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. Author manuscript; available in PMC: 2013 Mar 1.
Published in final edited form as: J Allergy Clin Immunol. 2011 Dec 15;129(3):708–714.e8. doi: 10.1016/j.jaci.2011.11.015

Asthma Diagnosis and Airway Bronchodilator Response in HIV-infected Individuals

Matthew R Gingo 1, Sally E Wenzel 1, Chad Steele 2, Cathy J Kessinger 1, Lorrie Lucht 1, Tammi Lawther 1, Michelle Busch 1, Maria E Hillenbrand 1, Renee Weinman 1, William A Slivka 1, Deborah K McMahon 1, Yingze Zhang 1, Frank C Sciurba 1, Alison Morris 1,3
PMCID: PMC3294124  NIHMSID: NIHMS339119  PMID: 22177327

Abstract

Background

Despite the high prevalence of respiratory symptoms and obstructive lung disease in HIV-infected persons, the prevalence of bronchodilator reversibility (BDR) and asthma has not been systematically studied during the era of combination antiretroviral therapy (ART).

Objective

To determine the prevalence of asthma diagnosis and related pulmonary function abnormalities in an HIV-infected cohort and to identify potential mechanisms.

Methods

A cross-sectional analysis of 223 HIV-infected individuals with data on respiratory symptoms and diagnoses, pulmonary function, sputum cell counts, and asthma-related cytokines and chemokines in serum/sputum.

Results

Doctor-diagnosed asthma was present in 46 (20.6%) and BDR (≥200ml and ≥12% increase in FEV1 or FVC) in 20 participants (9.0%). Pulmonary symptoms and function were worse in those with doctor-diagnosed asthma. Doctor-diagnosed asthma was independently associated with female sex (p=0.04), body mass index >29.6kg/m2 (vs.<29.6kg/m2) (p=0.03), history of bacterial or Pneumocystis pneumonia (p=0.01), and with not currently taking ART (p=0.04), and in univariate analysis with parental history of asthma (n=180; p=0.004). High sputum eosinophil percentages (>2.3% based on the highest decile) were more likely in those with doctor-diagnosed asthma (p=0.02) or BDR (p=0.02). Doctor-diagnosed asthma tended to be more common with high sputum IL-4 (p=0.02) and RANTES (p=0.02), while BDR was associated with high plasma macrophage inflammatory protein (MIP)-1α (p=0.002), and sputum MIP-1β levels (p=0.001).

Conclusion

Asthma diagnosis and BDR are prevalent in an HIV-infected outpatient cohort, and associations with family history, obesity, allergic inflammation, prior infection, the absence of ART, and elevated HIV-stimulated cytokines suggest possible mechanisms of HIV-associated asthma.

Keywords: HIV, asthma, airway obstruction, allergy

INTRODUCTION

While HIV-infected individuals are living longer with fewer infectious pulmonary complications, respiratory symptoms and chronic lung disease remain common.(1, 2) Obstructive lung diseases such as asthma and chronic obstructive lung disease (COPD) may actually be increasing in this population as rates of hospitalization and deaths from obstructive disease have been growing.(3) Recent studies in HIV-infected individuals demonstrate that 31–64% have respiratory symptoms and 8–21% have airway obstruction by spirometry.(1, 2) Although asthma is a common disease in the non-HIV-infected population, relatively little is known about its prevalence or risk factors in those with HIV. Prior to effective combination antiretroviral therapy (ART), HIV-infected persons had a high prevalence of small airway disease and airway hyperresponsiveness.(4–7) Since the introduction of ART, there has been little work examining asthma in this population, and data are lacking regarding the epidemiology, mechanisms, and effects of antiretroviral treatment in HIV-associated asthma. One study found that HIV-infected children receiving ART had greater use of inhaler medications, but asthma diagnoses were not quantified.(8) A recent study of pre-and post-bronchodilator spirometry in an HIV-infected outpatient cohort found that nearly 10% of HIV-infected individuals had reversible airway obstruction, suggesting that asthma or airway hyperresponsiveness may be a notable cause of obstructive lung disease in this population during the current era of effective ART(2); however, specific features of asthma in this population were not examined.

Determining the pathogenesis and impact of asthma and airway hyperresponsiveness in the HIV population is important. For example, certain inflammatory pathways related to T-helper (TH)-2 inflammation, driven by cytokines such as interleukin (IL)-4, IL-5, and IL-13, are important mediators of asthma, but inflammatory pathways related to asthma in the setting of HIV infection have not been assessed. In addition, protease inhibitors, an important part of ART, have interactions with the inhaled corticosteroid fluticasone, one of the mainstays of asthma therapy and may lead to elevated peripheral corticosteroid levels.(9–11) Inhaled corticosteroids have other adverse effects such as increased risk of pneumonia or tuberculosis which in theory might be worse in HIV-infected individuals.(12, 13) Given the limitations of current therapy in this population, improved understanding of the relationship between HIV infection, ART, and the development of asthma and airway hyperreactivity is important in guiding investigations into unique mechanisms and potential therapies for asthma in HIV infection.

In this study, we determine the prevalence and associated demographic, social, and clinical factors of asthma diagnoses, asthma-related respiratory symptoms, and asthma-related pulmonary function abnormalities in an HIV-infected cohort. We also explore biomarkers associated with asthma diagnosis and asthma-related pulmonary function abnormalities.

METHODS

Study population

Persons with documented HIV infection were recruited between July 1, 2007 and September 30, 2010. A description of study procedures and a subset of the cohort has been published previously.(2) Details can be found in the online repository. Recruitment was performed using posted advertisements, word of mouth, and by contacting patients in a research registry. All participants signed written informed consent, and the University of Pittsburgh IRB approved the protocol.

Data collection

Demographic and clinical data were collected by participant interview and medical record review. Self-report of a diagnosis of asthma was ascertained by asking the participant: “Has a doctor or health care provider EVER told you that you had asthma?” Age of asthma diagnosis was determined by asking: “How old were you when your doctor FIRST told you that you had asthma?” Although all participants were currently attending a single clinic, the diagnosis of asthma could have been made at the clinic or elsewhere. Participants determined to have asthma during the study visit did not count as providing a self-report of ever having asthma. Respiratory symptoms were assessed using a modified version of the St. George’s Respiratory Questionnaire(14, 15) and were considered significant if occurring at least monthly over the past year and were not related to colds. Sputum eosinophil counts and percents were determined from induced sputum as previously described.(16)(17) Adequate induced sputum samples (squamous cell percent<30) were available from 161 participants. Serum IgE levels were measured using an Elecsys© 2010 Immunoassay System (Roche Diagnostics, Indianapolis, IN). In participants with an available sample (n=123 for plasma, n=116 for sputum), selected asthma-related cytokines (IL-4 and IL-13) and chemokines (eotaxin-1, macrophage inflammatory protein [MIP]-1α, MIP-1β, and Regulated on Activation Normal T Cell Expressed and Secreted [RANTES]) were measured using Luminex (Luminex Corporation, Austin, TX, USA).

Pulmonary function testing

All participants performed pre- and post-bronchodilator (480 μg of albuterol administered through a spacer from a metered-dose inhaler) spirometry in accordance with American Thoracic Society (ATS) standards(18, 19) as previously described(2) and further detailed in the online repository. Bronchodilator reversibility (BDR) between pre- and post-bronchodilator spirometry was used as a surrogate for airway hyperresponsiveness. Participants were determined to have BDR if they had an improvement in either the FEV1 or FVC of at least 200ml and 12%.(20)

Statistical analysis

Statistical analyses were performed using Stata version 10 (StataCorp, College Station, Texas, USA). For further details of statistical analysis see the online repository. BMI data were normalized using 1/BMI and categorized as the highest quartile vs. the lower three quartiles. IgE level was log-normalized. Sputum eosinophil percent was also not normally distributed, and the highest decile (>2.3%) was classified as high, a cut-off similar to the upper limit of normal eosinophil percentages from induced sputum of healthy subjects.(21, 22) Demographic and clinical criteria were compared between participants with and without a diagnosis of asthma and participants with and without BDR using t-tests, Wilcoxon rank sum test, Fisher’s exact test, and chi-square test where appropriate. Serum and sputum cytokines and chemokines were not normally distributed, and values were dichotomized to low (≤ median) or high (> median). To determine associations with cytokines and chemokines data, we used t-tests for continuous outcomes (FEV1 % predicted, FEF25%–75%% predicted, and change in FEV1 with bronchodilator) and chi-square test for categorical dependent variables (doctor-diagnosed asthma and BDR). A p≤0.01 was considered significant for associations of the cytokine data to account for multiple testing. Multivariable logistic regression was used to determine independent associations between potential demographic or clinical predictors and presence of doctor-diagnosed asthma or BDR. Sputum cell counts, and plasma and serum cytokine and chemokine levels were available for only a subset of participants and were therefore not considered in the multivariable modeling. Clinically relevant variables significant at a p≤0.10 were entered into the model in order of increasing univariable logistic regression p-values. The likelihood ratio test was used to compare hierarchical models, and those variables reaching a significance level of p≤0.10 were retained in the model. Step-down regression was then performed by removing variables in order of decreasing p-value. Variables were retained in the model if the likelihood ratio test was significant at a level of p≤0.05. We tested for interactions between smoking and other significant predictors, and the models were assessed for colinearity. To assess for confounding by parental history of asthma, race, and smoking status, we included these variables with the model as a sensitivity analysis and found no significant impact on the results of the final model except that including parental history in the model decreases the association of sex and doctor-diagnosed asthma; however, a greater proportion of women with doctor-diagnosed asthma had missing information on parental history. Hosmer-Lemshow test was used to assess models for goodness of fit.(23)

RESULTS

Participant characteristics

Of 239 participants recruited, ten failed screening, three did not attend their study visit, and three had pulmonary function testing that did not meet ATS criteria. There were 223 HIV-infected participants who completed the study. Forty-six participants (20.6%) reported doctor-diagnosed asthma. This prevalence was nearly twice as high as that of doctor-diagnosed COPD in the cohort (11.4%). Using inhaler medication or oral steroids for breathing was common with 30% using inhaler medication within the last year. An albuterol inhaler was used by 25.6% of the cohort, while an inhaled steroid was used by 7.2%, and an oral steroid was used specifically for breathing problems within the past year by 9.0%.

Doctor-diagnosed asthma

Participants with doctor-diagnosed asthma were different in certain demographic and clinical characteristics (Table 1). Participants who had doctor-diagnosed asthma were younger than those who did not (mean [standard deviation] age in years, 42.6 [9.7] vs. 45.9 [9.6]; p=0.04) and were more likely to be female (41.3% vs. 22%; p=0.008). In 180 participants with information on family history, those with doctor-diagnosed asthma were more likely to have a parent with asthma (37.5% vs. 16.4%, p=0.004). Participants with asthma were also more likely to be current smokers (73.9% vs. 52.5%; p=0.03). A history of having either bacterial pneumonia or Pneumocystis pneumonia was also more likely in participants with asthma (60.9% vs. 39.9%; p=0.01). Participants with asthma were less likely to be taking ART (67.4% vs. 81.9%; p=0.03), but not less likely to have ever been on ART (82.6% vs. 88.1%; p=0.3). In addition, there were no significant differences in average CD4+ T-cell counts or HIV RNA levels between the two groups. Those diagnosed with asthma compared to those not diagnosed with asthma were more likely to have had significant recurrent respiratory symptoms over the past year (91.3% vs. 59.9%; p<0.001), wheezing at times other than respiratory infection (56.5% vs. 18.6%; p<0.001), and recurrent phlegm production (50.0% vs. 30.5%, p=0.01)(Figure 1). The use of any inhaled respiratory medication was also more common in those diagnosed with asthma (82.6% vs.16.4%; p<0.001)(See Table E1 in the Online Repository). Participants with doctor-diagnosed asthma had worse spirometry than those without: pre-bronchodilator FEV1/FVC (mean [SD] 0.69 [0.11] vs. 0.76 [0.09]; p<0.001), FVC percent predicted (94.9% [17.3] vs.101.1% [14.9]; p=0.02), FEV1 percent predicted (80.7% [18.9] vs. 95.8% [16.9]; p<0.001), and FEF25%–75% percent predicted (56.2% [32.5] vs. 88.1 [34.8]; p<0.001). Despite worse spirometry, participants with doctor-diagnosed asthma were no more likely to have BDR than those who had not been diagnosed with asthma (13.0% vs. 7.9%; p=0.28). The DLCO % predicted in each group were low on average, but not significantly different (62.4% [16.4] vs. 67.1% [15.2]; p=0.07).

Table 1.

Characteristics of participants with and without doctor diagnosed asthma

No Asthma (n=177) Asthma (n=46) p-value
Age, mean years (range) 45.9 (9.6) 42.6 (9.7) 0.04
Female, n (%) 39 (22.0) 19 (41.3) 0.008
African-American, n (%) 89 (50.3) 26 (56.5) 0.50
Parental history of asthma, n (%)* 23 (16.4) 15 (37.5) 0.004
Men who have sex with men, n (%) 94 (53.4) 19 (41.3) 0.14
Current smoker, n (%) 93 (52.5) 34 (73.9) 0.03
Ever smoker, n (%) 135 (76.3) 41 (89.1) 0.057
Intravenous drug use, n (%) 38 (21.5) 7 (15.2) 0.34
Marijuana use, n (%) 141 (79.7) 33 (71.7) 0.20
Cocaine use, n (%) 75 (45.5) 17 (39.5) 0.49
History of PCP or BP, n (%) 69 (39.9) 28 (60.9) 0.01
ART in past 3 months, n (%) 145 (81.9) 31 (67.4) 0.03
Ever on ART, n (%) 156 (88.1) 38 (82.6) 0.32
On PCP prophylaxis currently, n (%) 66 (37.7) 15 (33.3) 0.60
CD4 cells/ml, median (range) 472 (6–1921) 479 (41–1107) 0.50
HIV RNA, median copies/ml (range) <50 (<50–1.96×106) <50 (<50 –1.25×106) 0.10
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*

Data only available or known for 180 participants for parental history of asthma. ART = combination antiretroviral therapy; BP = bacterial pneumonia; PCP = Pneumocystis pneumonia; RNA = ribonucleic acid.

Figure 1.

Figure 1

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Prevalence of respiratory symptoms (a) and pulmonary function values (b) in participants diagnosed with asthma by their physician in the past and those without an asthma diagnosis. DLCO = diffusion capacity for carbon monoxide, FEV1 = forced expiratory volume in 1 second, FEF25%–75% = forced expiratory flow between 25% and 75% of vital capacity, FVC = forced vital capacity, % = percent predicted.

Bronchodilator reversibility

BDR was present in 9.0% of the cohort. Participants with BDR were similar to those without BDR in age, gender, HIV risk factor, drug use, infection history, antiretroviral medication use, CD4 counts, and HIV RNA levels. Those with BDR were more likely to wheeze (45.0% vs. 24.6%; p=0.05)(See Figure E1 in the Online Repository) and to have used an oral steroid for their breathing in the past year (25.0% vs. 7.4%; p=0.009)(See Table E2 in the Online Repository). Spirometry was also significantly lower in participants with BDR compared to those without: pre-bronchodilator FEV1/FVC (0.63 [0.12] vs. 0.76 [0.09]; p<0.001), FVC percent predicted (91.1% [19.3] vs. 100.6% [15.0]; p=0.01), FEV1 percent predicted (70.5% [18.1] vs. 94.9% [16.9]; p<0.001), and FEF25%–75% percent predicted (41.5% [27.7] vs. 84.4% [35.0]; p<0.001). The DLCO percent predicted was also lower in those with BDR compared to those without (57.0% [19.2] vs. 67.1% [14.9]; p=0.01).

Body mass index and asthma

There was an association between doctor-diagnosed asthma and obesity. Median (quartile [Q]1-Q3) BMI for the cohort was 25.6 (22.7–29.7), and those with doctor-diagnosed asthma had a higher BMI than those without doctor-diagnosed asthma (median [Q1-Q3] BMI, 28.4 [23.9–33.5] vs. 25.4 [22.5–28.8]; p=0.003). There was no difference in respiratory symptoms or wheezing among the BMI quartiles. Prevalence of doctor-diagnosed asthma increased with each BMI quartile and was significantly greater in the highest BMI quartile, and this association persisted when controlling for gender and ART use (odds ratio [OR] of highest vs. other quartiles 2.28; 95% CI, 1.09–4.76; p=0.03)(Table 2). There was no difference in BMI between those with and without BDR, and there was no association between FEV1 % predicted or FEF25%–75% % predicted and BMI.

Table 2.

Multivariable regression results

Outcome Covariate OR (95% CI) p-value
Doctor-diagnosed asthma
Female 2.21 (1.05–5.07) 0.04
BMI, Q4 vs. Q1–Q3 2.28 (1.18–9.02) 0.03
ART, current 0.43 (0.19–0.95) 0.04
History of BP or PCP 2.65 (1.21–5.40) 0.01
BD response none
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ART, antiretroviral therapy; BMI, body mass index; BP, bacterial pneumonia; PCP, Pneumocystis pneumonia; Q, quartile.

Sputum eosinophils, serum IgE levels, and inflammatory cytokines and chemokines

Several biomarkers were associated with asthma. Median (Q1–Q3) eosinophil percentage was 0.36% (0–0.9%). A high eosinophil count (>2.3%) was found in 16 (9.9%) participants, and a high eosinophil count was more common in those with doctor-diagnosed asthma (OR, 3.6; 95% CI, 1.2–10.4; p=0.02) and BDR (OR, 5.0; 95% CI, 1.3–18.8; p=0.02)(Figure 2). When controlling for age, gender, race, smoking status, and ART use, the association remained significant between sputum eosinophils and doctor-diagnosed asthma (OR, 3.3; 95% CI, 1.1–10.3; p=0.04) and was stronger for BDR (OR, 5.3; 95% CI, 1.4–20.8; p=0.02). In the cohort, median (Q1–Q3) IgE level was 42.3 international units (IU)/mL (11.0–175.7 IU/mL), and while IgE level correlated with sputum eosinophil percent (Spearman r=0.24; p=0.002), IgE level was not associated with respiratory symptoms, doctor-diagnosed asthma, BDR, or airway obstruction.

Figure 2.

Figure 2

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Prevalence of a high (>2.3%) eosinophil count in induced sputum between participants with or without doctor-diagnosed asthma or positive bronchodilator reversibility (BDR).

Specific sputum and plasma cytokines were associated with doctor-diagnosed asthma and BDR. Doctor-diagnosed asthma tended to be more common with high sputum IL-4 (27% vs. 10.5%; p=0.02) and RANTES (26.6% vs. 9.8%; p=0.02), though not statistically significant at a level of <0.01 to account for multiple comparisons (See Tables E3 in the Online Repository). BDR was more common in those with high plasma MIP-1α (26.3% vs. 4.8%; p=0.002), and high sputum MIP-1β (26.1% vs. 4.3%; p=0.001 (See Figure E2 in the Online Repository). A greater % change in FEV1 with bronchodilator was seen in those with high plasma MIP-1β (4.6% [6.2] vs. 1.0% [5.1]; p<0.001)(See Table E4 in the Online Repository). High sputum % eosinophils was associated with high sputum MIP-1β (OR, 8.57; 95% CI 2.14–34.30; p=0.001)(See Figure E3 in the Online Repository), but not with other cytokines or chemokines. There were no associations of doctor-diagnosed asthma, BDR, FEV1 % predicted, or FEF25%–75%% predicted with plasma or induced sputum IL-13 or eotaxin-1.

Multivariable analysis

In multivariable models, doctor diagnosis of asthma was more common in females (OR, 2.21; 95% CI, 1.05–5.07; p=0.04), those in the 4th quartile of BMI compared to those in the other 3 quartiles (OR 2.28; 95% CI 1.18–9.02; p=0.03), and those with a history of bacterial or Pneumocystis pneumonia (OR, 2.65; 95% CI, 1.21–5.40; p=0.01), but less common in those on ART (OR, 0.43; 95% CI, 0.19–0.95; p=0.04)(Table 2). BDR was not independently associated with any factors other than sputum eosinophils.

DISCUSSION

In a cohort of HIV-infected outpatients, we found that asthma was the most commonly diagnosed chronic pulmonary disease. Asthma-related symptoms such as wheezing, medication use, and BDR were also common. Doctor-diagnosed asthma was associated with parental history of asthma, female sex, obesity, prior pneumonia, and not being on ART. Higher sputum eosinophils were associated with doctor-diagnosed asthma and BDR, and inflammatory cytokines and chemokines were associated with BDR and sputum eosinophilia.

The prevalence in our cohort of doctor-diagnosed asthma was 20.6%, more than double the most recent estimate in the general adult population of 8.2%.(24) However, it should be noted that the HIV population has a higher prevalence of smokers and African-Americans than the general population which may affect the estimate for prevalence of doctor-diagnosed asthma, and making a determination of whether asthma is more prevalent in the HIV population is difficult without a well-matched control population.(25)

We found several risk factors associated with doctor-diagnosed asthma in the cohort. ART use was associated with a lower risk of doctor-diagnosed asthma and was not associated with BDR, in contrast to prior studies that suggest that ART is associated with airflow obstruction in adults and asthma in children.(1, 2) The variance between these studies and the current findings may be explained by differences in asthma between children and adults or by differences in the outcomes examined. In adults, the association of ART use with airway obstruction likely represents a phenotype of COPD, not asthma, as the majority of these individuals had irreversible obstruction and decreased DLCO. In asthma, ART use may be protective by decreasing pneumonia which we found associated with asthma diagnosis. In addition, participants with asthma were less likely to be using ART currently, but were no less likely to have ever taken ART, indicating that those with asthma were more likely to have discontinued ART. We do not know if this finding could be due to the onset or worsening of asthma associated with ART. Studies have found that children on ART are more likely to use inhaler medications than those not on ART(8), and 28% of children during the ART era were treated for persistent asthma compared to none prior to ART.(26)

Higher BMI was also associated with doctor-diagnosed asthma. We did not find that greater BMI was associated with more respiratory symptoms, suggesting that the association between obesity and asthma was not due to an increased tendency of doctors to diagnose asthma in a more symptomatic population.(27) Obesity and asthma have been linked in the general population (28–31), and HIV-infected individuals are at risk for similar types of metabolic disturbances with development of lipodystrophy and metabolic syndrome with certain antiretroviral agents.(32–34) Potential mechanisms linking obesity to asthma in HIV include changes in adipocytokine levels (such as increases in leptin or decreases in adiponectin) that are common to obesity and HIV-related lipodystrophy and occur secondary to certain antiretroviral medications linked to HIV-related lipodystrophy.(33, 35, 36)

Allergic inflammation is another important component of asthma in HIV-uninfected populations and is manifested by increased eosinophils and IgE levels.(37) Sputum eosinophils, but not IgE levels, were associated with asthma in our HIV-infected cohort. The high sputum eosinophils found in those diagnosed with asthma suggest the importance of TH-2 immunity in HIV-associated asthma. Prior work has not examined eosinophils in respiratory disease and HIV, but one previous study found elevated IgE levels in HIV-infected individuals and a correlation with response to methacholine challenge.(6) In contrast, we did not find that IgE levels correlated with BDR, but we used a less sensitive test for airway hyperresponsiveness (pre- and post-bronchodilator spirometry) than methacholine challenge.

Increased atopy and allergy characterized by a TH-2 inflammation may be a particular problem in HIV-infected persons due to abnormal T-regulatory cell function(38, 39), but relationships of specific cytokines and chemokines to HIV-associated asthma have not been explored. While there were trends for associations of traditional TH-2 cytokines such as IL-4 with doctor-diagnosed asthma, the strongest associations were between MIP-1α and MIP-1β with airflow obstruction and BDR. These chemokines (along with RANTES) are released by CD8+ T-cells as HIV suppressive factors in chronic HIV infection(40) and have been implicated in airway inflammation related to asthma in HIV-uninfected populations(41–44), suggesting that HIV infection may increase risk for asthma via stimulation of chronic inflammation.

Although diffusing capacity abnormalities are not typically associated with asthma, the average DLCO was decreased in our cohort, including in participants with asthma. Diffusion impairment and emphysema are widespread in the HIV-infected population.(45, 46) With as many as 64% of HIV-infected adults having an abnormal DLCO(2), it is likely that there is overlap between asthma and abnormal DLCO. The decreases in DLCO seen in those with HIV may represent emphysema, pulmonary vascular disease, or other factors associated with HIV that could overlap with an asthma diagnosis.(47, 48) In addition, in the non-HIV population, overlap between COPD and airway hyperresponsiveness is not uncommon, and 17–19% of the population with obstructive lung disease report both a COPD and asthma diagnosis.(49, 50) Additionally, although BDR is greater in asthmatics, it may not be necessarily sensitive or specific to differentiate asthma and COPD.(51)

There are several limitations of our study. It is a single center cross-sectional assessment, and it is possible that participation was biased. Applicability to all HIV populations may be limited as this cohort had a higher prevalence of smoking and intravenous drug use compared to prior studies.(1) Smoking and intravenous drug use, however, are much more common among HIV-infected individuals than the general population(25, 52); therefore, the results of the study are likely applicable to many HIV-infected individuals. Asthma history was based on patient report of a doctor diagnosis of asthma, and we could not accurately determine time of asthma onset in relation to HIV infection. Our cohort is young and has a high prevalence of smoking, and it is possible that some participants were misdiagnosed with asthma as opposed to COPD, which would account for the finding that the prevalence of BDR and IgE levels did not differ between those with and without doctor-diagnosed asthma. Even though BDR did not correlate exclusively with doctor-diagnosed asthma, pre- and post-bronchodilator spirometry may fail to detect airway hyperresponsiveness, and prevalence of airway hyperresponsiveness is likely higher if tested by methacholine challenge. Finally, BMI may not capture subtleties of body composition, and more specific measures for visceral versus peripheral adiposity could provide more detailed insight into the relationship between obesity and asthma.(53)

In conclusion, our study is the first to systematically assess asthma in HIV-infected individuals during the current era of ART. We found that asthma diagnosis and BDR are quite prevalent and an important cause of chronic respiratory disease in the HIV population. The relationship in HIV between parental history of asthma, allergic inflammation, HIV-stimulated cytokines, and obesity with asthma/BDR suggest possible mechanisms of HIV-associated asthma including TH-2 related immune responses, inflammation related to chronic HIV infection, and inflammation related to metabolic syndrome/disease. Appropriate diagnostic evaluation is important as HIV-infected persons are at risk for a wide range of acute and chronic respiratory diseases and have a high prevalence of frequent respiratory symptoms, particularly in those already diagnosed with asthma. Our findings indicate that asthma should be considered in HIV-infected patients with respiratory symptoms fitting the clinical syndrome.

Clinical Implications.

Asthma diagnosis and reversible airway obstruction are common in HIV-infected persons. Metabolic derangements prior infections, or allergic inflammation may play an important role in asthma in HIV.

Acknowledgments

Sources of support: NIH T32 HL007563, K23 HL108697 (MG); P50 HL084948, N01 HR46163R01 (FS); R01 HL083461 and HL083461S (AM); and the University of Pittsburgh CTSI (UL1 RR024153)

Abbreviations

AIDS

acquired immune deficiency syndrome

ART

combination antiretroviral therapy

ATS

American Thoracic Society

BD

bronchodilator

BDR

bronchodilator reversibility

BMI

body mass index

CD4

CD4+ T-lymphocyte

CI

confidence interval

COPD

chronic obstructive pulmonary disease

DLCO

diffusion capacity for carbon monoxide

FEF25%-75%

forced expiratory flow between 25% and 75% of vital capacity

FEV1

forced expiratory volume in one second

FVC

forced vital capacity

HIV

human immunodeficiency virus

IgE

immunoglobulin E

IL

interleukin

IU

international units

MIP

macrophage inflammatory protein

OR

odds ratio

RANTES

Regulated on Activation Normal T Cell Expressed and Secreted

RNA

ribonucleic acid

SD

standard deviation

TH

T-helper

Footnotes

This manuscript contains an Online Repository.

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