Increased incidence of asthma in HIV-infected children treated with highly active antiretroviral therapy in the National Institutes of Health Women and Infants Transmission Study

Article Outline

• Abstract
• Methods
  • WITS
  • Use of antiretroviral medications
  • Laboratory studies
  • Diagnosis of asthma
  • Statistical analysis
• Results
  • Patient cohorts
  • Survival analysis relating HIV infection and HAART use (for HIV+ infants) to the risk of initiating asthma medication
  • Analysis of the prevalence of asthma medication use
  • Effects of HAART on the rate of change of CD4+ T-cell percentage at the time of the initiation of asthma medication
• Discussion
• Acknowledgment
• References
• Copyright

Background

Immunoreconstitution of HIV⁺ patients after treatment with highly active antiretroviral therapy (HAART) appears to provoke inflammatory diseases.

Objective

We sought to determine whether HIV⁺ children receiving HAART (HIV⁺ HAART⁺) have a higher incidence of asthma than HIV⁺ children not receiving HAART (HIV⁺ HAART⁻).

Methods

Two thousand six hundred sixty-four children (193 HIV⁺ and 2471 HIV⁻ children) born to HIV⁺ women were evaluated for the incidence and prevalence of asthma (ie, asthma medication use) and change of CD4⁺ T-cell percentage with time.

Results

The HIV⁺ HAART⁺ children had higher CD4⁺ T-cell percentages, lower CD8⁺ T-cell percentages, and lower viral burdens than the HIV⁺ HAART⁻ children (P ≤ .05 to P ≤ .01). The cumulative incidence of asthma medication use in HIV⁺ HAART⁺ children at 13.5 years increased to 33.5% versus 11.5% in HIV⁺ HAART⁻ children (hazard ratio, 3.34; P = .01) and was equal to that in the HIV⁻ children. In children born before the HAART era, the prevalence of asthma medication use for HIV⁺ HAART⁺ children at 11 years of age was 10.4% versus 3.8% for HIV⁺ HAART⁻ children (odds ratio, 3.38; P = .02) and was equal to that of the HIV⁻ children. The rate of change of CD4⁺ T cells around the time of first asthma medication for HIV⁺ HAART⁺ versus HIV⁺ HAART⁻ children was 0.81%/y versus −1.43%/y (P = .01).

Conclusion

The increased incidence of asthma in HIV⁺ HAART⁺ children might be driven by immunoreconstitution of CD4⁺ T cells.

Key words: Pediatric HIV infection, CD4⁺ T cell–mediated induction of asthma, highly active antiretroviral therapy–produced immunoreconstitution

Abbreviations used: ART, Antiretroviral therapy, GEE, Generalized estimating equation, HAART, Highly active antiretroviral therapy, NNRTI, Nonnucleoside reverse transcriptase inhibitor, NRTI, Nucleoside reverse transcriptase inhibitor, PI, Protease inhibitor, WITS, Women and Infants Transmission Study

Asthma or asthma-like conditions can be seen in animal models with pulmonary infections and immunoreconstitution.¹ CD4⁺ T cells are essential for the development of animal models of asthma because animals lose their asthma when depleted of CD4⁺ T cells.², ³ B cell–, IgE-, and mast cell–deficient mice can still have asthma, but CD4⁺ T cell–, signal transducer and activator of transcription 6–, and IL-13–deficient mice cannot.⁴ There are studies that document an increase in bronchial hyperresponsiveness and asthma in HIV-infected adults,⁵, ⁶, ⁷, ⁸ but other studies do not confirm these findings.⁹, ¹⁰ For example, Lin and Lazarus⁷ made the seminal observation that a recent CD4⁺ T-cell count of 200 cells/μL or greater was significantly associated with current asthma (P = .01). The weight of this evidence suggests that adults with HIV infection have an increased prevalence of asthma, but most of these studies took place in the pre–highly active antiretroviral therapy (HAART) era when the immunoreconstitution inflammatory syndrome¹¹ was unknown, and most studies did not stratify patients by their CD4⁺ T-cell count.

Galli et al¹² reported a reduced frequency of wheezing (not defined as asthma) in infants with HIV infection who were followed for 2 years of life, but Foster et al,¹³ in a single-center retrospective study of 83 older children and young adults, reported a several-fold increased asthma prevalence of 34%. In the latter study there was substantial evidence that antiretroviral medications either restored the CD4⁺ T-cell count in children inadequately treated or preserved the CD4⁺ T-cell count in children adequately treated from birth. Gutin and Secord¹⁴ reported, in an abstract publication, that 24 of 85 children with HIV infection were given diagnoses of asthma. Of these 24 children, 65% had asthma within 3 years of beginning HAART, and 22 were immunoreconstituted or immunopreserved at the time of their asthma diagnosis.

To expand on these preliminary findings, investigators of the Women and Infants Transmission Study (WITS), a large multicenter HIV⁺ pediatric cohort, reviewed the cohort for the incidence and prevalence of asthma, and the results of that investigation are reported herein.

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Methods 

WITS 

WITS is a prospective, natural history, noninterventional study of HIV⁺ pregnant women and their offspring conducted by the National Institute of Child Health and Human Development, National Institute of Allergy and Infectious Diseases, National Institute on Drug Abuse, and National Institute of Mental Health from 1988 to 2006 at multiple sites in the United States (Boston and Worchester, Massachusetts; Chicago, Illinois; Houston, Texas; New York, New York; and San Juan, Puerto Rico) with a total enrollment of 193 HIV⁺ and 2,471 HIV⁻ children. Pregnant women and their infants began enrollment in 1989, and CD4⁺ T-cell and HIV culture/HIV DNA PCR assays were performed at regular intervals: birth; 1, 2, 4, 6, 9, and 12 months; and every 6 months thereafter for HIV⁺ children and every 12 months thereafter for HIV⁻ children. Similarly, secondary diagnoses of the subjects and their medication use were an integral part of the extensive WITS protocol that were recorded by medical personnel at each WITS study visit.¹⁵ All WITS study data were collected in a systematic manner on case report forms in face-to-face study visits between the patient and the research nurse and physician-investigator. The institutional review board at each center approved the protocol, and written informed consent was obtained from all parents or legal guardians before study enrollment.

In June 1998, a procedure (randomization mailers using a Bernoulli selection sequence) was instituted to reduce the large cohort of the WITS HIV⁻ infants by two thirds. This random selection of HIV⁻ children who would stop WITS follow-up prevented a selection bias from being introduced in the cohort of HIV⁺ patients remaining in the study. The medical care of children was not a function of the WITS follow-up protocol visits.

Use of antiretroviral medications 

All visits for each HIV⁺ child available for study were categorized into one of 3 antiretroviral therapy (ART) eras, and the proportion of visits with HAART was computed for each ART era. In ART era I (before February 28, 1994), none of the 127 HIV⁺ children had received HAART. In ART era II (March 1, 1994, to July 31, 1996), 122 HIV⁺ children had not received HAART; 8 had 20% to 40% of visits with HAART. In ART era III (after July 31, 1996), 26 HIV⁺ children had not received HAART, 6 had less than 20% of visits with HAART, 17 had 20% to 40% of visits with HAART, 18 had 40% to 60% of visits with HAART, 29 had 60% to 80% of visits with HAART, and 44 had more than 80% of visits with HAART. In WITS, HAART is defined as therapy with 3 drugs in 2 of the 3 available classes of ART drugs: (1) nucleoside reverse transcriptase inhibitors (NRTIs), (2) nonnucleoside reverse transcriptase inhibitors (NNRTIs), and (3) protease inhibitors (PIs). Before the availability of PIs, 26 children had received 1 NRTI, 29 had received 2 NRTIs, and 1 had received 1 NRTI plus 1 NNRTI.

Laboratory studies 

Complete blood counts were performed at hospital laboratories that had been certified by the College of American Pathologists or other nationally recognized quality assurance programs. All sites participated in the laboratory quality assurance program of the AIDS Clinical Trials Group for flow cytometry and the Virology Quality Assessment for HIV culture and HIV DNA PCR assay.¹⁶ For flow cytometry, samples were prepared for staining and analysis by means of whole-blood lysis, as previously described.¹⁷

The diagnosis of HIV infection required 2 positive assays, HIV culture, or HIV DNA PCR. Two to 3 negative HIV assays after 1 month of age were required for the assignment of a child to the HIV⁻ group.

Diagnosis of asthma 

In this prospective analysis of the WITS completed database, asthma was defined in terms of asthma medication use rather than parental report of wheezing, reactive airways disease, or asthma. Medication use was preferred rather than reported symptoms because asthma does not develop in most infants with wheezing¹⁸ and most pediatricians identify the response to asthma medications as necessary in establishing a diagnosis of asthma.¹⁹

All medications were recorded at each study visit from birth for all WITS patients. Short-acting and long-acting bronchodilators (eg, albuterol), inhaled corticosteroids (eg, fluticasone), and leukotriene antagonists (eg, montelukast) were all considered asthma medications in this study.

Statistical analysis 

All statistical analyses were performed with SAS software (SAS Institute, Inc, Cary, NC). Means, SDs, and percentages were estimated by using Proc Means and Proc Freq, respectively.

Longitudinal data analyses were carried out with generalized estimating equations (GEEs)²⁰ and mixed-model ANOVA.²¹, ²² In some figures data are presented by using 3-point moving averages to improve the signal-to-noise ratio of the curves. Both GEEs and mixed models can account for the correlation introduced by using this type of smoothing technique through the use of structured correlation matrices for the regression coefficients. Proc Genmod and Proc Mixed were used to carry out these analyses. Multivariate survival analysis models were carried out with the Cox proportional hazards model.²³ Proc Phreg was used to carry out these analyses.

The GEE, mixed-model, and survival analysis models used time-dependent HAART-use variables to indicate when a child was and was not receiving HAART during a specified interval of time. When performing survival analysis, this technique allows the estimation of β coefficients that indicate how much a patient's risk of the event being studied is being changed in response to the patient's change in HAART use. For the GEE and mixed-model analyses, the β coefficient indicates how much the expectation of the response variable (eg, CD4⁺ T-cell percentages) changes in response to the patient's change in HAART use. For both of these models, it is possible to output from the SAS analysis a model curve corresponding to the instance in which the patient took HAART over the entire interval. The procedure for survival analysis is presented by Kalbfleisch and Prentice.²⁴ These types of curves are seen in our presentation of the comparison of the HIV⁺ HAART⁺, HIV⁺ HAART⁻, and HIV⁻ groups in Fig 1 (see Results). The “cumulative incidences” presented in this figure correspond to the expected incidences that would be obtained if it were possible to segregate a group of HIV⁺ children into a group who took HAART for the entire interval and those who did not take HAART for the entire interval. Fig 2 (see Results). presents a 3-point moving average of the marginal prevalence of asthma use without using model parameterizations. Fig 3 (see Results). presents a marginal presentation of the median and interquartile range of CD4⁺ T-cell percentages analyzed according to the child's HIV status and HAART therapy at the time of CD4⁺ T-cell evaluation. Statistical assessments comparing the curves were done by comparing the change of CD4⁺ T-cell percentage/time (slope) coefficients obtained from the Proc Mixed analysis.

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• Fig 1. 

  Survival analysis results for the time to first asthma medication use. Cox model estimates relating differences between children according to HIV infection status and HAART use (in the HIV⁺ group) and respective P values are annotated in the lower right-hand portion of the graph. Estimated cumulative incidences for each group at 2, 5, 10, and 13.5 years of age are annotated in the upper left-hand portion of the graph.

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• Fig 2. 

  Prevalence of asthma medication use for children born in the pre-HAART era using GEEs. Data are presented by using a 3-point moving average. No asthma medications were used by any group before 60 months.

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• Fig 3. 

  Median CD4⁺ T-cell percentages in children aged 6 to 10 years indexed according to the time of first asthma medication use (Time 0). The slope estimates of CD4⁺ T cell percentages from the mixed-model analysis are annotated in the upper portion of the graph.

In some instances we have presented pairwise comparison results from analyses that originally had 3 different parameters. These pairwise comparisons were only generated if the P value associated with the 3-parameter comparison was significant. Once the 3-parameter test P value was declared significant, each pairwise test was carried out by using the .05 significance level of Hayter.²⁵

All statistical tests were carried out with a .05 α level to declare statistical significance.

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Results 

Patient cohorts 

Table I summarizes the clinical characteristics of the study subject cohorts by HIV status (HIV⁺ or HIV⁻) and whether an HIV⁺ child ever used HAART (ever used HAART vs never used HAART). The distribution of mean follow-up time (also mean age) among the 3 groups was statistically different (P < .001). The shorter mean follow-up time of the never used HAART group is due to the death of many patients in this group (33/80) compared with the ever used HAART group (8/113). The shorter follow-up times for the HIV⁻ group is due to randomization of these children out of the WITS protocol (see the Methods section, n = 1418), a parent's refusal to allow a child to continue in the study (n = 502), and loss to follow-up (n = 436). Sex, race/ethnicity, and ability to pay for medical costs (socioeconomic status) did not differ among the 3 cohorts. All 3 cohorts of the study were predominantly of minority racial and ethnic groups and were inner-city dwellers. The percentage survival of patients shows that the HIV⁺ HAART⁺ children were somewhat older than the HIV⁺ HAART⁻ children (94.4% vs 85.5%), respectively. These survival rates are somewhat different from those in Fig 1 (see below), where time-dependent analysis was used to compare the incidence distributions.

Table I. Patient cohort clinical characteristics of the WITS study population by HIV status and HAART use as fixed variables (ever used or not)

	Ever used HAART, HIV+ (n = 113)			Never used HAART, HIV+ (n = 80)			HIV− (n = 2471)
	N total	n	Percentage (mean)	N total	N	Percentage (mean)	N total	n	Percentage (mean)	P value∗
Mean follow-up (y)∗	113		(10.4)	80		(3.0)	2471		(2.5)	<.001
Time on HAART (mo)∗	113		(59.4)	80		0.0	2471		(0.0)	<.001
Survival rate at 5 y∗	113		94.4	80		85.5	2471		87.8	.1268
Sex
Male	113	64	56.6	80	33	41.2	2471	1257	50.8	.107
Female		49	43.3		47	58.7		1214	49.1
Race/ethnicity
White	113	16	14.1	80	13	16.3	2471	271	11.0	.195
Black		53	46.9		29	36.2		1189	48.1
Other/missing		44	38.9		38	47.5		1011	40.9
Insurance coverage
Self	107	3	2.8	77	5	6.4	2446	113	4.6	.149
Public insurance/aid		78	72.8		59	76.6		1676	68.5
Private insurance		8	7.4		6	7.7		345	14.1
Other individual pays		18	16.8		7	9.0		289	11.8
Free care/does not pay		0	0.0		0	0.0		23	0.9

Table II records the average percentages of CD4⁺ T cells, CD8⁺ T cells, CD4/CD8 ratio, CD8⁺DR⁺ T cells, and HIV RNA levels at several time points, with HAART serving as a time-dependent variable (ie, children are assigned to their respective group depending on whether they were or were not taking HAART at the time of the clinic visit). In general, HIV⁺ children who were receiving HAART at the time of measurement had higher CD4⁺ T-cell, lower CD8⁺ T-cell, and lower CD8⁺DR⁺ T-cell percentages; higher CD4/CD8 ratios; and lower viral burdens than the HIV⁺ children not receiving HAART (P ≤ .05 to P ≤ .01). The HIV⁺ HAART⁺ and HIV⁺ HAART⁻ children's values at each time were also significantly different from those of the HIV⁻ children (P ≤ .05 to P < .01). Although there were age differences with groups, the GEE analyses and time-dependent covariate analyses that were performed corrected for these age differences through the formation of the respective risk sets and marginal analyses that were evaluated over time.

Table II. Average CD4 percentage, CD8 percentage, CD4/CD8 ratio, CD8DR percentage, and HIV RNA level by age and HIV status and grouped according HAART at the time of the child's visit

At each time point, HIV⁺ subjects are assigned to a group based on HAART medication (ie, HAART⁺ or HAART⁻). Pairwise comparison differences are significant at a P value of less than .05 (boldface: P < .01).

Survival analysis relating HIV infection and HAART use (for HIV⁺ infants) to the risk of initiating asthma medication 

The time of first asthma medication use for each child was analyzed beginning at 1 month of age and continuing up to 13.5 years of age by using a time-dependent Cox model (Fig 1). The β coefficients obtained from this analysis and “cumulative incidence curves” compare the expected incidence of asthma medication use for a model group of HIV⁺ infants receiving HAART over the entire follow-up interval, a model group of HIV⁺ infants not receiving HAART at any time over the entire follow-up interval, and the HIV⁻ infants. The cumulative incidence at 13.5 years of age for the model HIV⁺ HAART⁺ group was 33.5%, and that of the HIV⁻ group was approximately 31.2%. In contrast, the cumulative incidence curve for the model HIV⁺ HAART⁻ group was 11.5%. By using the Cox model estimates to assess whether HIV infection status and HAART therapy (in HIV⁺ children) were related to the risk of first asthma medication use, the exponential of the difference in the coefficients for the HIV⁺ HAART⁺ and HIV⁺ HAART⁻ groups yielded a hazard ratio estimate of 3.34 (P = .01), and the difference between the HIV⁺ HAART⁻ and HIV⁻ coefficients yielded a hazard ratio estimate of 0.33 (P ≤ .01). The difference between the HIV⁺ HAART⁺ and HIV⁻ coefficients was not significant. A Cox analysis model was also used to examine the relationship between asthma medication use and time-dependent treatment with NNRTIs or PIs. The results were similar to those observed in the HAART analysis (data not shown).

Analysis of the prevalence of asthma medication use 

Fig 2 shows the prevalence of asthma medication use for children born in the pre-HAART era (before February 28, 1994), as assessed at the time of each follow-up visit (approximate child's age). The first asthma medication use for all groups was recorded at the 60-month (5-year) visit. Most (65%) of the HIV⁺ HAART⁺ children had reported asthma medication use on at least 2 clinic visits. The maximum prevalence of asthma medication use for HIV⁺ children receiving HAART at the same time was 10.4%, the maximum prevalence of asthma medication use in the HIV⁻ group was 10.5%, and the corresponding prevalence for HIV⁺ children not receiving HAART at the same time as the asthma medication was 3.8%. All of these maximums are achieved at 132 months (11 years) of follow-up. By using a GEE model analysis, the odds ratio for receiving asthma medication was 3.38 (P = .02) when comparing the HIV⁺ HAART⁺ and HIV⁺ HAART⁻ groups, 1.40 (P = .51) when comparing the HIV⁺ HAART⁺ and HIV⁻ groups, and 0.41 (P = .15) when comparing the HIV⁺ HAART⁻ and HIV⁻ groups.

There were too few HIV⁺ children not receiving HAART to allow the statistical analysis of the WITS children born in ART eras II (after March 1, 1994) and III (after August 1, 1996).

Effects of HAART on the rate of change of CD4⁺ T-cell percentage at the time of the initiation of asthma medication 

Mixed-model analysis was used to compare CD4⁺ T-cell percentage trajectories (percentage per year) among children ages 6 to 10 years indexed by their initiation of asthma medication use (Fig 3). We have chosen to use the CD4⁺ T-cell percentage because this is a constant indicator of CD4⁺ T-cell sufficiency across different children's ages. Assignment of an HIV⁺ child to a HAART group was made at the time of the CD4⁺ T-cell percentage evaluation (a time-dependent analysis). Data points 3 years before and 3 years after the initiation of asthma medication were recorded at each time according to the child's HIV status and whether he or she was receiving HAART at that time (HIV⁺ HAART⁺, HIV⁺ HAART⁻, and HIV⁻). The average slopes of the trajectories were as follows: 0.81%/y for HIV⁺ HAART⁺ children, −1.43%/y for HIV⁺ HAART⁻ children, and 0.15%/y for HIV⁻ children. Analysis of these slope coefficients shows significance for the comparison of HIV⁺ HAART⁺ and HIV⁺ HAART⁻ children (P = .010) but not for other comparisons (HIV⁺ HAART⁺ vs HIV⁻, P = .41; HIV⁺ HAART⁻ vs HIV⁻, P = .08). If data points 1 year before and 1 year after the initiation of asthma medication were used to calculate slopes, again significant differences existed between the HIV⁺ HAART⁺ and HIV⁺ HAART⁻ children (P = .01, data not shown).

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Discussion 

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 (Fig 1) and prevalence (Fig 2) of asthma, as assessed based on asthma medication use, are higher in HIV⁺ HAART⁺ children compared with those in HIV⁺ HAART⁻ children. Our data show a much lower cumulative incidence and prevalence of asthma in HIV⁺ HAART⁻ children than in 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, ², ³ and suggests that the loss of CD4⁺ T cells in children with untreated HIV infection protects against asthma and that the gain of CD4⁺ T cells with HAART therapy serves as a risk factor for asthma. Our findings are in agreement with those of most studies of adult patients with HIV infection⁵, ⁶, ⁷, ⁸ but not other studies.⁹, ¹⁰ Most of these adult studies were performed in the pre-HAART era,⁶, ⁷, ⁸, ⁹, 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 and adult HIV pathogenesis is the rapid and persistent (≥3 years) increase in HIV RNA levels (hundred thousand to million range) in newborns²⁶ compared with a much lower HIV viral set point observed 6 to 8 weeks after infection in adults.

It is possible that the immunoreconstitution of CD4⁺ T cells with HAART therapy plays a role in inflammatory response because active CD4⁺ T cells initially confront HIV antigens or those of opportunistic organisms colonizing the airway,²⁷, ²⁸ which results in a clinical state of bronchial hyperresponsiveness (Fig 3). It is reasonable to speculate that inflammatory cytokines (eg, IL-4, IL-5, IL-9, and IL-13), might participate in this production of asthma.²⁹ Activated CD8⁺ T cells (ie, DR⁺) might 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 Virus-specific CD8⁺ T cells can switch from IFN-γ to IL-5 production³² and might be operating in patients with HIV infection who have asthma during HAART therapy. In another area of clinical immunology, Reveille and Williams³³ have noted the marked change in the pattern of rheumatologic 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⁺ T cells.

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 to 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, ³⁵, 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 through 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 proinflammatory cytokines of the HIV-infected mother. This HIV exposure perhaps renders the HIV⁻ group a nonideal control against which to compare the incidence of asthma. Because the control study subjects lived in inner cities, for the most part, environmental exposures might 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 compared with historical control subjects.³⁸ Although the authors at that time discounted an HIV exposure factor as the basis for causation, in retrospect this might 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 increase 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 have 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 might hold clues for a better understanding of the molecular and cellular mechanisms responsible for the epidemic of asthma in children.³⁹

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Ms Carolyn Jackson assisted with the preparation of the manuscript.

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