Risk assessment in fever and neutropenia in children with cancer: What did we learn?

Abstract

Children with cancer treated with chemotherapy are susceptible to bacterial infections and serious infectious complications. However, fever and neutropenia can also result from other causes, for which no antibiotic treatment is needed. In the past decades attempts have been made to stratify the heterogeneous group of pediatric cancer patients with fever and neutropenia into high- and low-risk groups for bacterial infections or infectious complications. Strategies for risk assessment have resulted in treatment regimens with early discharge or even no hospital admission at all, and/or treatment with oral or no antibiotics. We will provide a historical overview of the changing approach to low-risk fever and neutropenia, and we will also try to identify clear and objective parameters for risk assessment strategies and illustrate their relationship to innate immunity. In the future, new insights into genetic susceptibility on neutropenic fever might be of use in children with cancer with fever and neutropenia.

Introduction

Historically, subjective and objective parameters have been used in various attempts to divide children with cancer and chemotherapy-induced fever and neutropenia (FN) into high- and low-risk groups in order to customize their treatment and provide a better quality of life. This review will focus on clear and objective prognostic parameters for risk assessment in separating pediatric cancer patients with FN into high- and low-risk groups.

Chemotherapy-induced neutropenia is one of the major side effects of cancer treatment. In 1966 Bodey et al. published some calculated relative risks as follows. In patients with less than 1000 granulocytes/mm³, the risk of infection increased from about 38% to 63% from the onset of the neutropenia to 3 weeks after onset [1]. In patients with less than 100 granulocytes/mm³, the infectious risk after 3 weeks of neutropenia even increased as much as 100%. In severe infections the mortality risk was approximately 46% when the initial granulocyte count was less than 1000 mm⁻³, and when the granulocyte count decreased below 100 mm⁻³, the mortality risk increased as much as 80%. These results underscore the importance of both the duration and depth of the neutropenia for an increased risk for and fatal outcome of infectious diseases [1]. Internationally, the most frequently used definition of neutropenia in relation to fever is an absolute neutrophil count <0.5 × 10⁹ l⁻¹ (or <1.0 × 10⁹ l⁻¹ and expected to fall, or a leukocyte count <1.0 × 10⁹ l⁻¹).

Fever (defined as a single body temperature of >38.5 °C or two repeated readings of >38.0 °C [2], [3], [4], [5]) can be the first sign of bacterial infection. Other signs of inflammation such as local heat, swelling, exudate, fluctuation and ulceration are often diminished in neutropenic cancer patients due to an impaired inflammatory response [6].

Historically, standard care for pediatric cancer patients with FN consists of routine hospitalization and empirical treatment with parental administration of broad-spectrum antibiotics (AB), in the light of the relative risk for infectious complications. These episodes of FN might be the result of bloodstream infections with pathogenic micro-organisms. However, 70–89% of the episodes of FN have no causative micro-organisms demonstrated in their blood cultures (BC) [7], [8], [9], [10], [11]. It can be hypothesized that many episodes of FN can be the result of inflammatory responses to, for example viruses, transfusions of blood products, malignancy itself, chemotherapeutic drugs or mucosal damage.

Historically, patients are considered to be eligible for discharge when they have completed their antibiotic course, are afebrile and when the absolute neutrophil count has recovered to at least 0.5 × 10⁹ l⁻¹ [12], [13], [14]. This approach results in overtreatment of the subgroup of patients without a proven bacterial infection, in a risk of increased bacterial resistance, and in a decrease in quality of life and increase in health care costs. In 2002 the Infectious Diseases Society of America (IDSA) published a clear protocol for adult cancer patients with FN [15]. Early discharge of pediatric patients was a yet more delicate question; after ≥48 h of in-hospital treatment with parental AB and observation, early discharge with oral cefixime may be considered for selected children at low risk for bacterial infections [15] (Fig. 1). Low-risk selection criteria were defined as: absence of severe comorbidity, good clinical condition, negative BC, no MRSA in cultures in the last 12 weeks, control of local infection and afebrile for the past 24 h [16], [17]. In these guidelines, initial therapy with oral AB alone or without AB is not recommended for children.

Therefore, it is appropriate to use less intensive antibiotic treatment regimens in children with cancer at low risk. How can we define low risk using objective parameters? To answer this question we will first discuss the mechanisms of the innate immunity in oncology patients. Second, a summary of possible prognostic parameters found in various studies will be provided. Finally, clinical studies will be discussed, along with the possible ways to handle the dilemma of “low risk.”

It is commonly accepted that the host response to fever in neutropenia patients results from the effector cells of the immune system. The immune system is divided into the nonspecific innate immune system and the specific adaptive immune system. The adaptive immune system consists of components that are acquired after birth; it is the response of antigen-specific lymphocytes to antigens and includes the development of immunological memory. The innate immune system (including the mucocutaneous barriers) is the first line of defense against microbes. In healthy people all the components of innate immunity are already present prior to exposure to microbes and will act immediately against them. The complement system and its’ lectin pathway are essential in the opsonization of pathogens. Granulocytes and macrophages are the main executers of defense [18] (see Fig. 2). These effector cells of innate immunity mediate the earliest phases of inflammatory response [18], [19]. The effector cells recognize groups of pathogens by using a limited number of receptors. Molecular patterns on the bacterial cell wall, the so-called pathogen-associated molecular patterns such as lipopolysaccharide, are bound by these receptors, for example the Toll-like receptor family. This binding induces signal transduction pathways, resulting in up-regulation of the production of cytokines and stimulation of the adaptive immune system in order to develop specific effector cells against the infectious micro-organism [20], [21]. Moreover, pro-inflammatory cytokines, for example, interleukin (IL) 1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-6 and their receptors [22], cause local (e.g., redness and pain) and in the end systemic inflammation (e.g., fever and metabolic changes) (see Fig. 2). The innate immunity system might therefore provide objective parameters for risk assessment of FN.