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(Chest. 2003;123:1977-1982.)
© 2003 American College of Chest Physicians

Respiratory Symptoms Among HIV-Seropositive Individuals*

Philip T. Diaz, MD; Mark D. Wewers, MD; Eric Pacht, MD; Janice Drake, CCRA; Haikady N. Nagaraja, PhD and Thomas L. Clanton, PhD

* From the Division of Pulmonary and Critical Care Medicine (Drs. Diaz, Wewers, Pacht, and Clanton, and Ms. Drake), Department of Internal Medicine, and Department of Statistics (Dr. Nagaraja), The Ohio State University, Columbus, OH.

Correspondence to: Philip T. Diaz, MD, 201 Heart Lung Research Institute, 473 W. Twelfth Ave, Columbus, OH 43210; e-mail: diaz-1{at}medctr.osu.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Recent evidence suggests that chronic or latent viral infection may be an important predisposing factor in the development of COPD among smokers. As such, understanding if HIV-seropositive smokers are at heightened risk for respiratory symptoms may have relevance with regard to COPD pathogenesis. The current study was done to systematically identify the prevalence of respiratory symptoms among an HIV-seropositive population and to identify associated clinical features.

Design and setting: Cross-sectional analysis at an academic medical center.

Participants: Three hundred twenty-seven HIV-seropositive individuals without a history of AIDS-related pulmonary complications. Fifty-two HIV-negative individuals with a similar age and smoking history served as a comparison group.

Measurements: Administration of the American Thoracic Society Division of Lung Diseases respiratory questionnaire, and pulmonary function studies.

Results: Respiratory symptoms including dyspnea (41.6% vs 7.7%), cough (40% vs 25%), and phlegm production (41.9% vs 23.1%) were extremely common in the HIV-group and significantly more common than in the HIV-negative group. Current or prior cigarette smoking was the most important predictor of respiratory symptoms among the HIV-seropositive group. The use of the antiretroviral agent lamivudine was associated with a significant reduction in dyspnea.

Conclusion: HIV-seropositive individuals are at increased risk for the development of respiratory symptoms even prior to the onset of AIDS-related pulmonary complications. This may reflect a heightened susceptibility to the effects of cigarette smoking.

Key Words: American Thoracic Society Division of Lung Diseases respiratory questionnaire • cigarette smoking • cough • dyspnea • HIV


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
A number of reports have suggested that HIV-seropositive individuals are predisposed to respiratory symptoms including cough and dyspnea even in the absence of overt AIDS-related pulmonary complications.1 2 3 To date, however, no validated respiratory questionnaire has been used to study this population, and there has not been systematic identification of associated clinical factors. The overall relevance of understanding the nature of respiratory symptoms among individuals with HIV is underscored by data suggesting that chronic or latent viral infection may be an important predisposing factor in the development of COPD among smokers.4 5 As such, understanding if HIV-seropositive smokers are at heightened risk for symptoms such as cough, phlegm, and dyspnea may have relevance with regard to COPD pathogenesis.

In the current study, we administered the American Thoracic Society Division of Lung Diseases (ATS-DLD)6 questionnaire to a cohort of HIV-infected individuals without a history of AIDS-related pulmonary complications. We sought to determine the prevalence of respiratory symptoms in this cohort and to explore the relation between respiratory symptoms and a number of clinical variables, including tobacco and drug use, medications, and pulmonary function.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects and Study Protocol
Three hundred twenty-seven HIV-seropositive subjects with no history of AIDS-related pulmonary complications comprised a cohort participating in a longitudinal study evaluating pulmonary physiology, respiratory symptoms, and chest CT. Data included in this report represent baseline data and were collected between 1993 and 1998. All subjects completed the ATS-DLD questionnaire and underwent pulmonary function testing. All subjects provided written consent under an approved protocol of The Ohio State University Human Subjects Review Committee.

To determine the prevalence of respiratory symptoms in a population without HIV, we administered the ATS-DLD questionnaire to 52 HIV-negative subjects with a similar age and smoking history. Body mass index (BMI) was compared against a set of standard predicted values in the US population.7

ATS-DLD Questionnaire
All subjects completed the ATS-DLD questionnaire. The questionnaire was expanded to include details of HIV infection; it also detailed use of illicit drugs as well as prescribed medications. A description and abbreviations for relevant symptoms is listed in Table 1 .


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  		Table 1. Description of Abbreviations for Respiratory Symptoms

 
Pulmonary Function Testing
Pulmonary function tests were performed on an S&M Keystone Pulmonary Function Analyzer (S&M Instrument; Doylestown, PA) or a SensorMedics V3600 series body box (SensorMedics; Yorba Linda, CA). The steady-state, helium-dilution method (Keystone) or nitrogen-washout technique (SensorMedics) was used to obtain the functional residual capacity. Standards of the American Thoracic Society were used for all testing procedures, and results were compared to established normal values for spirometry,8 lung volumes,9 and diffusing capacity of the lung for carbon monoxide (DLCO).10 DLCO was normalized for distribution volume (alveolar volume) and hemoglobin concentration.

Statistical Methods
All data are expressed as the mean ± SEM. To compare group means, a t test was used. Pearson {chi}2 was used to test equality of proportions.

In order to determine which clinical variables (ie, demographic, occupational, pulmonary function, tobacco and drug use) were associated with specific respiratory symptoms in the HIV-seropositive group, we first determined which of these differed significantly between HIV-seropositive subjects with and without symptoms. Those variables meeting statistical significance were then included in a stepwise logistic regression analysis to determine the most significant independent predictors of respiratory symptoms.

In order to determine odds ratios for various continuous variables, we expressed pack-years in 10–pack-year units, CD4 counts in 100 cells/µL units, and pulmonary function parameters in units of 10% of predicted. A p value < 0.05 was considered statistically significant for all comparisons. SAS JMP version 3.0 (SAS Institute; Cary, NC) and STATA 6.0 (Stata Corporation; College Station, TX) were used for statistical analyses.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Baseline Demographics and Clinical Variables
Table 2 summarizes the demographic data in both groups. As demonstrated in the table, there was no significant difference in age between the two study groups. In addition, the majority of subjects were white and male, and the groups were also similar with respect to sex and race (data not shown). Of note, the BMI, despite being normal (100.3 ± 1.0% of predicted), was significantly lower in the HIV-seropositive group. The prevalence of cigarette smoking was approximately equal in both groups; however, the pack-year history of smoking was somewhat higher in the control group, a difference that approached statistical significance. Table 2 also details the results of the pulmonary function tests. There was no significant difference between the HIV-seropositive and HIV-seronegative groups with respect to spirometry or lung volumes. There was, however, a significantly lower DLCO in the HIV-seropositive group.


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  		Table 2. Baseline Demographics*

 
We also examined a number of other relevant clinical variables from the questionnaire, including history of prior pneumonia, previous diagnosis of asthma, childhood respiratory illness, crack cocaine use, marijuana use, IV drug use, history of dusty job, and occupational exposure to fumes. There were no differences between the groups with respect to these variables except for a greater percentage of subjects with dusty job exposure in the HIV-seronegative group (50% vs 35.2%, p < 0.05) and a greater percentage with prior IV drug abuse in the HIV-seropositive group (12.8% vs 1.9%, p < 0.05).

Respiratory Symptoms
The prevalence of symptoms was far greater among the HIV-positive subjects. As demonstrated in Figure 1 , top, A, there was an increased prevalence of cough A (40% vs 25%, p < 0.05), cough B (23.9% vs 11.5%, p < 0.05), phlegm A (41.0% vs 23.1%, p < 0.01), phlegm B (26.9% vs 13.5%, p < 0.05), wheezing B (19.3% vs 3.9%, p < 0.01), dyspnea A (41.6% vs 7.7%, p < 0.0001), and dyspnea B (20.2% vs 0%, p < 0.0001) in the HIV-seropositive individuals compared to the HIV-seronegative subjects.



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  		Figure 1. Prevalence of respiratory symptoms among HIV-seropositive and HIV-seronegative subjects. See Table 1 for full symptom description.

 
Figure 1 , center, B, and bottom, C, shows the prevalence of respiratory symptoms among nonsmokers and smokers, respectively. While the overall prevalence of symptoms was clearly greater among the smoking group, HIV-seropositive subjects had a greater prevalence of respiratory symptoms regardless of smoking status. Note that when subgroup analysis was performed, significant differences between HIV-positive and HIV-negative nonsmokers were found with respect to phlegm A (p < 0.05), dyspnea A (p < 0.001), and dyspnea B (p < 0.01). Significant differences between HIV-positive and HIV-negative smokers were found with respect to wheeze B (p < 0.01), dyspnea A (p < 0.001), and dyspnea B (p < 0.001). Lack of statistical differences among the other respiratory symptoms was likely due to the small sample size of the HIV-seronegative subgroups.

Clinical Correlations
Variables associated with the development of respiratory symptoms among the HIV-seropositive group are demonstrated in Table 3 . The most consistent variable associated with respiratory symptoms is cigarette use (current smoking status and/or pack-year history of smoking). With regard to other drug use, IV drug abuse history (along with tobacco) was a significant predictor of phlegm production, and "crack" cocaine was associated with dyspnea.


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  		Table 3. Clinical Predictors of Respiratory Symptoms Among HIV Cohort

 
Among medication use, acyclovir was positively associated with cough while lamivudine use was correlated with a reduction in dyspnea. Although other antiretroviral medications, including protease inhibitors, were not found to have an effect on symptoms, many of our subjects were studied prior to the widespread availability of protease inhibitors. Interestingly, CD4 count was not associated with airway symptoms (cough, phlegm, or wheeze), but low CD4 count was an independent predictor of dyspnea.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Over the course of the HIV epidemic, pulmonary complications have been an important source of morbidity and mortality in this patient population. Both infectious and noninfectious complications have been well described.11 12 However, evidence exists that HIV-infected individuals may acquire unexplained alterations in pulmonary function1 2 and high-resolution chest CT13 14 15 independent of or prior to overt pulmonary complications. Our current study examining the results of the ATS-DLD respiratory questionnaire extends these objective findings and documents a very high prevalence of respiratory symptoms among HIV-seropositive individuals.

One potential limitation of our study is the small number of HIV-negative subjects relative to the HIV cohort; nevertheless, a significant difference was detected among nearly all the symptoms examined. Furthermore, historical data obtained from individuals without HIV infection are consistent with the observation that HIV-seropositive individuals are at heightened risk of acquiring respiratory symptoms. For example, Brodkin and colleagues16 used the ATS-DLD questionnaire to document cough (27%), phlegm (38%), and dyspnea (22%) prevalence among 816 asbestos-exposed workers (mean age, 58 years; mean pack-years, 33; 83% current or former smokers). This frequency of respiratory symptoms reported by Brodkin and colleagues18 is comparable to that found in our HIV-seropositive cohort, a much younger population with a substantially lower pack-year smoking history.

The etiology of dyspnea in the HIV-seropositive population is unclear; however, our data are consistent with other reports demonstrating an unusually high prevalence of unexplained dyspnea in this patient population.1 2 Of interest is the study of Johnson and colleagues,17 who noted a high incidence of unexplained dyspnea among otherwise healthy military recruits with HIV. Based on the results of cardiopulmonary exercise testing, this group hypothesized that a limitation of oxygen delivery to exercising muscles secondary to cardiac limitation was most likely. Evidence suggests that right ventricular abnormalities, secondary to pulmonary circulation alterations, may be more common than left ventricular abnormalities in advanced HIV.18 Indeed, our data linking decreases in DLCO with dyspnea are consistent with pulmonary circulation abnormalities. A number of other possibilities clearly exist. For example, data exist suggesting that skeletal muscle dysfunction, including weakness of the respiratory muscles, may be an important contributor to dyspnea development in HIV.19 Whatever the etiology, our data suggest that dyspnea is associated with the "stage" of HIV and is significantly related to the CD4 count. Furthermore, antiretroviral therapy with lamivudine appears to have an independent protective effect on the development of dyspnea.

The prevalence of airway symptoms, including cough, phlegm production, and wheezing, was also significantly higher among the HIV-seropositive subjects compared to control subjects. The subjective airway symptoms that we describe in this report are interesting in light of previous studies investigating high-resolution chest CT in the HIV-seropositive population.15 20 For example, both focal air trapping and bronchial dilatation are unexpectedly common, even among HIV-seropositive individuals without recognized pulmonary complications.15 20 The increased prevalence of airway abnormalities is particularly interesting in light of the relatively low pack-year smoking history in our HIV-group compared to the control group (12 pack-years vs 17 pack-years, p = 0.13). We hypothesize that HIV may add to the damaging effects of cigarette smoke on the airway, and this may have a number of potentially important clinical implications.

To begin with, there is a high prevalence of smoking among the HIV-seropositive population. Indeed, our data demonstrate that the percentage of HIV-seropositive individuals who are current smokers is approximately 50%. The overall implications regarding smoking and clinical outcome related to HIV are somewhat controversial, as data exist suggesting that smoking is an important risk factor for the development of bacterial pneumonia,21 but that smoking is not important with regard to progression to AIDS or death.22

It should be pointed out, however, that with the change in the natural history of HIV, other clinical end points rather than opportunistic infection may be relevant, particularly with regard to the effects of smoking. Long-term exposure to cigarette smoke may result in considerable difficulties with increasing airway symptoms consistent with chronic bronchitis. Such symptoms may ultimately prove to have significant implications for quality of life in this patient population. It is alternatively possible that control of viral load with potent antiretroviral therapy attenuates the increased risk of smoking among HIV-seropositive subjects. Our data suggesting a protective effect of lamivudine supports this hypothesis.

Finally, our results may have important implications regarding COPD pathogenesis, as information suggests that latent viral infection may be an important cofactor in the development of COPD. For example, epidemiologic evidence suggests that viral infection early in life is a risk factor for COPD later in life.5 Furthermore, evidence exists that adenoviral DNA and proteins are found more commonly in the lungs of smokers with COPD compared to smokers without COPD, and that latent expression of adenoviral proteins may increase airway inflammation caused by other inflammatory triggers.4 As such, we hypothesize that HIV or inflammatory changes related to HIV may add to the damaging effects of cigarette smoke on the lung. Further study regarding the relationship between latent and/or chronic viral infection and cigarette smoking may prove important in our understanding of the relevant mechanisms underlying COPD pathogenesis.


   Acknowledgements
 
The authors thank Tina Bees for assistance with manuscript preparation.


   Footnotes
 
Abbreviations: ATS-DLD = American Thoracic Society Division of Lung Diseases; BMI = body mass index; DLCO = diffusing capacity of the lung for carbon monoxide

Supported by National Institutes of Health, National Heart, Lung, and Blood Institute grants RO1 49730 and RO1 53229, and The Ohio State University General Clinical Research Center grant MO1 RR00034.

Received for publication April 19, 2002. Accepted for publication December 27, 2002.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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