Chemotherapy Induced Febrile Neutropenia and Its Association with Nosocomial Bacteraemia : Risk Factors and Prognosis

For decades, febrile neutropenia (FN) in cancer patients has been treated with utmost urgency, necessitating immediate initiation of empirical broad spectrum intravenous antibiotics. Recently, it has become evident that neutropenic cancer patients are not a homogeneous group and that practice guidelines may vary on their risk status. Thus, this study aimed to evaluate the significance and risk factors predisposing to a positive blood culture in febrile pediatric cancer patients with chemotherapy-induced FN, and to study the impact of nosocomial bacteraemia on clinical course and outcome of these febrile episodes. A prospective cohort study included febrile episodes occurring in a large group of pediatric patients with chemotherapy-induced FN at the National Cancer Institute over a period of one year. Blood cultures were drawn and micro-organisms were identified. Among 729 episodes of fever and neutropenia recorded in 475 patients, bacteraemia was detected in 46.2% of episodes of which 56% showed a lengthy episode (≥ 7days). Coagulasenegative Staphylococci (CoNS) were associated with the least complications while Gram negative bacteraemia (GNB) were associated with the most severe blood stream infections (BSI). The overall mortality rate was 7.5% (n=55) and was significantly higher among BSI (11%) than those episodes that were not bacteraemic (4.6%). In addition, the mortality was significantly higher in GNB and mixed BSI, than in Gram positive BSI with p< 0.001. Logistic regression determined BSI, a lengthy episode, younger age of child with a relapsing tumor and presence of a canula as independent factors affecting mortality and thus prognosis of the child with FN. Results of the study suggest significant differences in the clinical characteristics of BSI by the different classes of micro-organisms in pediatric cancer patients with chemotherapy-induced FN. BSI profoundly influences course and outcome of episodes. Continuous multi-disciplinary surveillance of BSI is warranted in this group of patients to develop strategies for antimicrobial resistance control and treatment of infectious complications.

Overall, childhood cancer constitutes a major problem of public health importance.
The incidence of childhood cancer worldwide varies between 100 and 180 per 1,000,000 child/year [1] .Childhood cancer differs tremendously from adults and the Bull High Inst Public Health Vol.38 No. 4 [2008]   principal groups are leukemias, and lymphomas [2] .intensive chemotherapy, and the use of stem cell transplantation [3] .Moreover, children with neoplastic diseases have more prolonged and repeated contact with the hospital environment, increasing the risk of nosocomial infections [4] .

Over
Febrile neutropenia affects an everincreasing number of persons worldwide and poses a major burden in health care and economic terms [5] .Febrile neutropenia among pediatric oncology patients is a frequent complication of chemotherapy.It occurs in 10 -50% of pediatric patients with solid tumors and in over 85% of those with blood malignancies.It usually requires treatment for 7 -12 days, at an estimated daily cost of over 1500 US $, and is also associated with a mortality rate of nearly 10% [6] .
In a potentially life-threatening situation, the major challenge in cancer care presents as nosocomial infection in terms of clinical assessment, diagnosis and treatment.Blood stream infections (BSI) comprise about 20% of all nosocomial infections affecting cancer patients, including children and adults, with reported proportions ranging from 10% to 36% [7] .
Hence this study was conducted to gain insight of the risk factors predisposing to blood stream infections, and to identify the Persistence of fever for 7 days or more was defined a lengthy episode.
❖ Bloodstream infections (BSI) were considered in case of any organism isolated from blood and included both bacteraemia and fungemia.

❖ Clinically documented infections (CDI)
.Blood cultures were performed in parallel with other cultures from existing clinical sites of infection whenever possible.The most common toxicity in pediatric cancer is chemotherapyinduced neutropenia.It is associated with considerable morbidity and mortality directly linked to duration and severity of episodes [9] .Findings from our study identified 46% of febrile episodes with BSI.

Ethical considerations:
Similar high figures were recorded by other researchers who carried out a surveillance study of nosocomial infections in pediatric hematology oncology patients, in Germany [10] .
The first line of defense in controlling bacterial invasion of the bloodstream is predominantly the neutrophils.Risk of developing infection significantly increases as the ANC falls below < 0.5 x 10 9 /L and is highest when it falls below 0.1 x 10 9 /L [11] .

This is consistent with findings of our study
where an ANC level below 0.1 x 10 9 /L significantly increased the risk of BSI by more than 70%.Additionally, episodes extending for more than 7 days were encountered more frequently in BSI episodes than in non-BSI episodes (56% versus 29% respectively) with an increased risk 1.8 times which was statistically significant.These findings are in line with those from another study that reported profound neutropenia and duration of episodes as strongly associated with bacteraemia [12] .ANC < 0.1 x 10 9 /L has consistently been reported as an important risk factor for bacteraemia [13] with some studies reporting more than a two-fold risk [14] .
Indicators of a positive blood culture in febrile children with cancer could be of help to stratify patients into low and high risk groups.In the present study, younger age group less than 7 years and the presence of CDI were significantly associated with more frequent BSIs.These are in line with other studies that reported young age as a risk factor for BSI [15] .It general, it is expected that younger children are more susceptible to infection and thus to bacteraemia especially with presence of Bull High Inst Public Health Vol.38 No. 4 [2008]   cancer.
Additionally, another study reported 64% of their patients displaying overt CDIs of which 14% were positive for blood cultures [16] .Other factors that were found, in our study, to increase the risk of BSI were presence of a central venous catheter (RR = 2.07), and thrombocytopenia (RR=1.65).However, although a relapsing tumor was associated with a 14% increased risk for BSI, yet this finding was statistically insignificant.Similar studies reported presence of a catheter as a risk factor for bacteraemia [17] , and others found relapsing leukemia and low platelet count to increase the risk of BSI by 80% and 70% respectively [18] .The type of underlying disease although associated with a minor increased risk of bacteraemia in our patient population yet proved statistically insignificant.Likewise, other authors found no significant effect of underlying disease in relation to BSI [19] .
In recent years, Coagulase-negative Staphylococci (CoNS) have been the most prevalent organisms [4] .In agreement, our results showed that CoNS were the commonest organisms isolated; they accounted for nearly 17% of all BSIs.Yet, not all CoNS bacteraemia constituted significant infections, as the majority of episodes were short with no CDI detected.
Only 21% of CoNS bacteraemia in the present study had episodes of 7 days or longer and all these cases showed a concomitant infection of diarrhea or skin infections.None of the cases with CoNS bacteraemia had an unfavorable outcome, either as a single isolate or mixed.
Similarly, other studies reported up to 13% of blood cultures positive for CoNS as true bacteraemia [20] .were previously reported on the morbidity and mortality caused by MRSA in patients with hematological malignancies [21] .
On the other hand, many centers are reporting an increase in the incidence of GNB [22] .This could be explained by the use of more intensified regimens of chemotherapy.In our study, 43.3% of all BSIs were attributed to Gram-negative organisms.A possible explanation could be that BSI in neutropenic patients is more likely derived from endogenous sources, such as the gastrointestinal tract [23] , and hence the high frequency of diarrhea in our patients might explain the high prevalence of GNB.Additionally, a significantly longer episode was recorded for GNB and mixed infections when compared to GPB.
Moreover, an unfavorable outcome, recognized by death of patients, was encountered more frequently with GNB and mixed infections, (18.0%), than in GPB (2.7%) and this finding was highly significant.These results follow other reports that showed BSI with Gram negative bacilli to be significantly associated with an increased risk of mortality [24] .
The overall mortality rate reported in our study was 7.5%.It was also recorded that mortality in episodes with BSI was significantly higher than those of episodes with no growth (11% versus 4.6% respectively).Our results are slightly higher than those found in other studies that reported a mortality rate of 3%, with mortality, for BSI, to be 9% versus 2% among patients without BSI [25] .

BSI and increased length of episodes
were shown in our study to be independent factors for mortality, as they increased the risk by more than a double.A relapsing tumor and younger age of the child triples the risk for death while presence of a Bull High Inst Public Health Vol.38 No. 4 [2008]   canula significantly increased the risk to about four folds.These findings are consistent with other studies that showed infants' age, presence of BSIs, in the form of Gram-negative and Gram-positive organisms, as well as presence of I.V. site infection, to be independent significant risk factors for death [18] .Additionally, others confirmed that prolonged profound neutropenia (> 14 days) and disease status were indicators of likelihood for complications [12] .

Conclusions:
Prospective surveillance for nosocomial infections in pediatric oncology units is an indispensable tool for its' internal quality control [10] .
cancer has improved dramatically.However, significant morbidity and mortality from infectious complications still limit the success of newer modes of therapy.Children with cancer have an added risk of infection because of the use of immunosuppressive chemotherapy and radiation.In recent years, the risk has increased by the use of indwelling central venous catheters, more

❖
Study site and design: This prospective, single center cohort study was conducted at the National Cancer Institute, Cairo University.Study population: All pediatric cancer inpatients treated with chemotherapy for a malignant disease and developing a febrile episode necessitating a blood culture test were included in the study.During the period from January to December 2007, defined as a single reading of 38.5 o C or more or between 37.5 -38.0 o C on two occasions during a 24 hour period.Patients were considered neutropenic if their Absolute Neutrophilic Count (ANC) was < 0.5 x 10 9 /L or between 0.5 -< 1.0 x 10 9 /L and was expected to decline dramatically below this level in the two successive days.During this period, children presenting with febrile neutropenia during their hospitalization for chemotherapy were treated with empirical, double agent, broad spectrum parentral antimicrobial therapy.Antibiotic therapy was continued until the patient became afebrile and ANC exceeded 1.0 x 10 9 /L.The episode was considered to be successfully controlled when patients remained afebrile for 72 hours and clinical signs resolved.

Table ( 1): Initial and clinical characteristics of episodes found in enrolled patients.
Findings of the present study, * Chi square test [All insignificant] † Student's t -test [All insignificant]