Hamid Jack Moallem, MD

SUNY-Downstate Medical Center

Pretest

Q1. True or False. Protein calorie deficiency exacerbates the immunological

effects of HIV-1 infection.

Q2. True or False. Malnutrition by itself can mimic AIDS.

Q3. Which vitamin is recommended in mega doses as a daily requirement in HIV-1 infection in children?

a. Vitamin C

b. Vitamin B family

c. Vitamin D

d. None

Q4. True or False. Most of the protease inhibitor medications that currently are used for the treatment of HIV-1 infection in children have some gastroenterological manifestations.

Q5. In the assessment of HIV-1 infected children for growth failure, what elements should be evaluated?

a. feeding,

b. vomiting

c. diarrhea

d. all of the above

Q6. Cardiomyopathy associated with HIV-1 infection in children is seen in

a. Iron deficiency

b. Folate deficiency

c. Selenium deficiency

d. None of the above

Q7. Is coffee, tea or any of the colas a substitute for drinking water?

a. Only colas may be substituted.

b. Tea and coffee are considered appropriate substitutes.

c. Coffee and colas are acceptable substitutes.

d. None of the above are substitutes for water, and water from a safe source should be used.

Objectives

At the conclusion of this section, residents will be able to:

Recognize protein calorie malnutrition -"wasting-syndrome"- and its effects on HIV infection.
Distinguish wasting syndrome from protein-energy malnutrition following caloric deprivation
Understand the role of vitamins in the nutritional care of HIV infected children.
State the effects of medications that are currently used in different aspects of HIV infections.
Assess for failure to thrive in HIV infected children and understand its management.

Facilitator Preparation

For this section, the facilitator should review:

Miller TL: Nutritional aspect of HIV-1 infected children receiving highly active antiretroviral therapy. AIDS 2003 (17) Suppl 1, S1 30-S1 40.
Solomon J, De Truchis P, Melchior: Nutrition and HIV infection. British J Nutrition: 2002 (87), Suppl 1, S111-S119.

Introduction

More than 20 years have passed since the first reports of infection with the Human Immunodeficiency Virus (HIV-1) in children. Acquired Immunodeficiency Syndrome (AIDS), caused by HIV-1 infection, in children differs from the disease in adults in many aspects. In prenatally transmitted disease, HIV-1 has serious effects on the developing embryo and fetus, leading to a broad range of pathology that affects the immune system as well as almost every organ. The World Health Organization (WHO) estimates that 25.8 - 41.8 million adults and children are infected with HIV-1, the majority of whom are in developing countries. Today, between 800,000 to 900,000 people are living with HIV disease. In the United States, almost 440,000 have died from it, and as many as 300,000 people may be HIV-1 positive without knowing their serostatus.

In Uganda, during the early years of the AIDS epidemic, it was known as "slim disease", because many people were dying there of severe malnutrition of unknown cause. Protein calorie malnutrition (wasting syndrome) is defined as one of the main features of AIDS in children by the Centers for Disease Control and Prevention (CDC) (1). The teams who are taking care of children with HIV-1 infection should be aware of potential nutritional challenges facing them.

Pediatric HIV-1 disease most often leads to significant multiple nutritional deficiencies, protein calorie malnutrition (wasting syndrome), and eventually, failure to thrive.

Case Presentation

Sandy, a 5-year-old girl with perinatally transmitted HIV infection, was referred from a clinic in South Carolina for follow-up. Sandy lost her parents to HIV six months ago, and she moved to New York to live with her grandmother who came to the U.S. two weeks ago.

Review of her medical chart showed that her past medical history was uneventful up to 18 months ego, when Sam, her 8-year-old brother, also HIV infected, was diagnosed with PCP and finally died. As the parents required multiple hospital admissions for their deteriorating medical conditions, Sandy's care was given to her aunt, a 17-year-old single mother of a 2-year-old girl. Sandy had chronic diarrhea for the past ten months. She was not evaluated by a physician because she had lost her medical insurance coverage and the aunt was too overwhelmed with her own problems to reapply.

Her current medications were zidovudine, lamivudine, and nelfinavir.

At first glance, she looked unhappy, her height and weight was less than the 5th percentile, and she had extensive oropharyngeal thrush.

Q1. Does Sandy have a growth problem? Due to what condition(s)?

A1. Let's review the criteria for "wasting syndrome" due to protein calorie malnutrition set by the CDC in Table 1.

Table 1. CDC Definition of Wasting Syndrome in Children Younger than Age 13 Years in the Absence of a Concurrent Illness other than HIV Infection (revised 1994)

TEACHING CAPTION: Malnutrition by itself may lead to acquired immunodeficiency similar to that caused by HIV-1 infection. In addition to growth (height and weight) retardation in children, progressive declines in lean body mass are reported in many studies.

Based on the guidelines set by CDC, Sandy has protein calorie deficiency.

Q2. How does "wasting syndrome" with immune deficiency or other infectious illness differ from the protein energy malnutrition that follows caloric deprivation.

A2. Many of the signs and symptoms are similar. In classic p-em, the weight loss precedes infections that follow. Marasmus (p-em without edema) and kwashiorkor (p-em with edema) both affect immune function. The ultimate killers in p-em are usually infectious. Measles and Tuberculosis are the most common. Weight loss criteria are more stringent in classic P-em and, of course there has to be a primary cause of food deprivation. See module on Failure to Thrive for further discussion. Table 2, below delineates specific differences.

Q3. Do protein calorie deficiency, or vitamin and mineral deficiencies play a role in immune function?

A3. There is a large body of evidence demonstrating that malnutrition, mainly protein calorie deficiency, but to a large extent, deficiencies of vitamins and minerals, exacerbates the Immunologic effects of HIV-1 infection (Table 2) (2).

Table 2. Effects of HIV-1 Infection, Protein Calorie Malnutrition (PCM), Vitamins and Minerals on Immune Function

Teaching Caption: The overlapping symptomatology suggests careful attention to the nutritional needs of HIV affected children.

Q4. Are iron, folate or selenium important elements in HIV infected children?

A4. Iron deficiency is common in children with HIV-1 infection, particularly those who were born prematurely. Iron deficiency anemia may coexist with the anemia of chronic disease and at times, it may be confused with it.

Folate deficiency is reported in two HIV-1 infected children with neurological disease and is linked to neurological degeneration in HIV-1 infection (3).

Selenium deficiency has been linked to cardiomyopathy in children.

Q5. Sandy was growing normally up to18 months prior to presentation. What went wrong? What caused significant growth retardation in her?

A5. Nutritional impairment in HIV-1 infected children (table 3) is multifactorial, working independently or synergistically. (4)

Table 3. Causes of Malnutrition in HIV-1 Infection

TEACING CAPTION: Note that these problems may be imbedded in the psychosocial conditions often found in affected children. A multi-systems approach to care is needed. (See FTT module)

The case continues

Sandy was started on multiple medications for her HIV -1 infection in South Carolina. Could any or a combination of these medications contribute to her growth failure? She is on PCP prophylaxis with a combination of sulfonamide and trimethoprim. Will it cause any nausea or vomiting?

We know that she is taking a prophylactic dose of acyclovir because of recurrent Herpes simplex.

Q6. Will it have any effect on her abdominal pain and diarrhea?

A6. Food and drug interactions are an important issue in the effectiveness and tolerability of antiretroviral medications. Drug-food interactions can influence the serum drug concentration and increase the side effects of medications if serum concentrations are above the recommended range, or lead to loss of viral suppression if serum concentrations are below the desired range. Antiretroviral agents and medications that commonly are used in HIV infection in children may cause gastrointestinal symptoms, pancreatic and biliary tract disease, and abdominal pain, leading to poor food intake and eventually contributing to malnutrition (Tables 4 and 5). (5)

Table 4. Antiretroviral Agents and their Common Gastrointestinal Complications

NRTIs: nucleoside reverse transcriptase inhibitors. NNRTIs: non-nucleoside reverse transcriptase inhibitors. PIs: protease inhibitors.

LFTs: liver function tests.

Table 5. Agents Commonly Used in HIV-1 Infected Children and Their

Gastrointestinal Complications.

Q7. Since Sandy is not a very active child, and thus is not wasting high amounts of calories, why is she not growing?

A7. As noted above, it is shown that HIV infected individuals with secondary infection have higher resting energy expenditure and lower energy intake. Nutrient intake in HIV-1 infected individuals is directly associated with CD4 cell count at base line and inversely to HIV-1 clinical symptoms. (5,6)

Following the introduction of Highly Active AntiRetroviral Therapy ( HAART ), a clinical syndrome of body fat redistribution and metabolic changes has been described. This syndrome includes peripheral insulin resistance, hyperlipidemia, and lipodystrophy (truncal obesity, dorsocervical fat pads and facial and extremity wasting) (6,7) and is associated with increased calorie expenditure. (8)

Q8. Now that it is clear that multiple factors are playing a role in Sandy's growth failure, how can we intervene and how can we assess her problems?

A8. Nutritional Assessment: The most effective role that the team taking care of the HIV-1 infected child can play is close surveillance of nutritional and metabolic complications over time and with evolving medical therapy. Frequent assessment of HIV-1 infected infants and children increase the likelihood of detecting growth failure as early as possible. Poor feeding, fever, vomiting, and diarrhea among the other problems should be searched in every clinical evaluation. The growth chart and its changes are the cornerstone of all the evaluations (Table 6).

Table 6. Assessment of HIV-1 Infected Children for Growth Failure

Interval history of: Poor feeding, vomiting, diarrhea, fever (intermittent or constant), sepsis

TEACHING CAPTION: Note the need for Social work and nutritionist (RD) support in therapy

Nutritional Management: Appropriate management includes a 24-hour diary of food intake, and calculation of approximate daily intake of protein and calories with particular attention to intake of vitamins (A, D, E, and the group of B vitamins including riboflavin, thiamine, folic acid, and pyridoxine) and minerals (calcium, iron, zinc and selenium). Encouraging the ingestion of iron-rich foods (meat, egg yolk, green vegetables, whole grains, legumes, and nuts) is recommended. Supplementation of multivitamins and minerals not greater than the recommended daily allowance (RDA) may be useful, since HIV-1 infected children suffer from a variety of complications that may interfere with food intake or absorption.

Sandy's aunt is reporting multiple episodes of intermittent fever lasting for a few days.

Q9. Should these episodes be considered in the adjustment of calorie requirement? . How can we calculate calorie requirement for Sandy? Is there any difference between calorie requirement of the HIV-infected child and that of a child who is not infected with this infection?

A9. Calorie Requirement: There is great variation in the calorie needs of children at different ages and under various conditions (Tables 7-8). The caloric goal in HIV-1 infected children should be targeted at 50% above the RDA for age.

Table 7. Basic Calorie Requirement of Normal Children by Weight

TEACHING CAPTION: Always start with the normal; child and work your way through any normal or pathological requirements that follow.

Table 8. Adjustment of Calorie Requirement in Children Under Different Conditions

Teaching Caption: These requirements are considered minimal; more calories may be needed if the child has clinical and biochemical evidence of nutritional deficiencies.

When the growth of the HIV-1 infected child is adequate for age and sex, regular follow up of the patient and reassessment of growth and nutritional requirements are the only needs of patient.

The case: Sandy's aunt mentioned that Sandy was taking her mother's breast milk for the entirety of her first year of life. Was it a good idea?

Q10. In the medical literature, breast milk is introduced as the best and safest source of nutrition.

A10. Breast milk is generally considered the best nutrition for children worldwide. Unfortunately, mothers infected with HIV-1 infection can transmit the virus to the infant through breast milk and therefore breastfeeding (in countries where other feeding sources are available) in this situation is strongly discouraged.

The case: Sandy is not drinking water, but drinks lots of Coke.

Q11. Should she be encouraged to drink water instead? Is there any preference in the type of commercial drinking water?

A11. Drinking Water: Drinking extra water can reduce some of the side effects of the medications and may prevent constipation as well. Boiled water or bottled water with the license number from the local Department of Health on the bottle is recommended. Tea, coffee and colas should not be substituted for water and they increase water losses.

The case: Sandy's aunt is living with a friend who recommended giving Sandy some antioxidant.

Q12. Should she consider taking special vitamin supplementation including megadose of antioxidants?

A12. Antioxidants: Free radicals, produced by chemical reaction in the body, are increased in HIV-1 infected patients. Antioxidants may repair some of the damages made by these free radicals. Nevertheless, the studies of high dose antioxidants are mixed. At times, there is a "superoxident effect" that is opposite of expected. Tread carefully.

The case: Sandy's mother used to supplement her diet with 1-2 cans of Ensure every day. Her aunt is concerned if she should continue it.

Q13. Should she?

A13. Liquid Calorie Supplements: Liquid calorie supplements may be used to help maintain body weight, but they should never replace the regular meals.

The case: Sandy's calorie requirement is calculated and adjusted for ongoing diarrhea, fever and high resting calorie expenditure and her diet is supplemented with vitamins. In the next few months she loses a few more pounds.

Q14. What should be considered?

A14. Enteral Supplementation: When oral interventions fail, because either the infant or child cannot consume or cannot absorb adequate calories to maintain growth, enteral supplementation should be considered. Night-time feeding through a nasogastric tube to evaluate the ability of the infant or child to gain weight with supplemented enteral feeding should be tried first. The advantage of night-time feeding is that it allows the infant or child to eat normal food throughout the day. Despite the difficulties that may arise by nasogastric tube feeding (safe insertion of the tube, technical limitations of administering the feedings), it is the first step to evaluate the adequate growth of the infant or child .

If desired weight is achieved by this means, then placement of a more permanent gastrostomy tube should be considered. Easy accessibility to the stomach with less physical and emotional trauma to the child is the advantage of it. Steady state weight gain for height, decreases in the number of hospitalizations and deaths and improvements in CD4 cell counts are reported following gastrostomy tube placement. (9,10) Since gastrostomy tubes may be used for administration of medications, it is a reliable means of delivery for antiretroviral medications, and it allows for a better clinical outcome. (11)

Parenteral Nutrition: Placement of a central venous catheter for provision of parenteral nutrition should be reserved only for the patients who continue to lose weight despite aggressive enteral feeding. It is practical for patients who have pancreatitis, biliary tract disease and intractable diarrhea with weight loss. However, central venous catheters carry an additional risk for infection.

Summary

Protein calorie malnutrition is the most common cause of wasting syndrome in children with HIV infection. All the medications that are used in the treatment of HIV-1 infection, or in the treatment or prophylaxis of opportunistic infections, may have some effects on the gastrointestinal tract that interfere with sufficient calorie intake.

In the assessment of these children, the intake of daily calories and the possibility of infection, diarrhea, cardiac pathology, and pulmonary infections should be considered. In calculating the calorie requirement of these children, high resting calorie expenditure, ongoing fever, diarrhea, and respiratory distress should be considered and the calorie requirement appropriately adjusted.

Vitamins should be supplemented at the RDA/DRI level, not megadoses.

Safe drinking water, and anti oxidants should be included in the daily nutrition of HIV-1 infected children.

References

1. Centers for Disease Control and Prevention. Revised classification for human immunodeficiency virus infection in children less than 13 years of age. MMWR, 1994, 43:1-19.

2. Amati L, Cirimel D, Puglies V, Covelli V, Resta F, Jirillo E. Nutrition and Immunity: Laboratory and Clinical Aspects. Current Pharmaceutical Design: 2003, 9, 1924-1931.

3. Smith I, Howells DW, Kendal B. Folate deficiency and demyelization in AIDS. Lancet: 1987, 2, 215.

4. Salommon J, De Truchis P, Melchior C. Nutrition and HIV infection. British J Nutrition: 2002 87, Suppl, 1 S111-S119

5. Miller TL. Nutritional aspects of HIV-infected children receiving highly active antiretroviral therapy: AIDS 2003, 17(suppl):S130-S140.

6. Abrams B, Duncan D, Hertz-Picciotto I. A prospective Study of dietary intake and acquired immune deficiency syndrome in HIV-seropositive homosexual men. J Acquir Immune Defic Synd: 1993, 6(8) 948-958.

7. Carr A , Samaras K, Chisholm DI, Cooper DA. Pathogenesis of HIV-1 protease inhibitor- associated peripheral lipodystrophy, hyperlipidemia, and insulin resistance. Lancet: 1998, 351, 1881-1883.

8. Saint Marc T, Partisani M, Poizot-Martin I. A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long term nucleoside- analog (NRTI) therapy. AIDS: 1999, 13, 1659-1667.

9. Apadi SM, Cutt PA, Hurlck M, Wong J,Kotler DP. Lipodystrophy in HIV infected children is associated with high viral load and low CD4-lymphocyte percentage at baseline and use of protease inhibitor and stavudine. J Acquir Immun Defic Synd : 2001,27,30-34.

10. Kosmiski LA, Kruitzkes DR, Sharp TA, Hamilton JT, Lichtenstein KA,Mosca CL, Grunwald GK, Eckel RH, Hill JO. Total Energy Expenditure and Carbohydrate Oxidation are increased in the Human Immunodeficiency Virus Lipodystrophy Syndrome. Metabolism: 2003, 62(5) 620-625.

11. Shingedia D, Viani RM, Yogev R, Binus H, Danker WM, Spector SA, Chadwick EG. Gastrostomy tube insertion for improvement of adherence to highly active anti retroviral therapy in pediatric patients with human immunodeficiency virus. Pediatrics, 2000, 105, e 80.

Annotated Pre-test Answers

A1. The Answer is True. Protein-energy malnutrition affects several immune mediated functions and thus would inhibit the body's response to HIV infection.

A2. The Answer is True. There are overlapping mechanism for the body fat and muscle mass to be depleted with exogenous malnutrition and advanced HIV disease. Thus, a malnourished child might look quite the same as a child with HIV.

A3. The Answer is D. Mega-dosing with vitamins is unwise for several reasons. First, there are toxicities associated with high doses of micronutrients. Second, focusing attention and resources to demonstrated treatment modalities will be more effective.

A4. The Answer is True. Unfortunately this is true. Careful attention to intake and absorption of energy and micronutrients is essential.

A5. The answer is D. All are necessary; none is sufficient!!

A6. The answer is C. Selenium deficiency cardiomyopathy has been demonstrated in HIV disease.

A7. The answer is D. Give water. Be especially sure that the water supply is clean.