Undernutrition, the Acute Phase Response to Infection, and Its Effects on Micronutrient Status Indicators^,

Abstract

Infection and undernutrition are prevalent in developing countries and demonstrate a synergistic relation. Undernutrition increases infection-related morbidity and mortality. The acute phase response (APR) is an innate, systemic inflammatory reaction to a wide array of disruptions in a host’s homeostasis, including infection. Released from immune cells in response to deleterious stimuli, proinflammatory cytokines act on distant tissues to induce behavioral (e.g., anorexia, weakness, and fatigue) and systemic effects of the APR. Cytokines act to increase energy and protein requirements to manifest fever and support hepatic acute phase protein (APP) production. Blood concentrations of glucose and lipid are augmented to provide energy to immune cells in response to cytokines. Additionally, infection decreases intestinal absorption of nutrients and can cause direct loss of micronutrients. Traditional indicators of iron, zinc, and vitamin A status are altered during the APR, leading to inaccurate estimations of deficiency in populations with a high or unknown prevalence of infection. Blood concentrations of APPs can be measured in nutrition interventions to assess the time stage and severity of infection and correct for the APR; however, standardized cutoffs for nutrition applications are needed. Protein-energy malnutrition leads to increased gut permeability to pathogens, abnormal immune cell populations, and impaired APP response. Micronutrient deficiencies cause specific immune impairments that affect both innate and adaptive responses. This review describes the antagonistic interaction between the APR and nutritional status and emphasizes the need for integrated interventions to address undernutrition and to reduce disease burden in developing countries.

Introduction

Undernutrition persists as a major global health concern, particularly in sub-Saharan Africa, South Asia, and regions of Latin America (1–3). Dietary intakes of populations in these areas are often chronically deficient in macronutrients [leading to protein-energy malnutrition (PEM)³], micronutrients (leading to specific micronutrient deficiencies), or both (2, 4–6). Poverty is the foundational cause of malnutrition and associated health determinants, such as infectious disease risk (7–9).

More than half of all deaths from infection are associated with malnutrition in children <5 y of age (10), and a synergistic relation exists between poor nutritional status and immunity and infectious disease. Malnutrition increases the vulnerability to infection through impaired immunity, and infection exacerbates the condition, further weakening the immune response (5). Even mild febrile infections negatively affect nutritional status; however, prior nutritional status of the host, extent of illness, and dietary intake during recovery determine the severity of the consequences (11–13). It is not surprising to find a high prevalence of microbial and parasitic diseases occurring in developing countries where undernutrition is common (6, 14).

PEM is associated with abnormal immune cell populations and impaired intestinal barrier function, which increases risk of microbial infection (5, 15–17). Micronutrient deficiencies can lead to specific immune impairments that negatively affect both innate and adaptive immune responses (16, 18). Innate immunity includes the acute phase response (APR), a systemic inflammatory reaction to a wide variety of imbalances in an individual’s homeostasis (19). During the APR to infection, metabolic processes and nutrient requirements are altered (19, 20). Furthermore, blood concentrations of micronutrients are affected, leading to inaccurate assessments of micronutrient status and misestimates of deficiency prevalence during infection, which are important in both public health and biochemical assessments of nutritional status (21–23).

We review here the relation between infection and nutritional status. We will first consider the effects of the APR to infection on nutrient metabolism and then the impact of infection on nutrient requirements and immune function. We will also consider acute phase protein (APP) measures in nutrition interventions and the impact of the APR on micronutrient status indicators.

Current Status of Knowledge

The APR to infection.

The APR is a systemic inflammatory reaction to disruptions in the body’s homeostasis due to infection, tissue damage, tumor development, certain chronic disease states, and immunologic disorders. Inflammation is believed to be protective to the host because it removes injurious stimuli and promotes the healing of damaged tissue. The magnitude of the APR varies with the severity of injury and by time.

Generally, the APR to infection initiates when a pathogen is detected by pattern recognition receptors, including Toll-like receptors, on a variety of immune cells. The activation of these receptors causes cells to secrete prostaglandins and cytokines that promote proinflammatory mechanisms, such as increased vascular permeability and the recruitment of more cytokine-secreting neutrophils and macrophages. Cytokines serve as short-lived, long-range mediators that act on various tissues to mount the systemic response, which is commonly characterized by fever, leukocytosis, increased secretion of adrenocorticotropic hormone (ACTH) and glucocorticoids, and alterations in plasma protein concentrations. Protein concentrations that are increased or decreased in the plasma during the APR are called positive or negative APPs, respectively, and are primarily regulated by the liver. The APR is limited by counter-regulatory mechanisms, including diffuse cell-mediated and targeted neural anti-inflammatory pathways. These mechanisms also promote tissue repair once the deleterious stimuli have been removed. The pathophysiologic changes that occur during the APR were previously reviewed in detail (19, 24–38). Aspects of the APR that relate to nutrient metabolism and nutritional status will be examined further herein.

Cytokine biology and nutrient metabolism.

Acute phase cytokines are multifunctional and can be divided into 3 categories: 1) proinflammatory cytokines, which include TNF-α and IL-1; 2) IL-6–type cytokines that promote systemic features of the APR; and 3) anti-inflammatory cytokines (26). These cytokines modulate the immune response and associated metabolic effects through complex interactions that can be additive, synergistic, or antagonistic. Cytokines regulate gene expression through intracellular signal transduction pathways that activate transcription factors (24, 39–41).

TNF-α and IL-1 are generated shortly after the initial stimulus, promoting the production of other cytokines, such as IL-6, and inducing sickness behavior by acting on distant tissue sites through cell-mediated and neural communication pathways (24, 42, 43). Cytokine-induced sickness behavior is characterized by symptoms of fever, anorexia, weakness, malaise, somnolence, and an inability to concentrate (19, 43–46). Fever increases energy expenditure by ∼7–11% per unit increase in temperature (°C) in children (Table 1) (47, 48). This, coupled with anorexia, produces a state of negative energy balance during infection. The fatigue and discomfort associated with illness are believed to have the adaptive advantage of energy conservation (43, 44).

TABLE 1.

Impact of the acute phase response to infection on energy expenditure and macronutrient metabolism¹

Metabolic indicator	Impact of infection
Energy	↓ Dietary intake due to appetite suppression, ↑ energy expenditure to produce fever
Macronutrient
Protein	↑ Muscle protein wasting, ↑ hepatic protein synthesis
Carbohydrate	↑ Blood glucose due to insulin resistance, glycogenolysis, and gluconeogenesis
Fat	↑ Peripheral lipolysis, ↑ hepatic TG and VLDL synthesis, ↓ serum cholesterol

¹↑, increase; ↓, decrease.

Proinflammatory cytokines shift metabolic processes to a catabolic state. TNF-α and IL-1 inhibit muscle protein synthesis and promote wasting (49–53). Through the stimulation of glucocorticoid release, IL-1 increases the whole-body flux of amino acids by promoting muscle catabolism and liver anabolism (54). During infection, mean losses are 0.6 g protein · kg body weight⁻¹ · d⁻¹, and can be as high as 1.14 g protein · kg body weight⁻¹ · d⁻¹ during peak febrile response (11). The high demands for aromatic amino acids in APP production are responsible for a substantial portion of the net loss in body nitrogen during the APR (55).

Hyperglycemia is directly induced by cytokines to fuel obligate glucose-consuming cells during infection. Proinflammatory cytokines act on the hypothalamic-pituitary-adrenal axis to increase production of ACTH and glucocorticoids, which promote glycogenolysis and insulin resistance (56). Additionally, TNF-α stimulates glucagon production, and both TNF-α and IL-1 promote gluconeogenesis (56, 57). The duration of hyperglycemia is dependent on the severity of infection and typically normalizes within 10 d (56); however, when infection is severe or septic, hypoglycemia can pose potentially lethal health risks (11).

Proinflammatory cytokines and IL-6 quickly increase serum TG concentrations by 1) promoting peripheral lipolysis, 2) increasing intracellular citrate concentrations to upregulate de novo FA synthesis and hepatic TG production, and 3) enhancing VLDL-cholesterol secretion (57, 58). Hepatic FA oxidation and ketogenesis are suppressed to ensure sufficient FA substrate for these processes. Serum cholesterol concentrations are decreased by TNF-α through suppression of LDL and HDL cholesterol. Alterations in lipid profile are protective to the host during infection because lipoproteins have the ability to bind bacterial endotoxin and viruses, resulting in rapid clearance by the liver and reduced activation of cytokine-induced inflammatory mechanisms. During inflammatory chronic disease states and sustained APR, the prolonged alteration of the lipid profile is associated with an increased risk of atherosclerosis (58).

IL-6 is the major regulator of the APR in hepatocytes and promotes the systemic effects of the APR by stimulating the growth and differentiation of many cell types. Although TNF-α and IL-1 can promote the production of certain APPs in the liver, IL-6 induces the production of the full spectrum of APPs in a dose-dependent manner (19, 24), which modulates the response to infection severity (24, 39). Additional APR functions facilitated by IL-6 include the maturation of B and T cells and hematopoiesis (24, 39, 59). IL-6 also displays anti-inflammatory attributes by suppressing TNF-α and IL-1 production in mononuclear cells and promoting ACTH and glucocorticoid production (24, 60, 61).

Infection and nutrient requirements.

Infection can lead to a reduction in food intake, impairment of nutrient absorption, and increased nutrient requirements (Fig. 1). Although breast-milk intake appears to be unaffected, food intake is suppressed in children during the APR according to the magnitude of infection. Caloric intake decreases between 8% and 22% in children with diarrheal diseases, malaria, and acute respiratory infection (62–64). During more severe infections, such as cholera and measles, decreases in caloric intake were reported to be 44% and 75%, respectively. In Peruvian infants with diarrhea or fever, breast-milk intake was unaffected; however, caloric intakes of non–breast-milk food decreased by 20–30%, resulting in an overall decrease in caloric intake of 5–6% (65). Infection-related caloric suppression results in both decreased macro- and micronutrient intake (63, 64).

FIGURE 1.

Infections can alter micronutrient status. For example, for vitamin A, illness can negatively affect status through 1) decreased dietary intake caused by cytokine-induced sickness behavior, 2) reduced intestinal absorption during both enteric and nonenteric infection, and 3) increased urinary excretion. Infection also suppresses the release of vitamin A from the liver, reducing plasma concentrations and thus possibly altering utilization of liver stores. CNS, central nervous system. Adapted from reference 110 with permission.

Nutrient absorption can be decreased during enteric and nonenteric infection. Gut helminths and diarrheal diseases can impair nutrient absorption by damaging epithelial cells (20, 63, 66). The extent of malabsorption corresponds to the severity of enteric infection and diarrheal output (20). Nutrient absorption appears to also be reduced during nonenteric infection. Carbohydrate malabsorption was observed in hospitalized American children with HIV infection (67). By using labeled tracer doses of vitamin A, Sivakumar and Reddy (68, 69) found that uninfected children absorbed 99% of the dose, children with diarrhea and Ascaris infection absorbed 70% and 80%, respectively, and children with nonenteric infection absorbed 74% of the dose.

In addition to increased energy requirements due to the metabolic cost of fever, macro- and micronutrient demands may be augmented through greater direct loss. Leakage of low-molecular-weight proteins in the urine is common during febrile infection (20). This phenomenon leads to protein loss in the urine, as well as loss of vitamin A bound to retinol-binding protein (RBP), which can exceed the daily requirement for children (70, 71). Tissue damage from parasitic infection can lead to blood loss and iron-deficiency anemia (20).

Undernutrition and immune function.

PEM and micronutrient deficiencies lead to underweight and stunting. As of 2011, 16% of children <5 y of age were underweight and 26% of children were stunted, which marks a great achievement in combating global malnutrition (72). However, half of all infectious deaths in developing countries are associated with a low weight-for-age (10). Although many interventions and research studies focus on severe PEM because of the associated sharp increase in mortality, Pelletier et al. (73) demonstrated that mild-to-moderate PEM accounts for 80% of childhood mortality in developing countries. Stunting also appears to compromise immune function, but the effect has not been studied comprehensively (15, 20).

PEM leads to increased susceptibility to and mortality from infection (74–76). Gut barrier function is decreased, increasing the risk of microbial infection (16). Undernourished individuals also experience a reduction in leukotrienes, which promote leukocyte accumulation and enhance macrophage phagocytosis, negatively affecting the host’s ability to kill microbial, fungal, and parasitic agents (77). During PEM, the structure and function of the thymus gland is damaged, leading to abnormal T-cell populations and reduced antigen response (78, 79). Compared with healthy children, B-cell response is lowered during malnutrition (80). However, the humoral response appears to be well preserved during the short-term seroconversion to whole inactivated viral and polysaccharide vaccines (81). Additionally, the development of antibody titers to common pathogens appeared to be normal in Kenyan children (82).

Conflicting evidence exists regarding the ability of children with severe PEM to mount a complete immune response. Although Doherty et al. (83) reported decreased TNF-α and IL-6 in an in vitro study using whole blood from malnourished children, Sauerwein et al. (84) found that children with PEM mount a greater immune response than do healthy children. A study in Kenyan children supports PEM as a proinflammatory state with a generalized increase in IL-6 (85). The APP response is impaired in children with severe PEM, with a greater deficit occurring in kwashiorkor as compared with marasmus (85–87). In children with marasmus, rates of protein catabolism are similar to healthy children during infection and higher than in children with kwashiorkor (88). These comparative differences in immunity may reflect an inappropriate response during kwashiorkor and are consistent with observations of a lower fatality rate in marasmic children with infection (89).

A high burden of infectious disease is associated with delayed linear growth and stunting (90–94). Similar to underweight, stunted children display an abnormal lymphocyte profile (15). Rural children in developing countries tend to experience more severe stunting and have higher plasma concentrations of APPs than do children living in urban settings (73).

Severe deficiencies frequently occur for multiple micronutrients simultaneously and can complicate PEM (17, 18). Certain micronutrients, including vitamin A, iron, and zinc, are important immunomodulators and thereby are crucial to the host in mounting an effective response to infection. Iron deficiency is a major global health concern, affecting 3.5 billion people (95). Iron is essential for redox reactions, gene regulation, oxygen delivery to tissues, and cell growth (96–98). Iron supports immunity through its involvement with peroxide- and NO-producing enzymes, cytokine production and function, and lymphocyte proliferation (96–98). Iron homeostasis is paramount because deficiency and overload negatively affect immune function (96). Many pathogens require iron to thrive, and therefore sequestration during infection is protective to the host (96, 97). Iron supplementation is controversial because excess and timing of repletion may promote pathogenic infection (97). In deficient children, iron supplementation improves status and promotes related growth and development (99). However, iron supplementation in children does not affect the incidence of infection or associated mortality and may increase the risk of diarrheal diseases and malaria (99, 100).

Zinc is essential for highly proliferating cells in the immune system and influences both innate and acquired immune functions (101–103). Zinc is a coenzyme in many important reactions during the immune response and is essential for thymic hormone function (102, 104). Phagocyte and lymphocyte activity are impaired or completely suppressed in zinc deficiency, resulting in weakened cytokine and antibody responses (101–103). Zinc deficiency affects approximately one-third of the global population and often coexists with PEM (18, 105). Zinc supplementation in children promotes gains in weight and height and protects against respiratory infections (106–108). Although zinc supplementation protected against diarrheal disease in children <5 y of age (107), Negi et al. (109) recently reported supplements to be ineffective in children between 5 and 12 y of age.

Vitamin A deficiency compromises innate immunity through the degradation of mucosal epithelial barriers and impaired development of neutrophils, macrophages, and NK cells (110). Pathogen-specific immunity is also lessened during vitamin A deficiency via reduction in antibody production in T cells (110). Vitamin A deficiency affects 190 million children and is the leading cause of preventable blindness (111). Xerophthalmia is associated with respiratory tract infection, measles, and diarrhea in children (112). This is not surprising considering that infection can worsen deficiency through anorexia and increase direct loss of vitamin A in the urine. The semiannual vitamin A supplementation program recommended by the WHO (111, 113) reduced malnutrition, which was assessed by increases in mid–upper arm circumference, and was protective against infection in Nepalese children (114). Additionally, vitamin A supplementation reduced the frequency of malarial episodes by 30% in children in Papua New Guinea and promoted ponderal growth and protection against malaria-related death in Tanzanian children (115, 116). Provitamin A carotenoid–biofortified staple crops provide a potentially effective method for alleviating vitamin A deficiency in the rural poor, who are disproportionally missed by supplementation interventions (117, 118). However, biofortification target concentrations of provitamin A carotenoids should be increased in areas with a high prevalence of infection to account for reduced food intake and increased requirements (23).

APPs as markers of infection for nutrition interventions.

The liver plays an important role in modulating the immune response and removing pathogens (119, 120). In mice, ∼7% of hepatic genes respond to APR cytokines, inducing a wide array of functional changes, including those in macronutrient metabolism and APP production (121, 122). Positive APPs broadly work to mitigate the consequences of infection and modify the host’s immune response (19, 28, 30, 33). The role of negative APPs remains unclear, but the downregulation is speculated to increase the availability of amino acids for positive APP production (28, 30). Many negative APPs are transporters; the hepatic suppression of these proteins allows for a temporarily increased free availability of their associated nutrients and hormones in the plasma followed by decreases in plasma concentration due to sequestration (19, 28, 33). It is important to note that much of the research concerning APP responses was conducted in adults undergoing trauma rather than infection. Additionally, relatively little is known about APP responses in children, particularly those in developing countries who may have compromised immune function.

The manner in which the liver alters APP concentrations in the plasma is dependent on the time stage of the APR, such that positive APPs become elevated in the plasma at different time points poststimulus. In nutrition interventions, C-reactive protein (CRP) and serum amyloid A are used as early markers of infection because they become elevated within 24 h poststimulus and normalize rapidly as infection resolves (23, 24, 33, 123, 124). Antichymotrypsin (ACT) and α₁-acid glycoprotein (AGP) are implemented as late-stage markers of infection because they increase after 48 h and can remain elevated after the infection convalesces (23, 33, 124, 125). By using these proteins, it is possible to identify different stages of infection including incubation (early-stage APP only increased), early convalescence (both early- and late-stage APPs increased), convalescence (late-stage APP only increased), and return to a healthy state (neither early- nor late-stage APP increased) (23, 124). Positive APPs provide a superior assessment of infection when compared with cytokines, which possess short half-lives.

The magnitude of the APP response is dependent on the severity of injury to the host. Contreras-Manzano et al. (126) reported positive APPs to be more elevated in children with respiratory infections than in children with diarrhea. Furthermore, direct correlations between plasma concentrations of positive APPs and indirect correlations between positive APP concentration and transporter-requiring micronutrients were found in children (23, 127–132). Duncan et al. (133) also found that alteration of several micronutrients assessed in the blood corresponded to the extent of the APR when assessed by CRP concentration in adults.

APP elevation cutoffs used to determine infection are not standardized for nutrition applications and may vary by age, sex, and nutrient. For example, elevation cutoffs for CRP of 5 or 10 mg/L are commonly reported in the literature to describe the APR (21, 23, 124, 134–138). Bresnahan et al. (23) found that a CRP concentration of 5 mg/L was an effective elevation cutoff to show the impact on traditional blood-based indicators of vitamin A and iron status in Zambian children, whereas Abraham et al. (139) found significant changes in the same micronutrient status indicators occurring at ≥0.6 mg/L with the use of high-sensitivity assays in apparently healthy German children. In adults, CRP cutoffs between 5 and 20 mg/L were necessary to detect changes in blood concentration for various vitamins and minerals (133). CRP concentrations increase with age and tend to be higher in women than in men (140). This increase is, in part, related to chronic inflammatory conditions, suggesting a higher CRP cutoff may be necessary to assess acute infection in adults (134, 141). Additionally, noninfectious inflammation can occur during pregnancy and lactation and is poorly understood (142–144). More research is imperative to establish APP cutoffs that are adequate for determining the impact of the APR on micronutrient status indicators.

Micronutrient status indicators during the APR.

The impact of the APR on micronutrient status indicators is well documented in the literature, yet no standardized method for adjustment during infection has been developed. In public health assessments, micronutrient status is commonly determined by using concentrations in blood as a surrogate for total body status. Blood concentrations of retinol, iron, and zinc can be altered by the APR to infection (Table 2) (21–23, 124, 127–134, 137, 145–160). Alterations in blood micronutrient concentrations result from hepatic suppression of transport proteins (RBP, transthyretin, albumin, and transferrin) and increases in serum ferritin and hepatic metallothionein, positive APPs that assist in iron and zinc sequestration, respectively (28, 98, 161–164). Although micronutrient demands can be increased during infection, significant changes in micronutrient status do not likely occur as early as decreases in blood concentrations suggest during the APR. Furthermore, blood concentrations are typically restored to preinfection values as the APR resolves, supporting measurements taken during febrile infection as inaccurate reflections of micronutrient status (127, 145, 146, 154).

TABLE 2.

Effect of inflammation on indicators of micronutrient status¹

Blood indicator	Impact of infection
Iron status
Ferritin	↑
Serum iron	↓
Transferrin	↓
Transferrin receptors	NC to ↓
Hemoglobin	NC to ↓
Zinc status
Serum zinc	↓
Vitamin A status
Serum retinol	↓
MRDR test	NC

¹MRDR, modified relative dose response; NC, no change; ↑, increase; ↓, decrease.

The APR rapidly affects common biomarkers for iron status, including serum iron, transferrin, and ferritin (164). Of the iron biomarkers, serum ferritin concentrations are the most significantly affected by infection, with reported increases of 30% to 1400% depending on the time stage and severity of infection in children (21, 23, 131, 132, 147, 152, 159). Serum iron and transferrin are suppressed by 50% and 30%, respectively, and the percentage of transferrin saturation is lowered to ∼20% (154, 164). The impacts of infection on soluble transferrin receptors and hemoglobin remain unclear. Although iron status appears to be the main factor affecting soluble transferrin receptor concentration, it was reported to be decreased in surgical patients and in individuals with malarial and HIV infection (154, 165–167). Hemoglobin was suppressed in British, Zambian, and Zanzibari children during the APR and found to be inversely related to serum ferritin concentration, supporting its role as a reactive iron status indicator (23, 131, 168). In Kenyan children, hemoglobin was negatively correlated to CRP and AGP and positively associated with serum ferritin (169). Upon adjusting for inflammation, the relation between hemoglobin and the APPs disappeared and that with serum ferritin was strengthened (169). However, Wieringa et al. (21) reported no effect of the APR on hemoglobin, and Das et al. (152) found no association between hemoglobin and serum ferritin.

Serum zinc concentration is suppressed by 12% in children during infection (21, 147). Similarly, in HIV-positive adults, a 12% decrease in serum zinc was observed (22). In children with malaria, CRP concentration and parasite density predicted low serum zinc concentration (158). It is important to also consider the definition of zinc deficiency when assessing the impact of infection on estimates of deficiency prevalence because cutoffs vary by sex, age, and time of day (170).

Serum retinol concentration is a widely used indicator for vitamin A status and is recommended for population assessment by the WHO when used in conjunction with another indicator (171, 172). The current deficiency cutoff is set at 0.7 μmol retinol/L serum (or plasma) regardless of inflammation or infection status (172). However, in children, serum retinol concentrations are suppressed by ∼25% during common infections (23, 124, 148) and up to 69% in children with Shigellosis (127). This decrease in serum retinol concentration is independent of vitamin A liver reserves (173). Therefore, individuals who are experiencing infection but have an adequate vitamin A status may be misclassified as deficient, leading to overestimation of deficiency prevalence in a population. The modified relative dose response (MRDR) test relies on the principle that RBP accumulates when vitamin A liver reserves are low (174). This phenomenon may continue during mild infection. The MRDR value (3,4-didehydroretinol:retinol) is measured by quantifying the rapid release of 3,4-didehydroretinol from the liver bound to RBP in the serum after a challenge dose of 3,4-didehydroretinyl acetate within a few hours (171). The 3,4-didehydroretinol:retinol is not appreciably altered by the APR during common infections, implying that the release of 3,4-didehydroretinol and retinol from the liver may be suppressed in a similar manner, such that the ratio between the 2 remains unchanged (21, 23). The MRDR test is more sensitive than serum retinol to changes in liver retinol reserves, supporting it as a superior tool for assessment, particularly in populations with a high or unknown prevalence of infection (21, 23, 171). Furthermore, it is recommended that all dose-response tests be administered to children without active fever to minimize effects that active illness may have on dose absorption (68). Plasma concentrations of provitamin A carotenoids are also suppressed during inflammation (150, 175). This may suggest an increased demand for vitamin A during infection, a reflection of alterations in blood lipid profile, or a decrease in dietary intake (175).

Developing a method for adjusting blood-based micronutrient status indicators that are reactive to the APR is challenging because the accurate measurement of micronutrient deficiency prevalence can be difficult in regions where dietary micronutrient intake is low and inflammation is high. Additionally, the relation between blood concentrations of micronutrients and APPs is not always linear (160, 176). The measurement of APP concentrations when assessing micronutrient status should become standard practice because APPs are elevated during subclinical inflammation (22, 177). Moreover, both early- and late-stage markers of infection should be evaluated because it is common to find more individuals in a population with elevated AGP or ACT than with elevated CRP (21–23). It is important to also consider sex differences when adjusting micronutrient status indicators for the APR. The precision of scientific studies and population-level estimates of micronutrient deficiency prevalence may be compromised by excluding individuals with elevated APPs. Therefore, Thurnham et al. (22) proposed a method of adjustment that modifies micronutrient status indicators by APP-determined infection stage with the use of a correction factor based on a healthy reference population. However, because individuals with infection are more likely to suffer micronutrient deficiency in at-risk populations, this conservative method may also result in misestimations of deficiency prevalence.

Conclusions

The synergism between nutritional status and the APR is apparent where malnutrition and infectious diseases are prevalent. The APR to infection increases energy expenditure to generate fever and accelerates catabolism of macronutrients. Furthermore, infection suppresses food intake, decreases nutrient absorption, and can increase requirements by augmenting direct loss of micronutrients. Malnutrition, in turn, increases susceptibility to infection by impairing both innate and adaptive immune responses. Integrated interventions are paramount to improve nutritional status and reduce disease burden in the developing world.

Blood-based micronutrient status indicators can be altered during the APR, leading to misestimates of deficiency prevalence. It is therefore paramount that the APR be measured and corrected for when blood-based micronutrient status indicators are assessed in populations with a high or unknown prevalence of infection. APP elevation cutoffs that are specific to nutrition applications are necessary, because current values reported in the literature vary widely. Additionally, it should become routine practice to assess both early- and late-stage APPs because micronutrient status indicators can remain altered into convalescence of the infection.