, NIs and FUO are common problems in pediatric hematology/oncology patients especially with neutropenia. Infections, predominantly via blood stream, caused by Gram-positive organisms show significant multi-drug resistance with a high incidence of MRSA, ESBL and VRE organisms.

Funding: None.

Ethical approval: Not needed.

Competing interest: No benefits in any form have been received or will be received from any commercial party related directly or indirectly to the subject of this article.

Contributors: Al-Tonbary YA proposed the study and wrote the first draft. Soliman OE analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. Sarhan MM is the guarantor.

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Received April 22, 2009 Accepted after revision October 19, 2009