The Open Respiratory Medicine Journal




ISSN: 1874-3064 ― Volume 14, 2020

Smoking and Predictors of Pneumonia Among HIV-Infected Patients Receiving Care in the HAART Era



David M Murdoch*, 1, 2, Sonia Napravnik3, Joseph J Eron Jr3, Annelies Van Rie2
1 Division of Pulmonary & Critical Care Medicine, Duke University Medical Center, Durham, North Carolina
2 Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
3 Division of Infectious Diseases, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

Abstract

Background: Smoking tobacco is disproportionably common among HIV-infected patients in the highly active antiretroviral therapy (HAART) era. Methods: An observational cohort study of 300 HIV-positive patients receiving care between 1996 and 2005 examined the effect of smoking on pneumonia risk. Multivariable analyses assessed the association between smoking and pneumonia risk and identified independent predictors of pneumonia during the HAART era. Results: Current smoking was common (67%). Eighty-two patients (27%) experienced 119 pneumonia episodes during 2151 patient-years of follow-up, with 7.2 episodes/100 person-years among smokers and 2.9 episodes/100 person-years among non-smokers (unadjusted incidence rate ratio (IRR): 2.50 (95% CI: 1.58, 4.09). Adjustment for age and HIV RNA level resulted in an IRR of 1.77 (95% CI: 0.98, 3.21). No prior antiretroviral therapy use (P-value <0.001), higher HIV RNA level (P-value = 0.01), lower CD4 count (P-value = 0.01), younger age (P-value = 0.01), and alcohol use (P-value = 0.04) were independent predictors of pneumonia. HAART use decreased pneumonia risk (IRR 0.28, 95% CI: 0.18, 0.44). Conclusions: While HIV-positive smokers had over a 2-fold increase in the rate of pneumonia, the trend did not reach statistical significance in multivariable models. Clinical factors such as HAART, alcohol use and immunological status are important in pneumonia risk.



Article Information


Identifiers and Pagination:

Year: 2008
Volume: 2
First Page: 22
Last Page: 28
Publisher Id: TORMJ-2-22
DOI: 10.2174/1874306400802010022

Article History:

Received Date: 1/1/2008
Revision Received Date: 4/2/2008
Acceptance Date: 11/2/2008
Electronic publication date: 26/2/2008
Collection year: 2008

Bentham Science Publishers Ltd.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.5/) which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.


* Address correspondence to this author at the Division of Pulmonary & Critical Care Medicine, Duke University Medical Center, Durham, North Carolina, USA; E-mail: david.murdoch@duke.edu





INTRODUCTION

Smoking tobacco is a major public health concern, with numerous adverse health effects, including increased risks of lung cancer, heart disease, peripheral vascular disease, laryngeal cancer, oral cancer, esophageal cancer, chronic obstructive pulmonary disease, and respiratory infections [1Centers for Disease Control & Prevention. Achievements in Public Health, 1900-1999: Tobacco Use -- United States 1900-1999 MMWR 1999; 48: 986-93.]. In the US, smoking is responsible for nearly 430,000 deaths each year [1Centers for Disease Control & Prevention. Achievements in Public Health, 1900-1999: Tobacco Use -- United States 1900-1999 MMWR 1999; 48: 986-93., 2American Cancer Society. Cancer facts and figures 1999 Atlanta Georgia American Cancer Society 1999.]. Although smoking has been declining in the general population [3Centers for Disease Control & Prevention. Cigarette smoking among adults - United States 2003 MMWR 2005; 54: 509-12.], tobacco smoking among people living with HIV remains high with estimates ranging from 39-70% [4Galai N, Park LP, Wesch J, Visscher B, Riddler S, Margolick JB. Effect of smoking on the clinical progression of HIV-1 infection J Acquir Immune Defic Syndr Hum Retrovirol 1997; 14: 451-8.-9Stall RD, Greenwood GL, Acree M, Paul J, Coates TJ. Cigarette smoking among gay and bisexual men Am J Public Health 1999; 89: 1875-8.].

Prior to the availability of highly active antiretroviral therapy (HAART), smoking increased the risk of bronchitis, hairy leukoplakia, oral candidiasis, oral warts, bacterial pneumonia, and pneumococcal bacteremia [6Miguez-Burbano MJ, Ashkin D, Rodriguez A, et al. Increased risk of Pneumocystis carinii and community-acquired pneumonia with tobacco use in HIV disease Int J Infect Dis 2005; 9: 208-17., 10Conley LJ, Bush TJ, Buchbinder SP, Penley KA, Judson FN, Holmberg SD. The association between cigarette smoking and selected HIV-related medical conditions Aids 1996; 10: 1121-6.-13Hirschtick RE, Glassroth J, Jordan MC, et al. Bacterial pneumonia in persons infected with the human immunodeficiency virus.Pulmonary Complications of HIV Infection Study Group N Engl J Med 1995; 333: 845-51.], but did not appear to affect progression to an AIDS defining clinical condition or mortality [4Galai N, Park LP, Wesch J, Visscher B, Riddler S, Margolick JB. Effect of smoking on the clinical progression of HIV-1 infection J Acquir Immune Defic Syndr Hum Retrovirol 1997; 14: 451-8., 14Burns DN, Hillman D, Neaton JD, et al. Cigarette smoking, bacterial pneumonia, and other clinical outcomes in HIV-1 infection.Terry Beirn Community Programs for Clinical Research on AIDS J Acquir Immune Defic Syndr Hum Retrovirol 1996; 13: 374-83.-18Nieman RB, Fleming J, Coker RJ, Harris JR, Mitchell DM. The effect of cigarette smoking on the development of AIDS in HIV-1-seropositive individuals Aids 1993; 7: 705-10.]. Even though pneumonia continues to be an important clinical condition among HIV-infected patients receiving HAART [19Sullivan JH, Moore RD, Keruly JC, Chaisson RE. Effect of antiretroviral therapy on the incidence of bacterial pneumonia in patients with advanced HIV infection Am J Respir Crit Care Med 2000; 162: 64-7., 20Tumbarello M, Tacconelli E, de Gaetano Donati K, Cauda R. HIV-associated bacterial pneumonia in the era of highly active antiretroviral therapy J Acquir Immune Defic Syndr Hum Retrovirol 1999; 20: 208-9.], the effect of smoking on respiratory morbidity since the availability of potent antiretroviral combination therapies remains largely unknown. Additionally, few studies have focused on identifying additional risk factors for pneumonia in HIV-infected patients exclusively during the HAART era. Therefore, we conducted the present study among HIV-infected individuals receiving HIV care at a tertiary hospital in the Southeastern United States between January 1, 1996 and September 1, 2005 to: (1) assess the association between smoking tobacco and the risk of developing pneumonia; and (2) identify independent predictors of developing pneumonia.

MATERIALS AND METHODOLOGY

Study Population

Patients were eligible to participate if they were enrolled in the University of North Carolina Center for AIDS Research (UNC-CFAR) HIV Clinical Cohort Study, completed a comprehensive in-person interview, the Clinical Socio-Demographic and Behavioral Survey (CSDBS), and received HIV care between January 1, 1996 and September 1, 2005. Data collection for the observational clinical cohort study include electronic transfer of institutionally available data and periodic comprehensive standardized medical record reviews [21Napravnik S, Eron JJ, McKaig RG, Heine AD, Menezes P, Quinlivan E. Factors associated with fewer visits for HIV primary care at a tertiary care center in the SoutheAstern U.S AIDS Care 2006; 18: 45-50.]. The CSDBS asks patients about social, demographic, and behavioral factors generally not consistently available in medical records, including detailed smoking history.

Pneumonia

For patients completing the CSDBS, the UNC-CFAR database was interrogated to identify all pneumonia events among study participants through abstraction of chart diagnoses.A retrospective chart review was then performed for all pneumonia events and classified by a pulmonary physician (DMM). Bacterial pneumonia was classified as “probable” or “confirmed.” Probable bacterial pneumonia required: (1) a medical diagnosis of pneumonia, including at least three clinical signs and symptoms (e.g., temperature>38.0°C, heart rate >100 beats/minute, respiratory rate >22 breaths/minute, consolidation on exam, cough, fever, shaking chills, pleuritic chest pain, and/or shortness of breath); (2) a chest radiograph with a new infiltrate; and (3) a positive clinical response to antibiotic therapy. Confirmed bacterial pneumonia required the above criteria and isolation of an organism by sputum Gram stain and culture, diagnostic bronchoalveolar lavage (BAL), positive blood culture, or a positive Streptococcus pneumoniae or Legionella pneumophila urine antigen.

Probable and confirmed diagnoses of Pneumocystis jirovecii pneumonia (PCP) were defined as for bacterial pneumonia above in the appropriate clinical setting, with confirmed PCP requiring evidence of P. jirovecii on microscopic examination of BAL or sputum specimens. A pulmonary mycobacterial infection was defined as a compatible clinical and chest radiograph presentation with isolation and culture of a typical respiratory mycobacterium from two or more sputum cultures or isolation in BAL or bronchial washings warranting appropriate anti-mycobacterial therapy.

Smoking

Since the immunological effects of smoking on the respiratory tract are likely not permanent, we elected to use current smoking and ignore history of smoking. Current smoking was assigned based on the self- reported current smoking reported at the time of the CSDBS interview. We subtracted the duration of smoking (pack-years) from the CSDBS interview date to avoid misclassification. Since patients contributed time before and after the CSDBS interview, and because the median number of years smoking in the study population was 20 years (Interquartile range (IQR): 15, 28), we carried the latest smoking status forward.

Covariates

For the first aim of this study we considered a number of clinical and demographic characteristics as possible effect measure modifiers or confounders of the association between smoking and risk of pneumonia. Covariates included sex, race, age, intravenous drug use (IVDU), alcohol abuse, crack cocaine abuse, vaccination history, HAART use, CD4 cell counts, and HIV RNA levels. Vaccination was defined as receiving an influenza vaccine within the prior one year or a pneumovax vaccine in the prior five years [22]. Intravenous drug use (IVDU), crack cocaine use, and alcohol abuse were based on self-reported behavior on the CSDBS and medical record reviews. These same factors were also included in the second aim of this study to identify independent predictors of pneumonia incidence.

Statistical Analyses

Patient follow-up (person-time at risk) began on the latter of January 1st, 1996 or the date of entry to HIV care, and ended on the earlier of September 1st, 2005 or the last HIV clinic visit. All factors which vary over time were calculated relative to study entry, each pneumonia event, and end of follow-up. Crude incidence rates for pneumonia were calculated by dividing the number of pneumonia events by person-time at risk and expressed as number of pneumonia cases per 100 person-years.

Demographic and clinical characteristics were contrasted by current smoking status relying on basic descriptive statistics, including the chi-square test for categorical variables and the Mann-Whitney test for continuous variables. Stratified analyses included calculating incidence rate ratios (IRR) and 95% confidence intervals (CI) for the effect of smoking on the rate of pneumonia within different strata of patient characteristics. Since each patient could have experienced more than one pneumonia event during follow-up, we fit multivariable Poisson distribution log-linear regression models with generalized estimating equations (exchangeable working correlation matrix) to account for repeat measures.

The first aim of this study was to arrive at the least biased estimate of the effect of smoking on the incidence rate of pneumonia in a subset of HIV-infected patients in the UNC CFAR cohort. We first fit a full model containing all factors identified in stratified analyses as either potential effect measure modifiers or confounders for the association between smoking and pneumonia. Interaction terms with P-values ≤0.20, indicated effect measure modification. Using a hierarchical backwards elimination procedure, covariates which changed the unadjusted estimate by at least 10%, indicating appreciable confounding, were retained in the final model. The 10% change-in-estimate was calculated as ln | IRRFULL / IRRREDUCED |.

The second aim of this study was to estimate independent predictors of acquiring pneumonia. We first fit a full model including all covariates that were associated with pneumonia as indicated by a P-value <0.05 in bivariate analyses. Factors which did not independently predict pneumonia based on an a priori significance level of <0.05 were removed using a hierarchical backwards elimination procedure. Only those variables with P-values <0.05 were retained in the final predictive model. All analyses were performed using STATA version 8.2 (College Station, Texas, USA). The study was reviewed and approved by the institutional review board.

RESULTS

Study Population

Between January 1996 and September 1, 2005, 1849 patients were enrolled in the UNC-CFAR Clinical Cohort Study. Among these, 303 completed the CSDBS interview. We excluded 3 patients because of missing CD4 cell counts or HIV RNA levels. The 300 patients included in this study contributed 2151 person-years of follow-up during the study period, for a median of 6.9 years of follow-up [IQR: 4.6,9.2]. Two-thirds were men (67%), 76% were African American and 24% White. The median age was 44 years (IQR: 38, 48). Substance abuse was common, with a high proportion of patients reporting prior and/or current alcohol abuse (60%), crack-cocaine use (73%), or IVDU (20%). During follow-up almost all patients received antiretroviral therapy (83%) and 55% received an influenza and/or pneumococcal vaccine. With the exception of a longer duration since HIV diagnosis, the CSDBS subjects in this study are clinically and demographically representative of the overall UNC CFAR cohort [21Napravnik S, Eron JJ, McKaig RG, Heine AD, Menezes P, Quinlivan E. Factors associated with fewer visits for HIV primary care at a tertiary care center in the SoutheAstern U.S AIDS Care 2006; 18: 45-50.].

Pneumonia Diagnosis

Eighty-two patients (27%) were diagnosed with 119 episodes of pneumonia for an overall incidence rate of 5.5 per 100 person-years (95% CI: 4.6, 6.6). The majority of pneumonias were bacterial (61%), with Streptococcus pneumoniae being the most commonly isolated organism (Table 1). The AIDS-defining diagnosis of PCP accounted for over one-third (34%) of pneumonia diagnoses. Of the PCP cases, 44% were on HAART at diagnosis. The diagnosis of mycobacterial infections in this cohort was uncommon, representing only 4.2% of pneumonia diagnoses.

Table 1

Clinical Characteristics of 119 Pneumonia Episodes Diagnosed in 82 HIV-Infected Patients, from January 1, 1996 to September 1, 2005




Table 2.

Demographic and Clinical Characteristics of 300 HIV-Infected Patients Stratified by Smoking Status




Table 3.

Multivariate Poisson Model Estimates of the Effect of Smoking on Pneumonia Incidence Rates in 300 HIV-Infected Patients Receiving Care Between January 1996 and September 1, 2005




Table 4.

Pneumonia Incidence Rates Among 300 HIV-Infected Patients Stratified by Demographic and Clinical Characteristics




Table 5.

Independent Predictors of Pneumonia Among 300 People Living with HIV in the Southeastern US, 1996-2005




Fifty of the 119 pneumonia events (42%) were confirmed, including 56% of PCP cases, 35% of bacterial pneumonia cases, and all mycobacterial cases. At the time of the pneumonia event the median CD4 cell count was 193 cells/mm3 (IQR: 35, 424) among patients with bacterial pneumonias and 35 cells/mm3 (IQR: 13, 118) among patients with PCP (P-value < 0.001).

Smoking Prevalence and Characteristics of HIV-Infected Smokers

Most patients (N=241, 80%) reported ever having smoked tobacco for at least six months, and reported a median of 20 years of smoking (IQR: 15, 28), 10 cigarettes per day (IQR: 5, 20), and 10 pack-years of smoking exposure (IQR: 5, 20). At the time of the interview 63% (N=188) reported currently smoking tobacco. On bivariate analysis, smokers were more likely to be male, to use other substances of abuse such as alcohol, intravenous drugs, and cocaine (Table 2). Additionally, median CD4 cell counts were lower in smokers compared to non-smokers (351 cells/mm3 versus 490, respectively; P-value = 0.01) and HIV RNA levels were higher (2.8 log10 copies/mL versus 1.9, respectively; P-value = 0.01).

Effect of Smoking on Pneumonia Incidence Rates

The majority of pneumonia episodes occurred among smokers (95 of 119; 80%). The incidence rate of pneumonia among smokers was 7.2 per 100 person-years (95% CI: 5.8, 8.8) in comparison to 2.9 (95% CI: 1.8, 4.3) among non-smokers, for an unadjusted incidence rate ratio (IRR) of 2.5 (95% CI: 1.58, 4.09). Effect measure modifiers were not identified. Age and most proximal HIV RNA level were the only confounders of the association between smoking and pneumonia incidence, and were retained in the final model. The adjusted incidence rate ratio for smoking was 1.77 (95% CI: 0.98, 3.21; P-value = 0.06) (Table 3).

Independent Predictors of Pneumonia

For the second aim, a number of patient characteristics were predictive of developing pneumonia in bivariate analyses, including smoking, African American race, younger age, alcohol use, crack cocaine use, antiretroviral use, a lower CD4 cell count and higher HIV RNA level (Table 4). In multivariable analyses, younger age, alcohol use, lack of antiretroviral use, a lower CD4 cell count, and a higher HIV RNA were identified as independent predictors of pneumonia among all patients (Table 5). Antiretroviral therapy use was highly protective of developing pneumonia (IRR 0.28). CD4 cell count was inversely associated with pneumonia incidence (for each 100 CD4 cell count increase the incidence rate decreased by 16% (IRR = 0.84). HIV RNA level was directly associated with an increase in pneumonia incidence rate (1.52 fold increase for each 1 log10 HIV RNA level increase). Consistent with the first study aim, smoking increased the risk of pneumonia but the trend did not reach statistical significance in the multivariable model (IRR 1.77, 95% CI: 0.99, 3.15).

DISCUSSION

We observed a high burden of pneumonia among people living with HIV and receiving care in the Southeastern US between 1996 and 2005. More than one in four (27%) patients had at least one pneumonia episode during an average of seven years of follow-up.

The majority of pneumonias were bacterial (61%), but a substantial number (35%) were PCP. Consistent with other studies, we observed an extremely high burden of tobacco use in this cohort. This observation suggests that, despite advances in HIV care [6Miguez-Burbano MJ, Ashkin D, Rodriguez A, et al. Increased risk of Pneumocystis carinii and community-acquired pneumonia with tobacco use in HIV disease Int J Infect Dis 2005; 9: 208-17., 23Crothers K, Griffith TA, McGinnis KA, et al. The impact of cigarette smoking on mortality, quality of life, and comorbid illness among HIV-positive veterans J Gen Intern Med 2005; 20: 1142-5.], respiratory infections continue to be a problem among people living with HIV in the US and tobacco use is disproportionably high in this population.

The majority (80%) of pneumonia episodes occurred among smokers. The estimated incidence rate of pneumonia among smokers was 7.2 per 100 person-years versus 2.9 in non-smokers. Smoking is reported to be associated with an increased risk of pneumonia in HIV-infected patients prior to the use of potent combination antiretroviral therapies [13Hirschtick RE, Glassroth J, Jordan MC, et al. Bacterial pneumonia in persons infected with the human immunodeficiency virus.Pulmonary Complications of HIV Infection Study Group N Engl J Med 1995; 333: 845-51., 14Burns DN, Hillman D, Neaton JD, et al. Cigarette smoking, bacterial pneumonia, and other clinical outcomes in HIV-1 infection.Terry Beirn Community Programs for Clinical Research on AIDS J Acquir Immune Defic Syndr Hum Retrovirol 1996; 13: 374-83.] and in studies that span the pre-HAART and HAART eras [24Kohli R, Lo Y, Homel P, et al. Bacterial pneumonia, HIV therapy, and disease progression among HIV-infected women in the HIV epidemiologic research (HER) study Clin Infect Dis 2006; 43: 90-8.]. The lack of association between smoking and pneumonia observed in this study may be a result of patients exclusively from the HAART era, the high proportion (83%) of HAART use, the relatively small sample size, and the small proportion of never smokers in this cohort. Additionally, the inclusion of PCP, which may be affected more by CD4 cell counts and HAART use rather than by smoking, may have affected the observed association. However, even though smoking was not an independent predictor of pneumonia in this study population, the two fold increase in incidence rates combined with the extremely high prevalence of smoking suggests that smoking cessation should be an important intervention to reduce the burden of pneumonia among people living with HIV, particularly since smoking negatively impacts on morbidity and mortality in this population [23Crothers K, Griffith TA, McGinnis KA, et al. The impact of cigarette smoking on mortality, quality of life, and comorbid illness among HIV-positive veterans J Gen Intern Med 2005; 20: 1142-5.].

The increased risk of pneumonia in smokers may be explained by a number of studies of smoking in both immunocompetent and HIV-infected individuals. In immunocompetent individuals, smoking impairs ciliary function [25Stanley PJ, Wilson R, Greenstone MA, MacWilliam L, Cole PJ. Effect of cigarette smoking on nasal mucociliary clearance and ciliary beat frequency Thorax 1986; 41: 519-23.], which may result in pathogen colonization and airway inflammation [26Drannik AG, Pouladi MA, Robbins CS, Goncharova SI, Kianpour S, Stampfli MR. Impact of cigarette smoke on clearance and inflammation after Pseudomonas aeruginosa infection Am J Respir Crit Care Med 2004; 170: 1164-71., 27Greenberg D, Givon-Lavi N, Broides A, Blancovich I, Peled N, Dagan R. The contribution of smoking and exposure to tobacco smoke to Streptococcus pneumoniae and Haemophilus influenzae carriage in children and their mothers Clin Infect Dis 2006; 42: 897-903.]. In addition, nicotine has been shown to suppress leukocyte migration, and cigarette smoke is directly cytotoxic to alveolar type II cells [28Hoshino Y, Mio T, Nagai S, Miki H, Ito I, Izumi T. Cytotoxic effects of cigarette smoke extract on an alveolar type II cell-derived cell line Am J Physiol Lung Cell Mol Physiol 2001; 281: L509-516., 29Sopori ML, Kozak W, Savage SM, Geng Y, Kluger MJ. Nicotine-induced modulation of T Cell function.Implications for inflammation and infection Adv Exp Med Biol 1998; 437: 279-89.]. Compared to HIV-infected non-smokers, HIV-infected smokers demonstrate decreased levels of secreted proinflammatory cytokines interleukin-1 (IL-1) and IL-6 by lung macrophages [30Twigg HL 3rd, Soliman DM, Spain BA. Impaired alveolar macrophage accessory cell function and reduced incidence of lymphocytic alveolitis in HIV-infected patients who smoke Aids 1994; 8: 611-8.] and reduced concentrations of IL-1β and TNF-α in BAL fluid [31Wewers MD, Diaz PT, Wewers ME, Lowe MP, Nagaraja HN, Clanton TL. Cigarette smoking in HIV infection induces a suppressive inflammatory environment in the lung Am J Respir Crit Care Med 1998; 158: 1543-9.]. Furthermore, alveolar macrophages recovered from HIV-positive smokers demonstrate decreased phagocytic function to both Escherichia coli bacteria and IgG-opsonized sheep red blood cells compared to HIV-infected non-smokers [32Elssner A, Carter JE, Yunger TM, Wewers MD. HIV-1 infection does not impair human alveolar macrophage phagocytic function unless combined with cigarette smoking Chest 2004; 125: 1071-6.]. These data may partially explain why smoking as an independent risk factor for invasive pneumococcal disease in HIV-infected and uninfected cohorts [12Grau I, Pallares R, Tubau F, et al. Epidemiologic changes in bacteremic pneumococcal disease in patients with human immunodeficiency virus in the era of highly active antiretroviral therapy Arch Intern Med 2005; 165: 1533-40., 33Jordano Q, Falco V, Almirante B, et al. Invasive pneumococcal disease in patients infected with HIV: still a threat in the era of highly active antiretroviral therapy Clin Infect Dis 2004; 38: 1623-8.].

To better understand how the burden of pneumonia in the HAART era could be further reduced, the second study aim identified independent predictors other than smoking for developing pneumonia among people living with HIV. Antiretroviral use was highly protective and, consistent with previous observations [13Hirschtick RE, Glassroth J, Jordan MC, et al. Bacterial pneumonia in persons infected with the human immunodeficiency virus.Pulmonary Complications of HIV Infection Study Group N Engl J Med 1995; 333: 845-51., 14Burns DN, Hillman D, Neaton JD, et al. Cigarette smoking, bacterial pneumonia, and other clinical outcomes in HIV-1 infection.Terry Beirn Community Programs for Clinical Research on AIDS J Acquir Immune Defic Syndr Hum Retrovirol 1996; 13: 374-83., 19Sullivan JH, Moore RD, Keruly JC, Chaisson RE. Effect of antiretroviral therapy on the incidence of bacterial pneumonia in patients with advanced HIV infection Am J Respir Crit Care Med 2000; 162: 64-7., 20Tumbarello M, Tacconelli E, de Gaetano Donati K, Cauda R. HIV-associated bacterial pneumonia in the era of highly active antiretroviral therapy J Acquir Immune Defic Syndr Hum Retrovirol 1999; 20: 208-9., 24Kohli R, Lo Y, Homel P, et al. Bacterial pneumonia, HIV therapy, and disease progression among HIV-infected women in the HIV epidemiologic research (HER) study Clin Infect Dis 2006; 43: 90-8.], a low CD4 cell count was significantly associated with pneumonia risk. These data indicate the importance of early diagnosis of HIV infection and access to care prior to the development of severe immunosuppression. In contrast to previous observations [13Hirschtick RE, Glassroth J, Jordan MC, et al. Bacterial pneumonia in persons infected with the human immunodeficiency virus.Pulmonary Complications of HIV Infection Study Group N Engl J Med 1995; 333: 845-51., 19Sullivan JH, Moore RD, Keruly JC, Chaisson RE. Effect of antiretroviral therapy on the incidence of bacterial pneumonia in patients with advanced HIV infection Am J Respir Crit Care Med 2000; 162: 64-7., 20Tumbarello M, Tacconelli E, de Gaetano Donati K, Cauda R. HIV-associated bacterial pneumonia in the era of highly active antiretroviral therapy J Acquir Immune Defic Syndr Hum Retrovirol 1999; 20: 208-9., 34Boschini A, Smacchia C, Di Fine M, et al. Community-acquired pneumonia in a cohort of former injection drug users with and without human immunodeficiency virus infection: incidence etiologies and clinical aspects Clin Infect Dis 1996; 23: 107-13.], intravenous drug use was not predictive of pneumonia in bivariate or multivariate analyses, possibly as a result of the relatively low use in this cohort. Younger age was predictive of pneumonia risk, which may be partially explained by early AIDS-related diagnoses at entry to HIV care in this population [35Gay CL, Napravnik S, Eron JJ Jr. Advanced immunosuppression at entry to HIV care in the southeastern United States and associated risk factors Aids 2006; 20: 775-8.]. Interestingly, alcohol use was identified as a predictor of pneumonia in the predictive modeling analyses. This observation is important because alcohol use among HIV-infected patients is high, is often associated with other substance abuse [36Galvan FH, Bing EG, Fleishman JA, et al. The prevalence of alcohol consumption and heavy drinking among people with HIV in the United States: results from the HIV Cost and Services Utilization Study J Stud Alcohol 2002; 63: 179-86., 37Stein M, Herman DS, Trisvan E, Pirraglia P, Engler P, Anderson BJ. Alcohol use and sexual risk behavior among human immunodeficiency virus-positive persons Alcohol Clin Exp Res 2005; 29: 837-43.], and is associated with pneumonia in HIV-uninfected cohorts [38de Roux A, Cavalcanti M, Marcos MA, et al. Impact of alcohol abuse in the etiology and severity of community-acquired pneumonia Chest 2006; 129: 1219-25.].

This analysis was limited by several factors. First, the diagnosis of pneumonia was made as part of routine care, and without bacteriological confirmation in 53% of cases. Increased rates of bronchitis and non-specific respiratory complaints in smokers may have led to misclassification of these subjects as pneumonia events. However, the use of chest radiographs minimized this bias. Second, this analysis relied on self-reported behaviors during the CSDBS interview. However, based on experiences in other studies, the self-reported current smoking status and amount of smoking measured in pack-years was unlikely to be biased [39Nyberg F, Agudo A, Boffetta P, Fortes C, Gonzalez CA, Pershagen G. A European validation study of smoking and environmental tobacco smoke exposure in nonsmoking lung cancer cases and controls Cancer Causes Control 1998; 9: 173-82., 40Verkerk PH, Buitendijk SE, Verloove-Vanhorick SP. Differential misclassification of alcohol and cigarette consumption by pregnancy outcome Int J Epidemiol 1994; 23: 1218-25.]. To minimize the impact of self-reported behavior, we attempted to corroborate self-reported behaviors with clinical diagnoses. Third, we were not able to adequately control for the use of opportunistic infection prophylaxis and antimicrobial use during the observation period. Attempts to control for these factors resulted in collinearity with antiretroviral use and unstable model estimates. Lastly, subjects who completed the CSDBS questionnaire represented a subset of the overall CFAR cohort. With the exception of a longer duration since HIV diagnosis, the CSDBS subjects in this study are clinically and demographically representative of the overall UNC CFAR cohort [21Napravnik S, Eron JJ, McKaig RG, Heine AD, Menezes P, Quinlivan E. Factors associated with fewer visits for HIV primary care at a tertiary care center in the SoutheAstern U.S AIDS Care 2006; 18: 45-50.].

CONCLUSIONS

With the introduction of highly active antiretroviral therapy (HAART), significant declines in the burden of pneumonia have occurred in people living with HIV. However, despite these declines, smoking and other substance abuse remains high, with increased incidences of pneumonia among smokers and those who report alcohol use. This observation, coupled with the increased risk in those presenting with advanced immunosuppression, suggest that early access to HIV care programs incorporating substance abuse treatment programs may further reduce the burden of pneumonia among people living with HIV.

ACKNOWLEDGEMENTS

We wish to thank all of the patients who agreed to participate in the UNC CFAR HIV Cohort Study and the Clinical Socio-Demographic and Behavioral Survey (CSDBS) and Rosemary McKaig for her efforts in database and questionnaire development.

We wish to acknowledge the following funding sources for the development and maintenance of the University of North Carolina Center for AIDS Research (UNC-CFAR) HIV Clinical Cohort Study: The University of North Carolina at Chapel Hill, Center for AIDS Research, National Institutes of Health funded program P30 AI 50410; The University of North Carolina, General Clinical Research Center, National Institutes of Health funded program RR00046; The US Department of Health and Human Services, HRSA, HAB, Office of Science and Epidemiology; the Epidemiology Department at GlaxoSmithKline; SAS Institute; The Medical Foundation of North Carolina, Inc.

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Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


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(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


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(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


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(Sapienza - University of Rome, Italy)

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Philippe Hernigou
(Paris University, France)

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Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


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(Chinese University of Hong Kong, Hong Kong)

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Jih Ru Hwu
(National Central University, Taiwan)


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