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JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/QAI.0b013e31814d6600
Commentary

Bystander Effects: Children Who Escape Infection But Not Harm

Kuhn, Louise PhD*; Thea, Donald M MD†; Aldrovandi, Grace M MD‡

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From the *Gertrude H. Sergievsky Center, and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY; †Center for International Health and Development, Boston University School of Public Health, Boston, MA; and the ‡Department of Pediatrics, University of Southern California, Los Angeles, CA.

Supported in part by grants from the National Institute of Child Health and Human Development (HD 39611 and HD 40777).

Correspondence to: Louise Kuhn, PhD, Columbia University, Sergievsky Center, 630 West 168th Street, New York, NY 10032 (e-mail: lk24@columbia.edu).

Few would disagree about the urgency of ensuring that pregnant HIV-infected women with advanced disease have access to highly active antiretroviral therapy (HAART). Not only is HAART a life-saving intervention for this critical societal stratum (young women and mothers), but it clearly reduces pre- and perinatal HIV transmission and is likely to be effective to reduce postnatal transmission through breast-feeding. The findings from Chatterjee et al1 in this issue suggest that further benefits may extend to exposed-uninfected infants, providing yet another reason for strengthening HIV care and treatment programs for pregnant women.

Within a large mostly breast-fed cohort in Tanzania recruited before the widespread availability of HAART, risk factors for mortality to 2 years of age among children who remained uninfected despite being born to HIV-infected mothers were investigated. The study found that uninfected children whose infected mothers had more advanced HIV disease (including low CD4 cell counts and high viral loads) were twice as likely to die compared with uninfected children whose infected mothers had less advanced disease.1 These intriguing results are consistent with 2 previous studies: 1 based on a pooled analysis2 and 1 that considered mortality between birth and 4 months.3 These results are also consistent with early work indicating that exposed but uninfected children had more episodes of acute and persistent diarrhea compared with unexposed controls.4

Any benefits of HAART to reduce women's mortality postpartum contributes alone to better child outcomes, because, for obvious social reasons, orphans have a poor prognosis regardless of their HIV status.5-7 HAART might also be expected to reduce the vulnerability of uninfected children born to immunosuppressed mothers if it improves women's capabilities to look after their children. Despite intuitive appeal, whether sicker mothers are less able to take care of their children is far from established. We have previously demonstrated that the association between low maternal CD4 cell counts and increased infant mortality in the first few months of life is independent of maternal mortality and morbidity and is independent of separation attributable to maternal hospital admissions.3 Although these powerful social factors may exacerbate the vulnerability of exposed-uninfected infants, other biologic vulnerabilities, such as nutritional or immunologic deficiencies, may also exist. The precise nature of these vulnerabilities is important, because HAART may correct some but not all.

HAART rapidly leads to improvements in CD4 cell count but reconstitution of B- and T-cell function lags behind.8 If started, on average, 3 months before delivery, it is unclear whether measurable improvements in maternal immunity to common pathogens that threaten infant health are achieved. It is well established that infants rely on passively acquired antibodies for protection during the neonatal period. From the third trimester, specific transport mechanisms ensure that maternal antibody crosses the placenta and enters fetal circulation. Preterm delivery precipitously interrupts this transfer, thereby contributing to preterm infants' increased vulnerability to infections. Breast-feeding provides additional protection not only by passive provision of immunoglobulin and other immune factors but by priming the infant's immune system.9 If low maternal CD4 cell counts are markers of deficits in mucosal immunity in breast milk, we might expect the association to be strongest among breast-fed infants. To date, there has been too little reported variability in infant feeding practices within the published studies to investigate this.

Exposed-uninfected children have been widely studied to characterize immune responses after HIV exposures that do not result in infection. Multiple immunologic changes have been observed in addition to HIV-specific T-cell responses, including changes in T-cell subsets, cytokine and chemokine production, and maturation factors among others.10 We might have expected exposed-uninfected infants to be less rather than more susceptible to other infections, given their successful prior encounters with HIV and attrition (into the infected group) of those with infection vulnerability genes. It is possible, however, that these concomitant responses, such as more vigorous activation, may not be beneficial against other pathogens and may compromise later developmentally appropriate responses.

An alternate explanation for the increased risk of uninfected children of women with low CD4 cell counts is increased exposure to other pathogens, given more symptomatic disease and increased shedding. It is therefore of considerable interest that recent data from South Africa observed that exposed-uninfected infants hospitalized with pneumonia were almost 6-fold more likely to fail antibiotic therapy than equally sick uninfected infants of uninfected mothers.11 Because all children in this study were admitted with severe clinical pathologic conditions, which, in effect, condition on pathogen exposure, these findings suggest some form of immune compromise among exposed-uninfected children. These results also raise the concerning issue of household transmission of multidrug-resistant organisms, which may be more common among immunosuppressed HIV-infected adults among whom routine cotrimoxazole is recommended and who are likely to have had multiple prior treatments for various infections.

The number of these vulnerable exposed-uninfected infants is large and growing. This is because there is no consistent decline in HIV seroprevalence among pregnant women in most countries, and there has been considerable progress in expanding access to programs to prevent mother-to-child HIV transmission. As access to HAART expands, we might expect some spin-off benefits for exposed-uninfected infants too; however, it is too soon for complacency. Why exposed-uninfected infants of mothers with advanced disease are at increased risk for severe morbidity and death remains unclear. These mechanisms are relevant to whether HAART is or is not fully able to benefit this group of children. Current funding streams and research agendas rightly focus on improving HIV prevention and expanding access to treatment. Unfortunately, this focus overlooks other adverse biologic consequences that maternal HIV infection may have for child health. Children of HIV-infected mothers are not only at risk of HIV infection and orphanhood but may also be affected by HIV in ways we do not yet fully understand. It is important to understand these vulnerabilities better so that interventions can be developed to complement existing prevention and treatment programs to improve the health of children.

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REFERENCES

1. Chatterjee A, Bosch RJ, Hunter DJ, et al. Maternal disease stage and child undernutrition in relation to mortality among children born to HIV-infected women in Tanzania. J Acquir Immune Defic Syndr. 2007;46:598-605.

2. Newell ML, Coovadia H, Cortina-Borja M, et al. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet. 2004;364:1236-1243.

3. Kuhn L, Kasonde P, Sinkala M, et al. Does severity of HIV disease in HIV-infected mothers affect mortality and morbidity among their uninfected infants? Clin Infect Dis. 2005;41:1654-1661.

4. Thea DM, St. Louis ME, Atido U, et al. A prospective study of diarrhea and HIV-1 infection among 429 Zairian infants. N Engl J Med. 1993;329:1696-1702.

5. Crampin AC, Floyd S, Glynn JR, et al. The long-term impact of HIV and orphanhood on the mortality and physical well-being of children in rural Malawi. AIDS. 2003;17:389-397.

6. Nakiyingi JS, Bracher M, Whitworth JA, et al. Child survival in relation to mother's HIV infection and survival: evidence from a Ugandan cohort study. AIDS. 2003;17:1827-1834.

7. Ng'weshemi J, Urassa M, Isingo R, et al. HIV impact on mother and child mortality in rural Tanzania. J Acquir Immune Defic Syndr. 2003;33:393-404.

8. Lederman MM, Valdez H. Immune restoration with antiretroviral therapies: implications for clinical management. JAMA. 2000;284:223-228.

9. Labbok MH, Clark D, Goldman AS. Breastfeeding: maintaining an irreplaceable immunological resource. Nat Rev Immunol. 2004;4:565-572.

10. Kuhn L, Meddows-Taylor S, Gray G, et al. Human immunodeficiency virus (HIV)-specific cellular immune responses in newborns exposed to HIV in utero. Clin Infect Dis. 2002;34:267-276.

11. McNally LM, Jeena PM, Gajee K, et al. Effect of age, polymicrobial disease, and maternal HIV status on treatment response and cause of severe pneumonia in South African children: a prospective descriptive study. Lancet. 2007;369:1440-1451.

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© 2007 Lippincott Williams & Wilkins, Inc.

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