In developing countries, wasting is a major manifestation of acquired immunodeficiency syndrome (AIDS) in children (1). However, wasting is a major problem even in countries in which highly active antiretroviral therapy (HAART) is widely available. In the United States, human immunodeficiency virus (HIV)–associated wasting has increased in relative frequency from the fifth to the second most frequent AIDS complication (2).
Malnutrition can be an early feature of HIV infection and is associated with a rapid decrease in CD4 cell numbers and an increased rate of opportunistic infections, with a chronologic association among those three features (3).
Intestinal dysfunction is frequent in pediatric HIV infection. It includes carbohydrate malabsorption, steatorrhea, increased intestinal permeability, and intestinal iron malabsorption. Intestinal dysfunction was observed in up to 60% of children before HAART therapy (4–6). We have previously shown that ritonavir combination therapy restores intestinal function while increasing CD4 cell numbers and increases body weight in children with HIV (7). These data suggested a close correlation among intestinal and immune functions and nutritional condition.
Thus far, there is no evidence that nutritional support is effective in restoring compromised intestinal function. Similarly, there is no evidence that improved nutritional affects HIV-associated immune impairment. Several studies in adult patients have shown the benefits of nutritional interventions in HIV disease. Malnourished adults with full-blown AIDS responded to enteral or parenteral nutrition with an increase in body weight and fat mass (8–10). In children with HIV, information on nutritional rehabilitation is scanty. Gastrostomy tube feeding was well tolerated but had little effect on linear growth and lean mass in 18 children with HIV (11). Better results were observed in 23 children with HIV supplemented through gastrostomy, and an association between caloric intake and weight growth was reported. Children with higher CD4 counts and better weight for height z scores responded better to nutritional treatment in terms of weight gain (12).
This study tested the hypothesis that nutritional rehabilitation restores intestinal absorption and improves immune response in children with HIV. We reviewed the effects of nutritional interventions, pursued through total parenteral nutrition (TPN) or enteral nutrition (EN), in children seen at tertiary care centers for HIV infection in Italy. All children received clinical nutritional support before HAART became available.
To test the hypothesis that improving the nutritional condition may delay or partially reverse the progression of immune impairment, we performed a comparative evaluation of the number of CD4 cells before and after nutrition therapy.
To test the hypothesis that nutritional rehabilitation reverses intestinal dysfunction, the results of the d-xylose absorption test before and after nutrition therapy were analyzed.
PATIENTS AND METHODS
All children receiving nutrition therapy and who were seen at the reference centers for pediatric HIV infection in Naples, Padua, Rome, and Milan were enrolled in the period from 1995 to 1998, before HAART was available. All centers participate in the Italian Register for Pediatric HIV infection, which provides pediatricians of regional reference centers with diagnostic and therapeutic guidelines (1,13). The effects of nutritional intervention with TPN or EN were evaluated. Total parenteral nutrition was defined as the administration of at least 80% of total daily calories through a central line for at least 15 days and was generally performed as reported previously (14–16). Enteral nutrition was defined as nutrient administration through a nasogastric or nasoduodenal tube for at least 15 days. Usually high caloric–low volume preparations, including lactose-free formulas or protein hydrolysates, were given through nasogastric tubes using peristaltic pumps, to maintain a constant 24-hour rate (continuous enteral nutrition). Subsequently, when stability of nutritional condition was achieved, enteral feeding was gradually shifted to nocturnal continuous nutrition, leaving normal access to diurnal oral feedings.
There are no HIV-specific recommended dietary allowances for children with HIV infection. Therefore, nutrient intakes were planned according to standard daily requirements but individually tailored to clinical status, metabolic tolerance, and age. Generally, caloric intake was gradually adjusted to meet that needed by an individual child of the same age having a body weight equal to his or her 50th percentile, as suggested for children with HIV (17). Standard therapeutic doses for micronutrient deficiencies were used if needed (17).
Clinical information was required from each of the four centers taking part in the study by use of a questionnaire, a procedure often used for multicenter studies by the Italian Register for Pediatric HIV infection (3). Information included the main indication for starting each child on clinical nutrition, weight for age, number of CD4 cells, and HIV class. Intestinal absorptive function was evaluated using the xylose oral load. All parameters were recorded at the time of starting clinical nutrition and when clinical nutrition was withdrawn. Data from children who eventually died were those closest to the terminal event. The outcome of children was also evaluated.
The cutoff value of blood D-xylose was 25 mg/dL. Each child's HIV infection was staged according to the Centers for Disease Control and Prevention 1994 classification system for pediatric HIV infection (18).
Results are expressed as mean ± standard error of the mean. Categoric data were analyzed using Pearson χ2, applying the Fisher exact test when required. All continuous variables were compared using the Student t test. Changes in CD4 cell count, xylose levels, and body weight before and after nutritional intervention were analyzed using the Wilcoxon signed rank test.
Sixty-two children (24 boys; mean age 5.5 ± 4.0 years) underwent nutrition therapy: 46 with TPN (14 boys; mean age, 6.2 ± 3.8 years) and 16 with EN (10 boys; mean age, 4.8 ± 2.5 years). Duration of nutrition therapy was established by the physician in charge of each patient, based on initial malnutrition, tolerance to oral feeding, and clinical response. Mean duration of TPN was 157 ± 146 days/child (25–180 days) and total duration was 7,100 days. Mean duration of EN was 142 ± 159 days/child (17–210 days) and total duration was 2,010 days.
The main HIV baseline features did not significantly differ between children in the TPN and the EN groups. All but three children were classified as C3, indicating full-blown AIDS. The remaining three were in class B3, and all were in the EN group. Therefore, all children had severe immune impairment according to the Centers for Disease Control and Prevention immunologic classification (18). All children were receiving one or two inhibitors of reverse transcriptase (generally zidovudine and/or dideoxyinosine) when started on nutrition therapy. There was no change of antiretroviral drugs in any child during the study period. In selected cases, oral drugs had to be withdrawn because of poor tolerance.
Table 1 reports the indications for clinical nutritional support. Overall, intestinal malabsorption and chronic diarrhea were the most common indications for either EN or TPN. Children receiving TPN and those receiving EN had wasting, according to the HIV-specific definition for children (18). All children in the TPN group were in life-threatening conditions, although this was the main indication for TPN in only 4 of the 46 cases. None could be fed through the oral or duodenal route, and in some cases, oral administration of antiretroviral drugs became unfeasible. In contrast, none of the children receiving EN was in a life-threatening condition. From clinical records, it was evident that children in the TPN group were in more severe clinical condition than were children receiving EN.
As shown in Figure 1, the average z score of weight for age was −2.0 ± 0.8 in the TPN group and −1.5 ± 0.5 in the EN group when nutrition therapy began (P < 0.01).
Nutrition therapy resulted in increased body weight in both groups. The average weight increase was significant in children receiving EN (P < 0.01). It was not significant for children receiving TPN, although a trend toward weight gain also was observed in this group (Fig. 1).
Increased body weight of at least 5% of the baseline weight was recorded in 36 of the 46 children receiving TPN and in 14 of 16 children receiving EN (P > 0.05).
All children receiving nutrition therapy had low CD4 cell counts. Baseline CD4 cell count was 143 ± 54 cells/mm3 in children receiving EN and 55 ± 15 in those receiving TPN (P > 0.05). The mean CD4 cell count significantly (P < 0.01) increased in children receiving EN (Fig. 2) whereas it was not modified in the group of children receiving TPN. The number of children in whom CD4 cells increased with nutritional rehabilitation was greater in the EN than in the TPN group (11/16 vs. 18/46, P < 0.05).
Data on xylose oral load were available for 30 children (18 receiving TPN and 12 receiving EN), and all had abnormally low baseline values, indicating intestinal malabsorption. The mean basal xylose levels were similar in children receiving TPN to those receiving EN (Fig. 3).
A significant increase in the mean xylose concentration was observed in children undergoing EN (P < 0.01). In those receiving TPN, a trend toward normalization of intestinal absorption was observed, and the difference in the mean values before and after TPN was exactly on the cutoff limit of statistical significance (Fig. 2). Overall, 10 of 18 children in the TPN group and 9 of 12 in the EN group achieved full normalization of xylose absorption tests (P > 0.05).
Table 2 summarizes the outcome. While receiving nutrition therapy, several children in the TPN group had additional infections with opportunistic pathogens, which often was the cause of death. The ratio of children who eventually died and those who were able to shift back to oral feeding was reversed in the two groups: most children receiving TPN eventually died, whereas most children receiving EN returned to oral feeding.
A combination of poorly defined nutritional, infectious, and metabolic factors contribute to wasting in HIV infection (19). Intestinal dysfunction also contributes to wasting (4–6,20). Malabsorption may be related to immune suppression in adults with HIV (21), and results obtained in adults indicate that progressive loss of intestinal functional absorptive surface occurs as HIV disease progresses (22).
In children with HIV, the association between intestinal and immune functions is not clear. In previous work in children with HIV, we were unable to detect an association between immune and intestinal dysfunction (6). However, in a small population of children, HAART administration was associated with a parallel chronologic pattern of weight gain, increased CD4 cell count, and restored intestinal function (7).
If a link exists among nutrition and immune and intestinal functions, nutritional rehabilitation could improve either intestinal or immune functions. The hypothesis that nutritional interventions may beneficially affect intestinal nutrient absorption and ultimately improve the immune response is highly relevant for children with HIV infection who live in developing countries without access to expensive antiretroviral drugs.
Previous studies have shown that gastrostomy tube feeding results in increased body weight in children with HIV (11,12). In one of these studies, EN was not associated with modifications in CD4 cell count although children with higher CD4 counts responded better to clinical nutrition (12).
For the children enrolled in this study, continuous EN was selected because of intestinal malabsorption and diarrhea, and it proved effective in increasing body weight. There were no changes in treatment, namely antiretroviral therapy, that could be responsible for such a change. The nutritional benefits of continuous EN in children with HIV resemble those obtained in chronic intestinal disease (23). Continuous feeding is based on the concept that reduced intestinal surface is used for a longer time to increase nutrient absorption, thus allowing better absorption than bolus feedings. Evidence for reduced intestinal functional surface in our patients came from the results of baseline xylose load. Enteral nutrition was associated with restoration of intestinal absorptive function in most patients, as judged by the increased post-EN xylose absorption test.
The parallel improvement of nutritional condition and absorptive intestinal function indicates that malabsorption in HIV infection may be a direct consequence of malnutrition.
However, in adults with HIV, intestinal malabsorption relates more to immune suppression than jejunal morphologic change (21), suggesting that a close interaction exists among intestinal absorption, nutritional condition, and immune derangement. Our data support such a link and the rise in CD4 cell count after nutritional rehabilitation provides the first evidence that malnutrition contributes directly to CD4 count decrease in children with HIV infection.
An increase in total lymphocyte numbers has been previously observed in adults with HIV receiving enteral alimentation, although CD4 cell count did not change. The hypothesis was posed that this failure could be caused by a direct viral cytopathic effect (8). Unlike in adults, naive CD4 cells increase in children after HAART, and this relates to thymus function (24). Therefore, we speculate that nutritional rehabilitation may increase naive CD4 cell count, thereby allowing partial functional recovery of the immune response in children with HIV infection.
However, independent of its cause, non–HIV-related malnutrition causes widespread atrophy of lymphoid tissue, and malnourished children show a decreased T-helper/suppressor ratio, a diminished CD4 count, impaired delayed hypersensitivity, and increased serum immunoglobulin concentrations (25). These features strongly resemble the effects of HIV infection but are reversible with nutritional rehabilitation. As suggested previously, when these abnormalities are found in children with HIV, one cannot determine whether they relate to HIV or to malnutrition (19). Therefore, nutritional rehabilitation may have a general, non–HIV-related, beneficial effect on immune response.
Children receiving TPN had similar but less evident effects compared with those receiving EN, caused by their more severe clinical condition as evidenced by the high rate of opportunistic infections. Rapid worsening of CD4 cell count and wasting of body weight, typical of the terminal stage of HIV infection, were delayed in several children, as judged by the stability of these parameters during the average 5 months of TPN. Stabilization of body weight with parenteral nutrition has been reported in adult patients, indicating its efficacy against progressive nutritional deterioration (26). A similar beneficial effect was observed in children with AIDS in this study.
In patients with AIDS, various factors may act as confounders when studying cause–effect association. Confounders other than antiretroviral drugs were not specifically looked for in this study, because of the long period of enrollment, the heterogeneous population, and the multicenter nature of the study. However, major confounders were likely to be opportunistic infections acting as negative prognostic factors. The high rate of infections observed in children receiving TPN limited the beneficial effects observed in this group.
We must be cautious in establishing unequivocal cause–effect associations, and further studies are necessary to support the findings of this work.
Nutritional rehabilitation may reverse immune derangement and restore intestinal digestive–absorptive function if provided at an early stage of HIV infection. In the terminal stage, nutritional support may delay the progressive derangement of immune function while partially improving intestinal absorption.
Malnutrition may directly contribute to malabsorption and to immune impairment in children with HIV and may have important implications for children with HIV in developing countries. In these countries, HIV acts in combination with intestinal infections, limited food, and lack of medical support for a high rate of death. In many children, HIV induces nutritional failure (27), which in turn accelerates the progression of HIV disease.
With the widespread availability of HAART, the need for aggressive nutritional interventions may be reduced. This is certainly not so for patients with no access to HAART or for those who are intolerant of antiretroviral combination therapy. Our data strongly suggest that nutritional interventions that are provided early, affordable, and largely available may have a dramatic impact on the course of HIV disease in children. This supports the recommendations by the HIV working group of the Federation of International Societies of Pediatric Gastroenterology and Nutrition (28).
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