The present large multicenter study of infants born to HIV+ women confirms and extends the findings of a smaller single center study.13
The cumulative incidence () and the prevalence () of asthma, as assessed by asthma medication use, are higher in HIV+ HAART+ children as compared to these HIV+ HAART− children. Our data show a much lower cumulative incidence and prevalence of asthma in HIV+ HAART− children than HIV+ HAART+ children and a restoration of the risk of asthma when HIV+ children were treated with HAART. This pediatric human model of asthma confirms what has been seen in animal models with asthma1–3
and suggests that the loss of CD4+
T cells in children with untreated HIV infection protects against asthma, and the gain of CD4+
T cells with HAART therapy serves as a risk factor for asthma. Our findings are in agreement with most studies of adult patients with HIV infection5–8
but not other studies.9, 10
Most of these adult studies were performed in the pre-HAART era6–10
and the timing of HIV infection (adults vs. infants) and immune ontogeny (developed vs. developing) most likely explains the lack of complete agreement. One clear example of the difference between pediatric adult HIV pathogenesis is the rapid rise and persistent (≥3 years) elevation in HIV RNA level (hundred thousand to million range) in newborns26
compared to a much lower HIV viral set-point observed 6–8 weeks after infection in adults.
It is possible that the immunoreconstitution of CD4+
T cells with HAART therapy plays a role in an inflammatory response as active CD4+
T cells initially confront HIV antigens or those of opportunistic organisms colonizing the airway27, 28
that results in a clinical state of bronchial hyperresponsiveness (). It is reasonable to speculate that inflammatory cytokines (e.g., IL-4, IL-5, IL-9, IL-13), may participate in this production of asthma.29
T cells (i.e., DR+
) may be contributing to a state of pulmonary hypersensitivity as well.30
These activated CD8+
T cells have been associated with HIV disease progression and other serious complications of HIV infection, such as encephalopathy.31
T cells can switch from IFN-γ to IL-5 production32
and may be operating in patients with HIV infection who develop asthma on HAART therapy. In another area of clinical immunology, Reveille and Williams33
have noted the marked change in the pattern of rheumatological complications of HIV infection in adults since the introduction of HAART therapy with the appearance of de novo autoimmune disorders as part of the immunoreconstitution of CD4+
Several limitations of the present study need mention. The WITS study was not designed to look at the incidence of asthma per se but to focus on HIV infection and its consequences. The diagnosis of asthma and reactive airways disease reported by parents and recorded by WITS medical personnel in the first 1–2 years life of the study subjects suggested an overuse of the diagnosis of asthma as applied to wheezing infants with respiratory syncytial virus or rhinovirus present with asthma-like symptoms (data not shown).17, 34–36
Many of these young infants infected with respiratory viruses, particularly those with underlying allergies, indeed go on to have persistent asthma, but a majority have their symptoms remit in a few years. The WITS program did not provide a long-term evaluation of the persistence of asthma symptoms with measurement of pulmonary function.
To mitigate these limitations we established a diagnosis of asthma in the WITS cohort by the use of asthma medications, a more conservative approach than using parental recall of wheezing in infants. We also observed a relatively high incidence of asthma in the HIV− group (roughly equal to that of the model HIV+ HAART+ group). These children might have been exposed to HIV antigens in utero and in the peripartum period, most likely becoming sensitized to HIV antigens and exposed to pro-inflammatory cytokines of the HIV-infected mother. This HIV exposure perhaps renders the HIV− group a non-ideal control against which to compare the incidence of asthma. As the control study subjects lived in inner cities, for the most part, environmental exposures may have contributed to a higher incidence and prevalence of asthma in all groups.37
There is some evidence in the pulmonary literature that HIV-exposed infants had a 20% lower partial forced expiratory flow as compared to historical controls.38
Although the authors at that time discounted an HIV exposure factor as the basis for causation, in retrospect, this may well have played a role in producing this diminution of infant lung function.
There is also a possibility that a treatment-related censoring function with patients who died could have biased our study results. HIV+ infants had a lower risk of death when they were being treated with HAART. However, the nature of the finding presented here suggests that the direction of the bias is to elevate the model incidence curve for the HIV+ HAART− infants. This would occur because the recovery of CD4+ T cells predicts resurgence of the risk for asthma (the finding here) and the death-censoring mechanism is selectively eliminating from the analysis asthma information from those infants with the lowest CD4+ T cell counts, who would be least likely to develop asthma in our hypothesis.
Despite these limitations, there is reason to continue to explore the interrelationships between HIV infection, HAART treatment, asthma, and CD4+
T cells and to expand the study to the evaluation of inflammatory cytokines and activated CD8+
T cells. A prospective study of HIV+ patients treated with HAART is now needed that relates pulmonary function data to immune responses. This AIDS model of asthma may hold clues for a better understanding of molecular and cellular mechanisms responsible for the epidemic of asthma in children.39