Susceptibility to infection in patients with neutropenia: the role of the innate immune system O. W. Neth, M. Bajaj-Elliott, M. W. Turner and N. J. Klein Infectious Diseases and Microbiology Unit, Institute of Child Health and Great Ormond Street Hospital NHS Trust, London, UK Summary Chemotherapy-induced neutropenia increases the risk of infection. There appears to be a wide variability in the severity and length of infective episodes. Susceptibility to infections is determined by the underlying malignant disease and its treatment, environmental factors (e.g. nutritional state of the patient and hygiene) and genetically determined variations of the immune system. The majority of primary immuno- deficiencies are rare (c. frequency one in 10 000), whereas some genetic polymorphisms in the innate immune system, such as profound mannose-binding lectin deficiency, are much more common (c. frequency one in 10). Here, we review the potential role of the innate immune system in determining susceptibility to infections in patients with neutropenia. Keywords: neutropenia, cancer, innate immunity, mannose- binding lectin, infection. In the Western world, more than one in 600 children will develop a malignancy in the first 15 years of life (Stiller, 1997). Although there have been major advances in therapy, most children have chemotherapy-associated complications, the commonest of which is infection. It is now nearly four decades since the relationship between the degree of neutropenia and the risk of bacterial and fungal infections was first recognized. Bodey et al (1966) published the first detailed account of the infectious complications of 52 patients treated with cytotoxic chemotherapy for acute leukaemia. They made the observation that, as granulocyte counts fell, the frequency, duration and severity of infections dramatically increased. This was partic- ularly marked when neutrophil counts fell <500 cells/ll (Fig 1). Lymphocytes were similarly affected and low counts were also related to increased infections. Infections were noted to be worse during relapse of the underlying disease and the failure of leucocytes to recover following an infection was associated with a very poor prognosis. It is now clear that this is largely determined by both the underlying disease and the potency of chemotherapy. Interestingly, however, it is apparent that patients differ in their susceptibility to infection in the context of neutropenia. This indicates that other factors are operating to protect patients from infection in their immunocompromised state. This article explores the potential role of the humoral arm of the innate immune system in providing protection from infections during neutropenia. The innate immune system The adaptive immune system provides highly specific recog- nition of both host and foreign antigens, allowing for effective handling of a multitude of microorganisms and the generation of targeted immunological memory. The innate immune system, which is a more ancient arm of immunity (Hoffmann et al, 1999), also provides host defence against a vast array of pathogenic microbes. However, the specificity of the recogni- tion systems employed is targeted against highly conserved structures common to large groups of microorganisms. This is achieved through interactions between host-derived pattern- recognition receptors (PRR) and pathogen-associated molecu- lar patterns (PAMP) on microbes, which are frequently the repeating sugar arrays expressed on microbial surfaces (Jane- way, 1989). Whilst the adaptive and innate systems are often considered as separate entities, the fact that the adaptive immune system has evolved in the presence of the innate system suggests the probability that the two systems may be linked. This has indeed been demonstrated in many ways, not least of which is the common use of certain effector cells and soluble mediators (Janeway, 1989; Janeway & Medzhitov, 2002; Iwasaki & Medzhitov, 2004) Pattern-recognition receptors The PRR can be expressed on the cell surface, in intracellular compartments, or secreted into the bloodstream and tissue fluids (Medzhitov & Janeway, 1997, 2002; Uronen-Hansson et al, 2004). They are expressed on most effector cells of the immune system and, of particular relevance to innate immu- nity, is their presence on macrophages, dendritic cells and Correspondence: Nigel J. Klein, Professor of Infectious Diseases and Immunology, Infectious Diseases and Microbiology Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. E-mail: n.klein@ich.ucl.ac.uk review ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 129, 713–722 doi:10.1111/j.1365-2141.2005.05462.x