Malnutrition and Infection: Complex Mechanisms and Global Impacts

doi:10.1371/journal.pmed.0040115.g001 Malnutrition and Infection: Complex Mechanisms and Global Impacts Ulrich E. Schaible 0 Stefan H. E. Kaufmann 0 0 Ulrich E. Schaible is at the London School of Hygiene and Tropical Medicine, Department of Infectious and Tropical Diseases, Immunology Unit , London , United Kingdom. Stefan H. E. Kaufmann is at the Max Planck Institute for Infection Biology, Department of Immunology , Berlin , Germany - I am not interested in the bloody system! Why has he no food? Why is he starving to death? Bob Geldof in The Observer, 1985 Aimmune responses during ctivation and sustenance of infection requires increased energy consumption. Protein energy malnutrition (PEM) is a critical, yet underestimated factor in susceptibility to infection, including the big three infectious diseases: HIV/AIDS, tuberculosis, and malaria. In this article, we discuss current concepts and controversies surrounding the complex influences of malnutrition on infection and immunity, and point to practical consequences of countermeasures in acute malnutrition. We call for new strategies to overcome worldwide morbidity and mortality caused by chronic malnutrition in impoverished countries and by the newly emerging public health threat of overnutrition in industrialized societies. In response to infection, the immune system first executes innate and then subsequently acquired host defense functions of high diversity. Both processes involve activation and propagation of immune cells and synthesis of an array of molecules requiring DNA replication, RNA expression, and protein synthesis and secretion, and therefore consume additional anabolic energy. Mediators of inflammation further increase the catabolic response. Studies in a simple system, involving measurement of the survival of malnourished bumblebee workers, showed that the energy cost of immunity further impairs fitness [1]. Consequently, the nutritive status of the host critically determines the outcome of infection. Apart from deficiencies in single nutrients, such as vitamins, fatty Research in Translation discusses health interventions in the context of translation from basic to clinical research, or from clinical evidence to practice. Figure 1. Protein Energy Malnutrition Increases Prevalence of Infection, Leading to Energy Loss for the Individual On the community level, this burden reduces productivity, including food production, and perpetuates the relentless spiral of further malnutrition, infection, disease, poverty, and socioeconomic and political instability. acids, amino acids, iron, and trace elements, undernourishment based on PEM greatly increases susceptibility to major human infectious diseases in low-income countries, particularly in children [24]. Malnutrition is responsible, directly or indirectly, for 54% of the 10.8 million deaths per year in children under five and contributes to every second death (53%) associated with infectious diseases among children under five years of age in developing countries [5]. Infection causes energy loss on the part of the individual, which reduces productivity on the community level and perpetuates the alarming spiral of malnutrition, infection, disease, and poverty (Figure 1). Malnutrition and Infection Malnutrition increases risk of infection. PEM is a common cause of secondary immune deficiency and susceptibility to infection in humans (Table 1). This Competing Interests: The authors have declared that no competing interests exist. Copyright: 2007 Schaible and Kaufmann. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abbreviations: BMI, body mass index; lg, immunoglobulin; PEM, protein energy malnutrition; RNI, reactive nitrogen intermediate; ROI, reactive oxygen intermediate; TH1, type 1 T helper cell; TH2, type 2 T helper cell *To whom correspondence should be addressed. E-mail: Table 1. Conditions of Under- and Overnutrition and Their Influence on Host Defense Functions Response Mechanisms Affected/Promoted Tuberculosis, diseases due to opportunistic, multibacterial, and fungal infections, osteomyelitis, diabetic foot (P. aeruginosa, Staphylococcus aureus, S. pneumoniae, Enterococcus) causal relationship is further supported by animal studies. Severe PEM in children is clinically defined as less than 70% weight-toheight and/or the appearance of pitting edema on both feet, described as either marasmus, a chronic wasting condition, or kwashiorkor, characterized by edema and anemia. Children with kwashiorkor often suffer from marked skin infections. Severe malnutrition during childhood affects thymic development, which compromises immunity in children by a long-term reduction of peripheral lymphocyte counts [6]. This immunodeficiency represents a key factor in susceptibility to infections and has therefore been termed nutritionally acquired immunodeficiency syndrome [7]. In severely malnourished patients, both acquired immunityi.e., lymphocyte functionsas well as innate host defense mechanismsi.e., macrophages and granulocytesare affected. Diminished immune functions render undernourished patients more susceptible to infections, notably those by opportunistic pathogens commonly prevalent in patients with HIV/ AIDS [24,8,9]. The opportunistic fungus Pneumocystis carinii, frequently diagnosed in patients with AIDS, was repeatedly identified in malnourished children after the Second World War [9]. Noma is an opportunistic infection in children between one and four years with PEM, which occurs worldwide, but is most common in sub-Saharan Africa. The infection evolves from gingival inflammation to orofacial gangrene and is commonly preceded by other infections such as measles, malaria, severe diarrhea, and necrotising ulcerative gingivitis. Noma coincides with the period of linear growth retardation in malnourished children [10]. In addition to promoting acute and chronic infections, PEM impairs the linear growth of children, leading to a further reduction in food intake, nutrient absorption, direct or catabolic nutrient losses, and increased metabolic requirements. It has been suggested that acute phase response and proinflammatory cytokines directly affect the bone remodelling required for longitudinal growth [11]. Correlation of malnutrition and growth retardation allows assessment of the individual nutritional state, which is usually measured as midupper arm circumference or body mass index (BMI). BMIs are given either as weight-for-height to indicate acute PEM (wasting), or as weightfor-age (underweight) or heightfor-age (stunting), correlations for chronic PEM. A study in Kenya found a significant association between HIV infection and lower mid-upper arm circumferences and serum albumin concentration, another measure of malnutrition, but found no such as (...truncated)