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Dysregulation of Growth in Pediatric HIV Infection


Stephen M. Arpadi, M.D.
St. Luke's-Roosevelt Hospital Center
Columbia University College of Physicians and Surgeons


Outline

  1. Growth in HIV-infected children
    1. Failure to thrive was reported in the earliest case reports of pediatric HIV/AIDS.
    2. Various patterns of disturbed growth are reported, including compromised ponderal and linear growth and weight loss.
    3. Multiple definitions for abnormal growth is problematic for data evaluation (e.g., attained wt and ht vs wt loss vs growth rate).
  2. Growth in HIV-exposed infants
    1. Effect of maternal HIV on pregnancy outcomes and intrauterine growth are inconsistent.
    2. Studies from Africa and Haiti indicate HIV-exposed infants have lower birth wt (St. Louis 1993, Ryder 1989).
    3. European and U.S. studies have not found differences after maternal drug use and alcohol is considered (Selwyn 1989, Minkoff 1990).
  3. Growth in HIV-infected infants
    1. Numerous studies have demonstrated that HIV-infected neonates are smaller than HIV- exposed but uninfected after adjusting for other factors.
    2. At birth HIV+ infants are .28 kg lighter lighter and 1.64 cm shorter than HIV-E.
    3. The effect on head circumference is .7cm (Moye 1996).
  4. Postnatal growth in HIV-infected infants
    1. HIV+ infants have progressively increasing decrements of ponderal and linear growth during the first 1-2 yrs of life.
    2. By 18 mos HIV+ are .71 kg lighter and 2.25cm shorter than HIV-E.
    3. Prenatal drug exposure has significant effect on 18 mos wt (-.445 z-score).
    4. Prenatal alcohol has significant effect on 18 mos linear growth (-.212 z-score).
  5. Growth in older HIV+ children
    1. Although data are limited, at present progressive stunting appears to be the most prevalent abnormality.
    2. 18/43(42%) prepubertal HIV+ children >5yrs have growth velocity <5th %-tile, (mean growth rate 3.1+ 1.5 cm/yr).
    3. A pattern of stunting without wasting was observed ( HAP 26 vs 60, p<.0001,wt/ht 54 vs 60%, p=.08).
    4. Growth abnormalities and survival
    5. Poor growth has been associated with poor survival in U.S., European, African, and HIV+ hemophilia populations.
    6. In U.S. children on antivirals, poor wt gain is an independent risk factor for death (RR=2) (95%CI:1.3-3.2) (McKinney 1994).
    7. In Uganda, infants with low wt had a 5-fold increase in risk of death by age 25 mos (Berhane 1997).
  6. Body composition in HIV-infected children
      II. Body composition characterized by a disproportionate decrease in BCM with preservation of BF (Arpadi 1998).
    1. This pattern is distinct from observations in children with nutritionally based stunting.
    2. It is similar to other wasting disorders including adult HIV infection and other conditions where anabolism is altered (e.g., GH/IGF-1, thyroid deficiency, etc.).
  7. Micronutrients in children with HIV
    1. A number of micronutrient and trace element deficiencies impair immune function in children (e.g., vit A, E, Zn, Se).
    2. Nutrient deficiencies appear to occur early in adult HIV infection and may be associated with disease progression.
    3. Pediatric data are derived from small samples, confounded by maternal status and drug exposure, and results are conflicting.
  8. Vitamin A
    1. Vitamin A important for normal immune function.
    2. Occurrence and frequency of childhood illnesses increased in vitamin A deficiency.
    3. Increased mortality with deficiency
    4. Depletion may occur during infection.
    5. Linear and ponderal growth in early childhood influenced by vitamin A status.
  9. Vitamin A and mother-to-infant HIV transmission
    1. In a population with high prevalence of vitamin A deficiency, reduced maternal vit A an independent risk factor for MTC T of HIV (Semba 1994).
    2. Mean vit A lower among non-transmitting compared to transmitting mothers (0.86 vs 1.07 umol/dl, p<.0001). IV. TR increased with decrease in maternal vit A.
  10. Vitamin A and MTCT
    1. Effect of maternal vit A independent of maternal CD4 #, CD4 %, CD4:CD8 ratio.
    2. No relationship has been observed in populations with low prevalence of vitamin A deficiency.
  11. Vitamin A-effect on infant growth
    1. Maternal vit A deficiency was related to ponderal and linear growth independent of infant HIV (Semba 1997).
    2. By 12 mos infants of vit A-deficient mothers weighed 8% less and were 2% shorter.
  12. Vitamin A
    1. Vitamin A deficiency in 70% of HIV-exposed infants in U.S. (Cunningham-Rundles 1995).
    2. Vitamin A was reduced esp in AIDS, but not deficient (Periquet 1995).
    3. GF+ children in the U.S. had increased vitamin A (Henderson 1997).
    4. Supplementation reduced diarrheal illnesses in HIV-E African infants (Coutsoudis 1995).
  13. Trace elements etc.
    1. No differences in serum and RBC Zn or Se observed in French children. Cu elevated in non-AIDS (Periquet 1995).
    2. No differences in Zn or Se in U.S. children, including those with GF (Henderson 1997). vRBC glutathione reduced in HIV especially with GF (Arpadi 1992).
  14. Neuroendocrine function in children with HIV
    1. A number of endocrine abnormalities with the potential to affect growth have been identified
    2. Isolated endocrine deficiencies are encountered (e.g., hypothyroidism).
    3. No single endocrine abnormality has consistently been associated with growth ds.
  15. Thyroid function in HIV-infected children
    1. While study results are inconsistent, thyroid abnormalities, clinical and subclinical, appear to be highly prevalent.
    2. Primary hypothyroidism, low free T4, elevated TSH seen in 18% (Hirshfeld 1996).
    3. Thyroid disease has not in general been established as an important factor in GF, but is a reversible cause for some children.
  16. Adrenal function in children with HIV
    1. Basal cortisol levels normal (Geffner 1993).
    2. Oberfield found elevated mean basal and stimulated cortisol levels in association with hypocampal atrophy (Oberfield 1994).
    3. Adrenal suppression does occur with megestrol acetate (Daaboul 1998).
  17. GH and IGF-1
    1. Laue, Geffner found IGF-1 to be normal.
    2. Lepage and Schwartz found IGF-1 to be reduced.
    3. In vitro resistance to IGF-1 and GH erythroid progenitor cells.
    4. No association low IGF-1 and poor growth (Matarazzo 1994).
    5. IGF-1 reduced in children with GF with decreased IGFBP-3/ternary complex (Frost 1996).
  18. Gastrointestinal disease in children with HIV infection
    1. The role of GI infections and malabsorption in malnutrition, poor growth, and immune dysfunction has not be established.
    2. Some enteric pathogens common in adults are rare in children (e.g., Isospora, E. histolytica Microsporidium, etc.) (Winter 1995).
    3. Cryptosporidium parvum, C. difficile, Salmonella spp, Camplobacter spp, CMV, HSV, rotavirus are common.
  19. Gastrointestinal disease in children with HIV
    1. Malabsorption of carbohydrates, fat, and protein are highly prevalent.
    2. CHO:30-50%, Fat: 30%, PRO: 32% (Miller 1991, Yolken 1991, Italian HIV study 1993).
    3. No association with malabsorption and growth.
    4. Association of malabsorption with diarrhea is inconsistent in studies.
    5. Studies is limited due to x-sectional design.
  20. Energy balance, viral replication, body composition, and growth in prepubertal HIV- infected children
    Arpadi S, Cuff P, Kotler D, Wang J, Matthews D.
    St. Luke's-Roosevelt Hospital Center
    Department of Pediatrics and Body Composition Unit
    Columbia University, New York, NY and
    Clinical Research Center, University of Vermont
  21. Objective
    1. To evaluate if abnormalities in energy balance contribute to growth failure in HIV- infected children.
    2. Examine the relationships among HIV replication, energy balance, body composition, and growth.
  22. Methods
    1. 43 prepubertal HIV-infected children, including 18 with growth failure (GF) defined as 12-mos growth velocity<5th%tile.
    2. Energy intake (EI) measured by 24-hr recall performed 3 times over 10 days.
    3. Viral replication measured by HIV RNA PCR (Amplicor).
    4. Resting energy expenditure (REE) measured fasting using open-circuit indirect calorimetry.
    5. Total energy expenditure (TEE) measured by differential excretion rates over 10 days of orally administered 18O and h3.
    6. Energy balance determined by subtracting EI from TEE (EI-TEE).
    7. Energy of physical activity determined by TEE-REE.
    8. Fat-free mass (FFM) was measured by dual x-ray absorptiometry (Lunar) using pediatric software.
    9. REE measures were compared with age norms based on FAO/WHO equations.
    10. t-tests were used to compare GF+ vs GF-.
    11. ANCOVA was used to adjust for the effect of age on EI, REE, TEE, FFM.
    12. Univariate and multiple regression models were also used.
  23. Conclusions
    1. HIV-infected children with GF have a negative energy balance despite relative reductions in REE and TEE.
    2. Dietary intake is an important determinant of GF.
    3. Viral replication appears to adversely affect FFM and growth.
    4. In contrast to findings in adults, no association was observed between HIV replication and REE.
    5. HIV replication was significantly correlated with the quantity of FFM.
    6. Future studies evaluating the effect of viral replication, antiviral therapies, and host immune response on energy intake, anabolism, and growth are warranted.

Abstract

Disturbances in growth and body composition occur commonly in children with HIV. 1 2 3 Poor growth affects survival, increasing the risk of death as much as 5-fold.4 The etiology of growth failure is likely multifactorial. While primary hypothyridiism appears to affect growth in some children, 5 and other abnormalities have been reported, 6 7 no single endocrine disturbance has been established as causally related to poor growth. Gastrointestinal dysfunction, including infection and malabsorption, has also been reported, but no clear relationship to growth failure has been documented.8 Although the prevalence and effects of micronutrients have not been fully evaluated, maternal vitamin A deficiency adversely affects the transmission of HIV as well as postnatal growth, irrespective of infant HIV status.9 10 Energy balance studies have not been performed in children with HIV. We measured energy intake and expenditures in 43 HIV-infected prepubescent children, including 18 with growth failure (GF+), defined as 12-month growth velocity <5th %-tile. Resting energy expenditure (REE), total energy expenditure (TEE), energy intake (EI), viral load (VL), and body composition were evaluated. The mean plasma HIV RNA content among the children with GF was significantly higher than in children with normal growth. HIV+/GF+ children had significantly less total calorie intake per day compared to the HIV+/GF- group. The mean age-adjusted REE and TEE were lower in GF+ children compared to GF- children; however, these differences did not reach statistical significance. Children with GF were estimated to have a daily energy deficit compared to GF- children who had an energy surplus. These data indicate an important role for viral replication and decreased dietary intake in HIV-associated growth failure. Despite relative decreases in total energy expenditure, a significant energy deficit was observed in children with HIV-associated GF.

References

Moye J, Rich KC, Kalish LA, Sheon AR, Diaz C, Cooper ER. Natural history of somatic growth in infants born to women infected by human immunodeficiency virus. J Pediatr 1996;128:58-69.

McKinney R, Robertson WR, et. al. Effect of human immunodeficiency virus infection on the growth of young children. J Pediatr 1993;123:579-82.

Arpadi S, Horlick M, Wang J, Cuff P, Bamji M, Kotler D. Body composition in prepubertal children with human immunodeficiency virus type-1. Arch Ped Adol Med. 1998152:688-93.

Berhane R, Bagenda D, Maurm L, Aceng E, Ndugwa C, Bosch RJ, Olness K. Growth failure as a prognostic indicator in pediatric HIV infection. Pediatr 1997;100e7.

Hirschfeld S, Laue L, Cutler G, Pizzo P. Thyroid abnormalities in children infected with human immunodeficiency virus. J Pediatr 1996;128:70-4.

Frost RA, Nachman SA, Lang CH, Gelato M. Protesolysis of insulin-like growth factor- binding protein-3 in human immunodeficiency virus-positive children who fail to thrive. J Clin Endocr Metabol 1996:81:2957-62.

Oberfield SE, Cowan L, Levine LS, George A, Raphael D, Litt A, Rojas V, Kairam R.Altered cortisol response and hippocampal atrophy in pediatric HIV disease. J Acq Immun Def Syn 1994;7:57-62.

Italian Pediatric Intestinal/HIV Study Group. Intestinal malabsorption of HIV-infected children: relationship to diarrhoea, failure to thrive, enteric micro-organisms and immune impairment. AIDS 1993;7:1435-40.

Semba RD, Miotti PG, Chiphangwi JD, Saah AJ, Canner JK, Dallabetta GA, Hoover DR. Maternal vitamin A deficiency and mother-to-child transmission of HIV-1 Lancet 1994;343:1593-7.

Semba RD, Miotti P, Chiphangwi JD, Henderson R, Dallabetta G, Li-Ping Y, Hoover D. Maternal vitamin A deficiency and child growth failure during human immunodeficiency virus infection. J Acq Imm Def Syn Hum Retrovir 199714:219-222.

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