Nutrition and Infsection

Alice M. Tang

Ellen Smit

Richard D. Semba

INTRODUCTION

This chapter provides a practical introduction to the relationship between nutrition and infectious diseases. Over the past few decades, our knowledge of the interactions between nutrition, infection, and immune function has steadily expanded. It has been established that adequate nutritional status is necessary for the normal functioning of various components of the immune system.¹, ² and ³ Malnutrition may affect the course of infectious diseases through a variety of mechanisms, including compromising host immune function, diminishing response to therapies, and promoting comorbidities.⁴

The relationship between nutrition, infection, and immune function is generally cyclical in nature⁵ (Figure 12-1). Even in a well-nourished host, the course of an infection will adversely affect nutritional status. If an infection is left untreated or becomes chronic, nutritional deficiencies may develop that further compromise the immune system, leading to more severe disease and increased susceptibility to other infections. If the host is already malnourished, acquiring an infection will lead to further nutritional deficiencies, such that the host rapidly progresses into a downward spiral leading to increased morbidity and mortality.

Figure 12-1 The relationship between nutrition, infection, and immune function is generally cyclical in nature

The nutritional consequences of infection, no matter which microorganism is causing the infection, tend to be predictable. Any infection, whether symptomatic or asymptomatic, is accompanied by losses of some nutrients from the body and redistribution of other nutrients. The magnitude of these changes depends on the severity and duration of the infection. Metabolic and nutritional responses that are specific to certain organisms occur when the infection becomes localized within a single organ system. For example, diarrheal infections cause sizable losses of fluid and electrolytes, whereas paralytic forms of infection result in wasting of bone and muscle. If the infection can be cured or eliminated naturally by the host immune system, lost body nutrients can then be replenished over a period of weeks to months. Conversely, if the infectious process is not eliminated and becomes chronic, body composition can become markedly altered and a new equilibrium of body nutrient balances is reached at a cachectic, or extremely wasted, level.

THE EFFECTS OF INFECTION ON NUTRITIONAL STATUS

Acute infections cause metabolic rates and oxygen consumption to increase. Both anabolic and catabolic processes are involved. The cells in the liver and lymphoid tissues rapidly increase their rates of synthesis of proteins needed for host defense mechanisms, and the proliferation of phagocytic and lymphoid cells is speeded up. To support these anabolic requirements and to maintain high metabolic rates in the presence of anorexia and a diminished food intake, catabolic processes are accelerated as well. The stores of available protein in muscle fibers and other tissues provide the additional supply of amino
acid substrates, which are used for glucose production and the synthesis of new proteins required for host defense. To fuel the increased metabolic activity required to fight off the infection, the body appears to increase its utilization of glucose, but not lipids. As a result of the catabolic processes, the body loses weight and muscle mass, as nutrient stores are consumed in excess of intake. If the infection becomes chronic, available nitrogen stores are used up, fat depots are consumed, and a wasted, cachectic state develops. During the acute phase of fever, the body also retains water and salt.

THE EFFECTS OF MALNUTRITION ON HOST DEFENSE MECHANISMS

Malnutrition is best understood as a syndrome associated with variable losses of protein, carbohydrate, and fat stores, along with changes in micronutrients such as vitamins and minerals. It is often complicated by infection-induced anorexia and catabolism. A common finding in malnourished patients is the depletion of lymphocytes, particularly in T-cell regions of the thymus, spleen, and lymph nodes. Studies suggest that a relative reduction in circulating mature T lymphocytes (both T-helper and T-suppressor cells) occurs, so that plasma is enriched with immature and functionally defective cells.⁶ As a result, there is a reduction in the efficacy of all host defenses that depend on T-cell function. Serum antibody levels are usually normal or elevated in the presence of malnutrition—an effect that may be due in part to the numerous infections and high antigenic loads faced by malnourished individuals in impoverished areas, and at the same time, a defect in T-suppressor cell function, which normally inhibits antibody production. One exception is that secretory IgA levels are often depressed in protein-energy malnutrition (PEM), causing more frequent mucosal infections of the gut and urinary tract. As a result, malnourished patients usually exhibit increased frequency and/or severity of certain bacterial, viral, fungal, and parasitic infections.

MALNUTRITION AND SPECIFIC INFECTIOUS DISEASES

Malnutrition is a major determinant of morbidity and mortality for many major infectious diseases, particularly among young children in developing countries, who often suffer from multiple serial infections.

Diarrheal Disease

Diarrheal disease is the second leading cause of death in children younger than 5 years of age, causing an estimated 1.5 million deaths each year worldwide.⁷ Malnutrition and associated immunodeficiency are important risk factors for diarrheal disease among infants and young children in developing countries. The main causes of diarrheal diseases among children in developing countries are rotavirus, Escherichia coli, Shigella, Vibrio cholerae, Salmonella, and Entamoeba histolytica. Children who are malnourished (low weight-for-age, low mid-upper-arm circumference) have an increased prevalence of diarrhea, which in turn can exacerbate their malnutrition, resulting in more severe disease and a higher mortality rate.⁷, ⁸ and ⁹ Frequent episodes of diarrheal disease can also cause significant damage to the lining of the gut and disrupt normal gut flora colonization, which further exacerbates poor nutrition status and immune function.

Micronutrient deficiencies that have been described during diarrheal disease include deficits in vitamin A, vitamin D, vitamin B₁₂, folate, copper, iron, magnesium, selenium, and zinc.¹⁰ Several clinical trials show that supplementation with vitamin A¹¹, ¹² and ¹³ or zinc¹⁴, ¹⁵, ¹⁶, ¹⁷, ¹⁸ and ¹⁹ can reduce the morbidity and mortality of diarrheal disease in children, although the benefit of vitamin A appears to be limited to children who are vitamin A deficient or malnourished, or to children with shigellosis. The current recommendation from the World Health Organization (WHO) does not include vitamin A as part of treatment of diarrhea.

Lower Respiratory Infections

Acute respiratory infections (ARIs) are a major cause of morbidity and mortality among infants and children in developing countries. According to a 2009 WHO report, these infections account for an estimated 2 million deaths per year.²⁰ The main causes of acute lower respiratory infections in children are respiratory syncytial virus, adenovirus, parainfluenza virus, influenza virus, Streptococcus pneumoniae, and Haemophilus influenzae.²¹ Zinc is essential for the growth and development of children, and randomized controlled trials have shown strong evidence that zinc supplementation reduces the incidence and prevalence of ARIs and pneumonia among children, especially in zinc-deficient populations.²², ²³, ²⁴, ²⁵, ²⁶, ²⁷ and ²⁸ Vitamin A deficiency causes pathologic alterations in the mucosal epithelium of the respiratory tract, including keratinization and loss of ciliated cells, mucus, and goblet cells. Epidemiologic studies have
demonstrated that vitamin A deficiency is associated with lower respiratory infections,¹¹ although vitamin A supplementation appears to have little effect on reducing the incidence of either lower respiratory infections in children²⁹ or respiratory syncytial virus infection,³⁰, ³¹ unless measles infection occurs at the same time.¹² Some evidence is emerging on the benefits of selenium, though further studies are needed to confirm this nutrient’s role in the treatment of ARIs.²¹

Measles

An estimated 278,358 cases of measles and 164,000 measles-related deaths were reported in 2008.³², ³³ This number reflects a decrease of 78% since the launch of the Measles Initiative in 2000; it is a vaccination campaign in high-risk countries jointly led by the American Red Cross, United Nations Foundation, U.S. Centers for Disease Control and Prevention (CDC), UNICEF, and WHO. Deaths from measles are largely the result of an increased susceptibility to secondary bacterial and viral infections, and the underlying mechanism includes immune suppression related to malnutrition.³⁴ Although most people recover from measles, those with malnutrition or coinfections are at increased risk of complications.³⁵, ³⁶, ³⁷ and ³⁸ In the classic early investigation of a measles outbreak in the Faroe Islands by Peter Panum and August Manicus in 1846, the most severe diarrheal disease and highest mortality were described among those patients with greatest poverty and poor diet.³⁹ In general, malnourished children have more severe disease and higher mortality.⁴⁰, ⁴¹ More persistent measles infection and viral shedding³⁷ have also been reported in malnourished children.³⁵

A close synergism exists between measles and vitamin A deficiency. Low serum vitamin A levels are associated with higher mortality in acute, complicated measles infection.⁴² Vitamin A supplementation for measles is one of the most important examples of the use of micronutrients as disease-targeted therapy. Randomized, placebo-controlled clinical trials show that such supplementation can reduce the mortality of measles by 50% or more, and high-dose vitamin A supplementation is now recommended as standard therapy for measles both in developing countries and in the United States.¹¹

Tuberculosis

Approximately 1.8 billion individuals—nearly onethird of the world’s population—are infected with Mycobacterium tuberculosis; most of these cases involve latent infection. In 2008 alone, an estimated 9.4 million new cases of tuberculosis (TB) occurred worldwide.⁴³ Malnutrition (along with poverty, overcrowding, and underlying human immunodeficiency virus [HIV] infection) is a major risk factor for the progression of latent tuberculosis infection to active infection.⁴⁴ Nevertheless, tuberculosis control programs tend to focus their efforts on chemoprophylaxis and chemotherapy alone, rather than upon improvement of host nutritional status.

Cod-liver oil—a rich source of vitamins A and D—was used as treatment for tuberculosis for more than 100 years, prior to the development of antibiotics.⁴⁵ Although the association between malnutrition and tuberculosis is well known, few controlled clinical trials have been conducted to investigate whether improved nutrition might reduce the risk of developing active disease or improve the clinical outcome of tuberculosis. A recent Cochrane review of randomized controlled trials comparing any oral nutritional supplement with no nutritional intervention, placebo, or dietary advice only among people being treated for active TB showed effects of high-energy supplements or combinations of multiple micronutrients including zinc and vitamin A on weight gain, but overall little evidence of effect on other clinical outcomes of TB.⁴⁶ The role of nutrition and tuberculosis remains a major area of neglect, despite the promise that micronutrients have shown as therapy for other types of infections and the long record of the use of vitamins A and D for treatment of pulmonary and miliary tuberculosis in both Europe and the United States.

Malaria

In 2008, there were an estimated 247 million cases of malaria and approximately 1 million deaths from this infection worldwide; more than 85% of all malaria cases occurred in Africa.⁴⁷ Vector control and antimalarial drugs have been the traditional strategy against malaria, and little attention, until recently, has been paid to improving host nutritional status.

Low levels of vitamin A, zinc, iron, and folate have been shown to be responsible for a substantial proportion of malaria morbidity and mortality.⁴⁸, ⁴⁹ Two separate randomized, placebo-controlled clinical trials conducted in Papua New Guinea demonstrated that vitamin A supplementation or zinc supplementation can reduce malarial morbidity in preschool children by 30-50%.⁵⁰, ⁵¹ Iron-deficiency anemia is widespread among malaria-endemic regions, and iron supplementation is often a key component of relief efforts. A meta-analysis of iron supplementation in malaria endemic regions, however, showed a tendency toward higher parasite counts in individuals who received iron supplements.⁵² In contrast, a
2011 Cochrane review reported that there was no increased risk of malaria with iron supplementation in areas that have regular malaria surveillance and where malaria treatment services were provided.⁵³ On this basis, it was recommended that iron supplementation should not be discontinued in areas that are malaria endemic.

Human Immunodeficiency Virus Infection

In 2009, there were an estimated 33.3 million persons infected with HIV worldwide, with 2.6 million new infections and 1.8 million deaths from this cause occurring in that year alone.⁵⁴ Currently, approximately half of the people living with HIV are women and 2.5 million are children younger than the age of 15. Malnutrition may affect the course of HIV infection through a variety of mechanisms, including compromising host immune function, diminishing response to therapies, and promoting comorbidities.⁴ Wasting and malnutrition were routinely observed in AIDS patients in the early years of the HIV epidemic.⁵⁵, ⁵⁶ With the advent of highly active antiretroviral therapy (HAART) in the mid-1990s, however, many of the more severe nutritional problems associated with HIV infection declined in prevalence, particularly in resource-rich countries where patients had access to HAART. Given that most people with HIV infection live in resource-poor countries with limited access to HAART, HIV-related malnutrition remains of important concern on a global basis.

HIV wasting syndrome has been associated with increased opportunistic infections (OIs), lower CD4 counts, and hyperactivation of the immune system.⁵⁷, ⁵⁸, ⁵⁹ and ⁶⁰ Weight loss of as little as 5% of total body weight is predictive of death.⁶¹, ⁶² Prior to the introduction of HAART, specific micronutrient abnormalities were more common in HIV-positive than HIV-negative individuals.⁶³, ⁶⁴ and ⁶⁵ Low serum levels of many of these nutrients (particularly, vitamins A, B₆, and B₁₂, as well as zinc) were associated with more rapid disease progression,⁶⁶ increased mortality,⁶⁷ impaired neurologic function,⁶⁸ diminished lymphocyte response to mitogens,⁶⁴ and increased maternal-fetal transmission.⁶⁹ These micronutrients may be involved in the pathogenesis of HIV infection through their roles as antioxidants and in immune function.

Several clinical trials of multiple micronutrient supplementation in HIV-infected adults have been published.⁷⁰, ⁷¹, ⁷², ⁷³, ⁷⁴, ⁷⁵, ⁷⁶ and ⁷⁷ The earliest and largest of these— a trial among HIV infected pregnant women in Tanzania—showed that multivitamin supplementation (compared to placebo) had several beneficial outcomes in HIV-infected pregnant women, including greater increases in T-cell counts during and after pregnancy, better birth outcomes (reduced fetal deaths and low birth weight),⁷⁸ and improved weight gain during pregnancy.⁷⁹ Further follow-up of the same women over several years’ time demonstrated continued benefits of supplementation with multiple micronutrients in the form of higher T-cell counts, lower viral loads, slower HIV progression, and improved overall survival.⁷⁰ Additional analyses of these trial participants showed a beneficial effect of micronutrients on maternal wasting,⁸⁰ maternal and child hemoglobin status,⁸¹ and maternal depression and quality of life.⁸²

The other, more recent clinical trials showed mixed results. These trials were much smaller and were conducted in different geographic regions (Southeast Asia, Africa, United States) with differing population characteristics (including differing levels of micronutrient deficiency at baseline) and used different mixes and doses of multiple micronutrients, making it difficult to draw any generalizable conclusions. Some of these studies were conducted among pregnant women,⁷⁶ others involved people coinfected with TB,⁷³, ⁷⁴ and only one took place in a population treated with antiretroviral therapy.⁷⁷ Currently, many people living with HIV in resource-poor countries are gaining access to antiretroviral therapy, so the effects of micronutrient supplementation on HIV outcomes need to be reassessed in light of this fact.

In terms of energy requirements, a 2003 WHO report recommended that energy requirements should be increased by approximately 10% to maintain body weight and physical activity in asymptomatic HIV-positive adults and growth in asymptomatic HIV-positive children.⁸³ For persons in the symptomatic stages of HIV and AIDS, WHO recommended that energy requirements increase by approximately 20-30% to maintain adult body weight; for children experiencing weight loss, the recommendation was that energy intake increase by 50-100% over normal requirements. For patients on HAART, however, resting energy expenditure and energy requirements appear to be more variable⁸⁴, ⁸⁵, ⁸⁶ and ⁸⁷—an issue that requires further study.

MICRONUTRIENTS AND IMMUNITY TO INFECTIOUS DISEASES

The relationship between micronutrients and the immunity to different infections is a rapidly growing and promising area of investigation. Micronutrients
can influence immunity to infectious diseases through their roles in the immune function (Table 12-1).³ Micronutrient deficiencies, such as that of vitamin A and zinc, can have a major impact upon T- and B-cell function, generation of antibody responses, and function of other immune effector cells. Micronutrients such as vitamin E, vitamin C, zinc, and selenium act as strong antioxidants and can influence the clinical course of infections. Oxidative stress, which occurs during infections, refers to the condition when the balance between pro-oxidants and antioxidants is upset, leading to overproduction of free radicals and resulting pathology.⁸⁸ Activated macrophages and neutrophils have important roles in the killing of microorganisms through the generation of free radicals. Host bystander cells can also be damaged by free radicals, which can cause oxidation of nucleic acids, chromosomal breaks, peroxidation of lipids in cell membranes, and damage to collagen, proteins, and enzymes.

Table 12-1 Micronutrients Can Influence Immunity to Infectious Diseases Through Their Roles in the Immune Function

Vitamin A, carotenoids	Vitamin A refers to three types of compounds that exhibit biologic activity: the alcohol (retinol), the aldehyde (retinal or retinaldehyde), and the acid (retinoic acid). Plants contain a group of compounds called carotenoids that are converted to retinol in the body. Beta-carotene is the most biologically active carotenoid. Has essential roles in vision and various systemic functions, including normal cell differentiation and cell recognition, growth and development, bone development, immune functions, and reproduction.
Vitamin B₆	Coenzyme in numerous enzyme reactions particularly amino acid transport and metabolism. Direct effect on immune system through its role in protein and nucleic acid synthesis. Deficiency leads to a reduction in nucleic acid synthesis that restricts proliferation of lymphocytes.
Vitamin B₁₂	Coenzyme involved in transmethylation from methylfolate to homocysteine. Released unmethylated folate becomes available for nucleic acid synthesis.
Vitamin E	Most important lipid-soluble antioxidant in cell membranes. Protects unsaturated phospholipids of the membrane from oxidative degradation from Reactive Oxygen Species (ROS) by donating a hydrogen (called free-radical scavenging). Is important component of the cellular antioxidant defense system, which involves other enzymes (e.g., superoxide dismutases, glutathione peroxidases, glutathione reductase, catalase), many of which depend upon adequate levels of other antioxidants. Therefore the antioxidant function of vitamin E can be affected by the levels of other nutrients (zinc, selenium, copper, vitamin C).
Selenium	Active form functions as selenoenzyme. Major function as part of glutathione peroxidase that reduces cellular peroxides to H₂O and alcohol and prevents oxidative damage to proteins, lipid, lipoproteins, and DNA.
Zinc	Zinc binds to protein, forming zinc fingers that are involved in DNA transcription factors, hormone receptors, and enzymes. Zinc deficiency has been shown to impair a variety of immune functions: ↓ lymphocyte counts, loss of helper T-cell function, ↓ killer T lymphocyte activities, delayed dermal hypersensitivity responses, depressed humoral and cell-mediated immunity. Excess levels of zinc intake can have toxic effects on the immune system and may promote viral replication.
Reproduced from Tang, AM, Lanzillotti J, Hendricks K, Gerrior J, Gosh M, Woods M, Wanke C Micronutrients: current issues for HIV care providers. AIDS. 2055;19:848, Table 1.

Investigators who wish to study the relationship between micronutrients and infectious diseases must often focus upon one or two micronutrients for practical reasons. Considerable cost and complexity arise when attempting a comprehensive study of micronutrient status during infection, although a comprehensive approach would be ideal because micronutrient deficiencies often occur simultaneously. A brief overview of the relationship of specific micronutrients in immunity to infection follows.

Vitamin A

Vitamin A, or all-trans retinol, is an essential micronutrient for immunity, growth, cellular differentiation,
maintenance of mucosal surfaces, reproduction, and vision.¹¹ Two main dietary forms of vitamin A are distinguished: preformed vitamin A, which is found in foods such as butter, egg yolks, and cod-liver oil; and provitamin A carotenoids, which are found in foods such as spinach, carrots, mangoes, and papayas. Approximately 90% of the vitamin A in the body is stored in the liver, and the adult liver can contain enough vitamin A to last for more than one year. Vitamin A acts as a regulator of more than 300 genes through its active metabolites, all-trans and 9-cis retinoic acid, and specific nuclear receptors (members of the steroid and thyroid hormone receptor superfamily).⁸⁹

Vitamin A exerts a wide-ranging effect on different compartments of the immune system, including the growth, maturation, and function of T and B lymphocytes; the expression of certain cytokines; and the maintenance of mucosal surfaces of the respiratory, gastrointestinal, and genitourinary tracts.⁹⁰, ⁹¹ Historically, the main clinical manifestations of vitamin A deficiency were known to be night blindness and xerophthalmia (changes in the conjunctiva and cornea of the eye),¹¹ but later research showed increased incidence and severity of infections as part of the spectrum of vitamin A deficiency effects. A hallmark of vitamin A deficiency is an impaired ability to mount an antibody response to protein antigens,⁹¹ although recent research also shows an important role for vitamin A in T-cell development and activation.⁹², ⁹³ Infants, preschool children, pregnant women, and lactating women are at the highest risk of developing vitamin A deficiency.¹¹ Abnormal urinary losses of vitamin A can occur during infections, however, which can accelerate the depletion of the body’s vitamin A stores.⁹⁴ Because vitamin A is a fat-soluble vitamin, steatorrhea can interfere with intestinal absorption of vitamin A.

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