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(Circulation. 1995;92:2220-2225.)
© 1995 American Heart Association, Inc.

Articles

Immunoglobulins and Left Ventricular Structure and Function in Pediatric HIV Infection

Steven E. Lipshultz, MD; E. John Orav, PhD; Stephen P. Sanders, MD; Steven D. Colan, MD

From the Department of Cardiology, Children's Hospital (S.E.L., S.P.S., S.D.C.); the Department of Pediatrics, Harvard Medical School (S.E.L., S.P.S., S.D.C.); the Department of Biostatistics, Harvard School of Public Health (E.J.O.); and the Department of Medicine, Brigham and Women's Hospital (E.J.O.), Boston, Mass.

Correspondence to Steven E. Lipshultz, MD, Department of Cardiology, Children's Hospital, 300 Longwood Ave, Boston, MA 02115. E-mail lipshultz@a1.tch.harvard.edu.

	Abstract

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Background Progressive left ventricular (LV) dilation is common in children infected with HIV-1 and may be a harbinger of congestive heart failure (CHF). In many HIV-infected children, dilation is associated with inadequate LV hypertrophy, elevated afterload, and reduced LV function. Because CHF has been observed empirically to improve after treatment with intravenous immunoglobulin (IVIG) in other conditions and because LV dysfunction in pediatric HIV may be immunologically mediated, we examined retrospectively the relation between immunoglobulins and LV structure and function in 49 HIV-infected infants and children without CHF.

Methods and Results A total of 106 echocardiograms were performed in these children within 30 days of serum immunoglobulin (IgG, IgA, and IgM) measurements; this includes 12 children treated with IVIG therapy. All echocardiographic parameters, blood pressures, and immunoglobulins were adjusted for age or body surface area and subjected to repeated-measures regression. Regression models were adjusted simultaneously for endogenous IgA, IgG, IgM, IVIG therapy, zidovudine therapy, age, HIV disease stage, and weight. Higher endogenous serum IgG levels and IVIG treatment were associated with significantly greater wall thickness and lower peak wall stress. Higher endogenous serum IgA levels were associated with more normal LV wall thickness and LV thickness-to-dimension ratios. LV contractility, fractional shortening, end-systolic wall stress, and thickness-to-dimension ratio all showed a trend toward more normal values with higher endogenous immunoglobulin values or during IVIG treatment.

Conclusions LV structure and function appear to be more normal in HIV-infected children who receive IVIG treatment and in those with higher endogenous IgG levels. These results suggest that both the impaired myocardial growth and the LV dysfunction observed may be immunologically mediated and responsive to immunomodulatory therapy.

Key Words: immunoglobulins • immune system • AIDS • cardiomyopathy • pediatrics

	Introduction

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Infants and children with HIV infection are a rapidly expanding population.¹ Worldwide, as many as 10 million children are projected to have HIV infection by the year 2000.¹ Meanwhile, we have reported a 20% cumulative incidence rate of transient and chronic CHF in HIV-infected children,² indicating that HIV-related heart disease is becoming a major health problem.

As HIV-infected children live longer, virtually all of them show progressive LV dilation with inadequate hypertrophy.³ These two changes result in excessive LV afterload, which reduces LV function and may contribute to the frequent cardiac morbidity and mortality seen in pediatric HIV.^{2 3} One third of all pediatric HIV deaths occur in the setting of significant LV dysfunction.² The pathophysiology underlying this process is incompletely understood but is likely to be multifactorial, including direct infection of cardiac cells by HIV,⁴ Epstein-Barr virus coinfection,² and immunologic mechanisms presenting as myocarditis.⁵ Worsening echocardiographic parameters of LV function correlate with increasing immune dysfunction in HIV-infected children.⁶

IVIGs are immunomodulatory agents that have been shown to be beneficial in the treatment of the myocarditis of Kawasaki disease,^{7 8} as well as in idiopathic or viral myocarditis and dilated cardiomyopathy in children.⁹ Monthly IVIG treatment of HIV-infected children has been shown to reduce the incidence of bacterial and viral infections^{10 11 12} and to slow the declining CD4+ count, suggesting an immunomodulatory benefit.¹³

Pediatric HIV provides a unique opportunity to improve our understanding of the relation between LV growth and function and immunoglobulins. First, endogenous serum immunoglobulin levels in HIV-infected children cover a much broader range than in uninfected children, because hypergammaglobulinemia is common. Second, because some HIV-infected children receive monthly IVIG treatment to reduce infectious complications, it is possible to follow LV growth and function in individual children before and after starting IVIG treatment. This report examines the relation between LV growth and function and endogenous immunoglobulin levels, as well as chronic IVIG treatment, in HIV-infected children.

	Methods

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Patients
The eligible patient population consisted of all 126 children with known HIV infection (CDC Pediatric [P] classes P1 and P2)¹⁴ followed at Children's Hospital from January 1984 through January 1993. Subjects enrolled in an NIH study of heart and lung complications of pediatric HIV infection were excluded because of a restriction on the use of study data (n=26). From the remaining cohort, we retrospectively selected children who had one or more echocardiographic evaluations during the study interval and who had serum immunoglobulin levels measured within 30 days of the echocardiographic evaluation. Forty-nine children, with a total of 106 echocardiograms, met study entrance criteria. These patients had been referred for cardiac evaluation, for routine patient care, or as mandated by research protocols. None of these children received echocardiography because of symptomatic cardiac disease. Institutional review board approval was obtained for the HIV natural history and ACTG studies, as well as for chart review. Informed consent was also obtained for all HIV natural history and ACTG study participants.

Serum Immunoglobulin Levels
Concentrations of IgG, IgA, and IgM were determined by clinical laboratory procedures, including nephelometry and electroimmunoassay.

IVIG Treatment
We recorded all instances of cardiac measurements made while a child was undergoing IVIG therapy, defined as an echocardiogram 7 days after the initiation of IVIG therapy and 30 days after the conclusion of therapy. A child who was on chronic IVIG was considered to be on IVIG. Patients treated with IVIG received 400 mg/kg body wt every 28 days (Gamimune N, Miles Laboratories) at infusion rates recommended by the manufacturer. Patients were treated with IVIG to prevent recurrent serious bacterial infections.

Echocardiographic Evaluation
Complete two-dimensional echocardiography and Doppler studies with stress-velocity and stress-shortening analyses¹⁵ were performed in each child, and the results were analyzed by cardiologists unaware of the clinical status or medications of the children. We measured systolic and diastolic blood pressures with a Dinamap automated vital-signs monitor (Critikon, Inc). The combined M-mode echocardiogram, phonocardiogram, pulse tracing, ECG, and blood pressure reading were analyzed by a computer program.¹⁵ We determined LV contractility using the relation between end-systolic LV wall stress and the rate-adjusted velocity of fiber shortening, a previously validated index of contractility that incorporates afterload and is independent of preload.¹⁵ Contractility was defined as the standardized difference between the observed and the expected values of the rate-adjusted velocity of fiber shortening. Afterload was measured as end-systolic LV wall stress. We determined a functional preload index by adjusting the fractional shortening for afterload and contractility. Left ventricular mass (in grams) was calculated from the M-mode measurements by the method of Devereux et al.¹⁶

Cardiac data are expressed as z scores relative to age or body surface area (see the Table) to adjust for the changes in LV size and structure associated with growth.¹⁵ We used the SAS procedure NLIN to fit a nonlinear model describing the relation between the cardiac measurement and age (or body surface area) in 191 healthy subjects. More details on the data from healthy children and the nonlinear models can be found in Colan et al.¹⁵

View this table: [in this window] [in a new window]   Table 1. Impact of Endogenous Serum Immunoglobulins and Intravenous Immunoglobulin Therapy on Left Ventricular Structure and Function1

Statistical Analysis
We standardized serum immunoglobulin levels for age by creating z scores from previously published¹⁷ data on 201 healthy children. We used polynomial regression against age to smooth the mean immunoglobulin levels, as well as the upper and lower confidence bounds, given in that article. For regression analyses, we divided the age-standardized IgG values into "high" (>4 SD above normal for age) and "low" (4 SD above normal) levels. We chose 4 SD as the cutoff to create roughly equal-sized groups; a more standard cutoff of 2 SD yielded only 24 echocardiograms in the normal range (see Fig 1) and inadequate power to investigate the effects of IgG. Similarly, IgA and IgM values were dichotomized at >2 SD and >4 SD above normal, respectively. In addition to these indicators for elevated IgG, IgA, and IgM, the regression models included a marker for IVIG therapy.

View larger version (18K): [in this window] [in a new window]   Figure 1. Scatterplot showing the observed endogenous IgG levels among the HIV study cohort, as well as the expected normal mean level by age for uninfected children (solid line) and 95% confidence bounds for expected normal levels (dashed lines). The immunoglobulin values are plotted as solid circles for values collected while a child had AIDS, open circles for values during ARC, and triangles for the child with asymptomatic infection.

We used repeated-measures regression models to test for associations between the cardiac measures and endogenous immunoglobulins and IVIG therapy. We used the generalized estimating equation approach of Zeger and Liang¹⁸ for longitudinal modeling. The analyses simultaneously included IgG, IVIG, IgA, IgM, treatment with zidovudine, and markers of disease severity (age, weight for age, and AIDS/ARC). Our models did not include the CD4 count, since these values were not collected routinely until recently. The findings did not change substantially when the analyses were modified to remove outliers, delete patients on IVIG, use IgG as a continuous predictor, or include hematocrit.

	Results

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Population
We used 106 echocardiograms on 49 children in this study. The median age at the time of echocardiography was 3.1 years and ranged from 2 weeks to 12.8 years, except for 2 echocardiograms at 16.3 and 17.9 years. Twenty-eight children had 2 or more echocardiograms. At the time of echocardiography, the children as a group had a median-weight z score of -1.09 SD below normal, with a range from -3.66 to +1.66 SD. Fifty-seven percent of the echocardiograms were done while children had CDC-defined AIDS, 42% while the children were classified as having ARC, and 1 while a child had asymptomatic HIV infection.

Serum Immunoglobulins
The IgG, IgA, and IgM values for the study cohort are shown by age in Figs 1, 2, and 3, respectively. Endogenous serum immunoglobulins varied widely regardless of the age of the child or the stage of disease, with IgG and IgM generally much higher than normal.

View larger version (18K): [in this window] [in a new window]   Figure 2. Scatterplot showing the observed endogenous IgA levels among the HIV study cohort, as well as the expected level by age for uninfected children (solid line) and 95% confidence bounds for expected levels (dashed lines).

View larger version (18K): [in this window] [in a new window]   Figure 3. Scatterplot showing the observed endogenous IgM levels among the HIV study cohort, as well as the expected level by age for uninfected children (solid line) and 95% confidence bounds for expected levels (dashed lines).

Sixteen study children had only "high" IgG levels and contributed 30 echocardiograms. An additional 18 children had only "low" IgG levels and contributed 29 echocardiograms. The remaining 15 children had both high and low IgG levels at different times and a total of 47 echocardiograms.

Intravenous Immunoglobulins
Thirty-seven children had 80 echocardiograms only when not on IVIG treatment, 7 had 10 echocardiograms only while on IVIG treatment, and 5 had 16 echocardiograms both before and after the initiation of IVIG treatment.

Univariate Analyses
Mean z scores for cardiac structure and function are shown in Fig 4A, 4B, and 4C for patients on IVIG therapy and for low and high serum IgG and IgA groups. Fig 4A and 4B indicates that LV wall thickness is significantly below normal in children with lower IgG levels but normal in children with high IgG levels or those on IVIG therapy. The thickness-to-dimension ratio and peak wall stress values show a similar relation to either high IgG levels or IVIG therapy. Similarly, children with lower IgA levels had significant abnormalities of all cardiac parameters except contractility. For children with higher IgA values, LV dimension, thickness, thickness-to-dimension ratio, and peak wall stress were all normal. IgM was not found to relate to cardiac parameters. Therefore, no univariate results are presented for IgM.

View larger version (23K): [in this window] [in a new window]   Figure 4. Bar graph showing average cardiac measurements compared between echocardiograms on and off IVIG (A), between echocardiograms with low and high endogenous IgG (B), and between echocardiograms with low and high endogenous IgA (C). All cardiac measurements are presented as age- or body surface area–adjusted z scores, so that an average of 0 represents a normal value, +1 represents a value 1 SD above normal, and so on. *Average measurements that were significantly different from normal at P.05 by analyses accounting for correlated measurements within children. ED indicates end-diastolic; ES, end-systolic.

Multivariate analyses are presented in the Table.

IVIG Treatment
When the echocardiographic studies that were done while children were receiving IVIG treatment were compared with those done without IVIG, we noted the following (Table): (1) LV thickness was greater, with IVIG therapy associated with an increased thickness of 0.93 SD; (2) LV peak wall stress was lower, with IVIG therapy associated with a reduction in peak wall stress of 1.12 SD; and (3) LV fractional shortening was higher, with IVIG therapy associated with an increase in fractional shortening of 1.00 SD (P=.09).

Endogenous IgG
Hypergammaglobulinemia was significantly associated with (1) greater LV wall thickness, with a higher IgG associated with an increased wall thickness of 0.57 SD; and (2) lower peak wall stress, with a higher IgG associated with a reduced peak wall stress of 1.15 SD (Table).

Endogenous IgA
Higher IgA levels were significantly related to (1) greater LV wall thickness, with higher IgA associated with a 0.74 SD increase in thickness; (2) a higher LV thickness-to-dimension ratio, with higher IgA associated with a 1.12 SD increase in the ratio; and (3) higher heart rate, with higher IgA associated with a 0.73 SD increase in heart rate (Table).

Endogenous IgM
No significant relation was found between endogenous IgM levels and parameters of LV structure and function (Table).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Monthly infusions of IVIG to HIV-infected children appear to be associated with more normal LV structure and function compared with untreated infected children. Similar benefits in infected children with higher endogenous IgG and IgA levels suggest that immunoglobulins may influence mechanisms of LV hypertrophy. Our analyses showed a significant increase in wall thickness and a reduction in peak wall stress with IVIG and with elevated IgG levels. Trends in other cardiac parameters (eg, fractional shortening and contractility for IVIG) also supported the beneficial effects of immunoglobulins on cardiac structure and function.

The improvement in LV function is similar to what has been documented in Kawasaki disease⁷ and non-HIV myocarditis,⁹ although in those instances, improved function was related to improved contractility rather than lower afterload. The association of IVIG with a more normal hypertrophic response of the myocardium may have important implications for understanding the continuum from myocarditis to dilated cardiomyopathy and its control.

Immune mechanisms of cardiac disease¹⁹ appear relevant to an understanding of HIV, in which myocardial damage may occur by viral, lymphocytic, cytokine, or autoimmune mechanisms. In patients with Kawasaki disease, IVIG reversed lymphocyte activation.²⁰ Activated T cells have been shown to induce myocardial damage and worsen immune-mediated cardiovascular disease.²¹ Increased CD8+ T lymphocytes have been found within the myocardium of adult AIDS patients with symptomatic HIV-associated cardiomyopathy.²² IVIG treatment of Kawasaki and other pediatric diseases appears to result in fewer activated natural killer cells at sites of potential target tissue injury.²³ Restoration of suppressor T-cell functions has been noted in children with AIDS after IVIG treatment.²⁴ An immune-mediated muscle disease, dermatomyositis, has been effectively treated with high-dose IVIG,²⁵ with the associated cardiomyopathy dramatically improving,²⁶ as has the inflammatory muscle disorder polymyositis, found in HIV-infected patients.²⁷

The mechanism of action of IVIG is unknown; theories include the presence in the infusion of anti-idiotypic antibodies, specific antibodies to a possible infectious agent or toxin, or antibodies to antigens that behave as superantigens.²⁸ Other potential contributors include nonspecific actions, such as (1) non–antigen-specific immunological suppression; (2) beneficial effects of soluble CD4+, CD8+, and class I and class II HLA proteins contained within IVIG; (3) saturation of Fc receptors; (4) feedback inhibition of antibody synthesis; (5) downregulation of the transcription of cytokine genes; (6) inhibition of the effector functions of activated T cells and released cytokines and lymphokines by blockage of cytokine receptors or neutralization of cytokine activity; (7) inhibition of intracellular viral replication; and (8) adsorption of cytotoxic fragments generated by complement activation.

HIV infection is strongly associated with abnormalities of cellular growth factors and cytokines,²⁹ which are also capable of adversely affecting the heart.³⁰ An association between HIV, TNF-, and IL-6 was noted in HIV-infected children.^{31 32} Levels of TNF- and IL-6 in HIV-infected adults are directly related to the presence of cardiomyopathy.^{33 34} Interferon- treatment of HIV-infected adults has also been associated with CHF.³⁵ The treatment of HIV-associated CHF with zidovudine has been shown to be beneficial.^{34 36} HIV-infected children had significant increases in LV wall thickness and mass after zidovudine therapy,³ results that may relate to the lessening of TNF- or IL-6 secretion by zidovudine.^{37 38} The blunted hypertrophic response to increased afterload in children with HIV infection may be partially explained by the effects of cytokines on growth factors and oncogenes, the primary factors controlling cardiac growth and hypertrophy induced by mechanical stimuli, such as the increased systolic wall stress observed in this study.^{39 40} CMV gene transcripts, capable of upregulating TNF- gene expression⁴¹ and, in turn, reactivating CMV, both of which may affect the heart,⁴² have been identified within cardiomyocytes from HIV-infected adults with symptomatic myocarditis.⁴³

IVIG inhibits the production of TNF- and IL-1 through the Fc portion of IgG.⁴⁴ Further indication that the inhibition of cytokine secretion is related to the therapeutic benefit of IVIG is seen in T-cell–mediated autoimmune diseases treated with IVIG, in which a downregulation of TNF- secretion was demonstrated.⁴⁵ Elevated cytokines, including TNF-, IL-6, and IL-8, predict cardiovascular involvement in children with Kawasaki disease.⁴⁶ High levels of these cytokines can be reduced by the administration of IVIG to patients with Kawasaki disease⁴⁷ or with HIV infection.⁴⁸ The therapeutic effect of IVIG may result from the induction of soluble cytokine receptors and the release of IL-1 receptor antagonist.⁴⁹

Circulating immune complexes are commonly elevated in HIV-infected children.⁵⁰ HIV-infected children and adults with myocardial or pericardial disease had elevated serum autoantibody titers, suggesting that cardiac involvement in HIV infection may be related to autoimmunity.^{33 51} Treatment of HIV-infected children with IVIG results in a significant fall in circulating immune complexes.¹¹

Our results argue for a possible association between immunoglobulins and the control of LV growth and function. This association must be confirmed by both a longitudinal study of changes in endogenous immunoglobulin levels and a controlled, randomized trial of IVIG therapy in relation to cardiac measurements. Any conclusions regarding the ability of IVIG to alter the course of HIV heart disease should be limited to the data presented, since the data were not collected as part of any formal trial. Although some patients had longitudinal data, no regular follow-up schedule was available, and discrepancies can occur between cross-sectional and longitudinal analyses because of natural changes with time. We tried to control for progressive disease severity in our analyses, but we did not have CD4 counts, and unexpected temporal or other factors may also play a role. Finally, the study cohort comprised children who had measurements of both immunoglobulins and echocardiographic parameters close in time; their results may not be representative of all children with HIV.

We adjusted the multivariate analyses for available measures of disease progression and severity: age, weight, CDC P classification, and zidovudine status. Our results remained significant. Moreover, our models simultaneously included the collinear factors of IgG, IgA, IgM, and IVIG therapy. Multicollinearity has the effect of increasing the variability and reducing the significance of predictors. Hence, the effects we found to be significant might truly be even more important, and our negative findings may be false-negatives.

The decision to use IVIG in the HIV-infected population should be evaluated on the basis of its overall effects. Although a recent trial found no additional benefit of IVIG in reducing bacterial infections in HIV-infected children receiving zidovudine and trimethoprim sulfamethoxazole,¹² our study suggests that IVIG may have beneficial effects on the heart. Although 20% of all HIV-infected children followed at our institution have had transient or chronic CHF,² none of the patients in this study who had high immunoglobulin levels or received IVIG treatment had heart failure during the study interval. The prevention of heart failure is likely to be associated with reduced morbidity, a better quality of life, and lower economic costs.

	Selected Abbreviations and Acronyms

 

ACTG = AIDS Clinical Trials Group ARC = AIDS-related complex CDC = Centers for Disease Control and Prevention CHF = congestive heart failure CMV = cytomegalovirus HIV = human immunodeficiency virus-1 IL = interleukin IVIG = intravenously administered immunoglobulin LV = left ventricular TNF = tumor necrosis factor

	Acknowledgments

 
This work was supported in part by the National Institutes of Health, Bethesda, Md (R01AI-28076, U01AI-25934, NO1HR-96041, 5MO1RR-02172, and R01HL-48012); the Pediatric AIDS Foundation, Santa Monica, Calif; Ronald McDonald's Children's Charities, Westwood, Mass; and a Clinical Investigator Award from the National Heart, Lung, and Blood Institute of the National Institutes of Health (HL-01816). The authors would like to thank Cynthia Barber, MPH, Tracie Miller, MD, and Nancy Borden for editorial suggestions; Kenneth McIntosh, MD, for support and encouragement; and the members of the Children's Hospital AIDS Program for their care and dedication to the children, and their families, in this report.

Received February 28, 1995; revision received May 4, 1995; accepted May 6, 1995.

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