Interactions between HIV infection and chronic obstructive pulmonary disease: Clinical and epidemiological aspects.

Abstract

An association between HIV infection and chronic obstructive pulmonary disease (COPD) has been observed in several studies.
we conducted a review of the literature linking HIV infection to COPD, focusing on clinical and epidemiological data published before and during widespread highly active antiretroviral therapy (HAART).
Interactions between HIV infection and COPD appear to be influenced by multiple factors. In particular, the bronchopulmonary tract can be damaged by HIV infection, the immunodeficiency it induces, and the resulting increase in the risk of pulmonary infections. In addition, the prevalence of smoking and intravenous drug use is higher in HIV-infected populations, also increasing the risk of COPD. Before the advent of HAART, respiratory tract infections probably played a major role. Since the late 1990s and the widespread use of HAART, the frequency of opportunistic infections has fallen but new complications have emerged as life expectancy has increased.
given the high prevalence of smoking among HIV-infected patients, COPD may contribute significantly to morbidity and mortality in this setting.

Full text

Page 1

REVIEWOpen Access
Interactions between HIV infection and chronic
obstructive pulmonary disease: Clinical and
epidemiological aspects
Christine Raynaud1*†, Nicolas Roche2†and Christos Chouaid3†
Abstract
Introduction: An association between HIV infection and chronic obstructive pulmonary disease (COPD) has been
observed in several studies.
Objective and methods: we conducted a review of the literature linking HIV infection to COPD, focusing on
clinical and epidemiological data published before and during widespread highly active antiretroviral therapy
(HAART).
Results: Interactions between HIV infection and COPD appear to be influenced by multiple factors. In particular,
the bronchopulmonary tract can be damaged by HIV infection, the immunodeficiency it induces, and the resulting
increase in the risk of pulmonary infections. In addition, the prevalence of smoking and intravenous drug use is
higher in HIV-infected populations, also increasing the risk of COPD. Before the advent of HAART, respiratory tract
infections probably played a major role. Since the late 1990s and the widespread use of HAART, the frequency of
opportunistic infections has fallen but new complications have emerged as life expectancy has increased.
Conclusion: given the high prevalence of smoking among HIV-infected patients, COPD may contribute
significantly to morbidity and mortality in this setting.
Introduction
Chronic obstructive pulmonary disease (COPD) is
defined by slowly progressive, incompletely reversible
chronic airflow obstruction. Smoking is the main risk
factor but the mechanisms linking smoking to COPD
are not completely clear, although they are known to
involve inflammation, oxidative stress, proteolytic injury
and both innate and acquired immunity [1,2]. Active
smoking and frequent exacerbations (often related to
lower respiratory tract viral or bacterial colonization and
infection) are associated with COPD progression, but
other factors may be involved.
The possibility of an increased susceptibility of HIV-
infected patients to COPD has been raised in recent
years [3-5]. Both HIV infection per se and the resulting
immune response have been implicated. Moreover,
HIV-infected patients appear to be at a particular risk of
developing COPD, owing to their high prevalence of
smoking, recurrent pulmonary infections (including
opportunistic infections), frequent drug use, and often
precarious socio-economic status [5]. However, these
features also represent confounding factors in analyses
of the possible association between COPD and HIV
infection [5].
The impact of highly active antiretroviral therapy
(HAART) adds to the complexity of this issue. HAART
consists of a combination of at least three antiretroviral
drugs taken simultaneously and regularly in order to
achieve a maximal reduction in viral load [6]. During
the pre-HAART period, mortality among HIV-infected
patients was mainly due to opportunistic infections.
Since the end of the 1990s and widespread HAART use,
life expectancy of HIV-infected subjects has increased
and new complications have emerged [7,8]. The high
prevalence of smoking in this now aging HIV-infected
population means that COPD may be a significant
source of morbidity and mortality [4,9].
* Correspondence: christine.raynaud@ch-argenteuil.fr
† Contributed equally
1Service de pneumologie, Centre Hospitalier Victor Dupouy, 69 rue du L.C.
Prud’hon, 95100 Argenteuil, France
Full list of author information is available at the end of the article
Raynaud et al. Respiratory Research 2011, 12:117
http://respiratory-research.com/content/12/1/117
© 2011 Raynaud et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.

Page 2

The aim of this literature review is to examine interac-
tions between HIV infection and COPD, focusing on
clinical and epidemiological data published in the pre-
HAART and HAART eras.
COPD-HIV interaction in the pre-HAART period (Table 1)
Several studies have examined the link between HIV
infection and bronchial hyper-responsiveness, a possible
early sign of airway damage. The prevalence of bronchial
hyper-responsiveness is not significantly influenced by
HIV infection [10-12]. In contrast, the prevalence of
bronchial hyper-responsiveness seems to be higher
among HIV-infected male smokers (enrolled between
1995 and 1996) than in their seronegative counterparts,
suggesting that HIV-infected men may be more sensitive
to the consequences of smoking [10].
Another study (conducted between 1993 and 1998)
showed a higher frequency of chronic bronchitis
(defined as near-daily expectoration for three months or
more per year) in HIV-infected patients than in a con-
trol group (26.9% versus 13.5%, p < 0.05), despite a simi-
lar proportion of current smokers (about 50%) and a
Table 1 Main published studies on COPD-HIV interaction in the pre-HAART era
Year of
publication author
Reference
First Study
period
Type of
study
Focus Number
of
patients
Main findings
1993 Moscato G
[12]
NR“One day”
Case-control
Bronchial hyper-
responsiveness
25
(25
controls)
Prevalence of bronchial hyper-responsiveness identical in the
two populations
1997Wallace
JM [11]
1988-
1994
Cohort
Case-control
Bronchial hyper-
responsiveness
62
(62
controls)
Prevalence of bronchial hyper-responsiveness identical in the
two populations
2001Poirier CD
[10]
1995-
1996
prospective
Case-control
Bronchial hyper-
responsiveness
248
(236
controls)
Prevalence of bronchial hyper-responsiveness identical in the
two populations Among smokers, bronchial hyper-
responsiveness more frequent in HIV-infected men than in
controls
2003 Diaz PT
[13]
1993-
1998
Cohort
Case-control
Chronic bronchitis327
(52
controls)
Chronic bronchitis more frequent in HIV-infected patients than
in controls (26.9% versus 13.5%, p < 0.05)
1998Shaw RJ
[16]
NRProspective?
descriptive
Airway obstruction 34Lung infections (PCP, bacterial pneumonia) associated with
lower FEV1and peak flow rates
Estimated prevalence of lower forced expiratory. flow rates: 33%1988O’Donnell
CR [14]
1983-
1986
Retrospective? Airway obstruction 99
(AIDS)
1999Gelman M
[15]
NRProspective
Case-control
Air trapping/CT48
(11
controls)
Degree of air trapping correlated with duration of HIV infection
2000Hnizdo E
[18]
1995-
1996
Cohort
Case-control
Impairment of lung
function and
tuberculosis
305
(1038
controls)
Functional respiratory decline due to tuberculosis not
aggravated by HIV co infection
2000Morris AM
[17]
1988-
1994
Cohort
descriptive
Airway obstruction141Acceleration of decline in FEV1, FVC and FEV1/FVC, for several
months after acute episode
1989 Kuhlman
JE [21]
NRRetrospective
descriptive
Emphysema
CT findings
55CT signs of emphysema, bullous lesions and cysts in 42% of
cases
1996Guillemi
SA [22]
NRProspective
descriptive
Emphysema
CT findings
32CT signs of emphysema in 31% of cases
1999 Diaz PT
[20]
NRProspective
Case-control
Emphysema 96
(30
controls)
CT signs of emphysema in 50% of cases in patients with
reduced DL, CO
2000Diaz PT
[23]
1994-
1997
Prospective
Case-control
Emphysema 114
(44
controls)
Increased incidence of emphysema in the HIV-infected
population (15% versus 2% in controls (p = 0.025)).
1993Nieman
RB [25]
1986-
1991
Cohort
descriptive
TL, CO
84 (AIDS)Decline in TL, COsignificantly associated with more rapid
progression to AIDS
1993Mitchell
DM [27]
NRCohort
descriptive
DL, CO
474DL, COdecline in case of acute respiratory disease. Decline not
specific for PCP diagnosis.
1995 Rosen MJ
[29]
1988-
1994
Prospective
Case-control
DL, CO
1127
(167
controls)
CD4 < 200/mm3, ethnic origin, smoking, IV drug use associated
with DL, COdecline
Raynaud et al. Respiratory Research 2011, 12:117
http://respiratory-research.com/content/12/1/117
Page 2 of 8

Page 3

trend towards lower cumulative smoking (12.2 ± 0.9 vs
17.2 ± 3.2 pack-years, p = 0.13) [13]. DL, COwas lower
in these patients, and a trend towards lower FEV1 was
reported (91.8 ± 0.7% vs 94.9 ± 1.8%, p = 0.12). Among
HIV-infected subjects, respiratory symptoms were more
frequent in smokers, IV drug users, patients with a his-
tory of asthma. In a population of AIDS patients under-
going routine pulmonary function tests (PFT), the
estimated prevalence of reduced forced expiratory flow
rates was 33% [14].
Airways involvement has also been suggested in a CT-
scan study of 59 subjects, which found evidence of
expiratory air trapping in 30/48 HIV-infected patients
versus 3/11 HIV-seronegative subjects [15]. Air trapping
was associated with lower FEV1 and DL, CO. Subjects
with air trapping tended to have lower CD4 counts, but
the difference was far from significant (p = 0.40). Both
acute and chronic respiratory tract infections play a note-
worthy role in bronchial obstruction [16]. Pulmonary
infections (Pneumocystis carinii pneumonia, bacterial
pneumonia) are associated with durable changes in
respiratory function in HIV-infected patients. The Pul-
monary Complications of HIV Infection Study Group
performed PFT every 3 to 12 months in 1149 HIV-
infected patients between 1988 and 1994 [17]. In this
cohort, 141 patients having had Pneumocystis carinii
pneumonia (PCP) or bacterial pneumonia were followed-
up, and a permanent decrease in FEV1, FVC and FEV1/
FVC ratio was observed, lasting several months after
resolution of the acute episode. In contrast, the decline in
respiratory function following pulmonary tuberculosis
was not accelerated by HIV co-infection [18].
HIV infection appears to be associated with parenchy-
mal involvement, and especially emphysema. In 1992,
Diaz et al. [19] reported the cases of four HIV-infected
patients (including 3 smokers) with no history of pul-
monary infection, who presented with dyspnea and were
diagnosed with “emphysema-like syndrome”. Pulmonary
function tests showed air trapping, hyperinflation and
reduction in CO diffusing capacity despite minimal air-
flow obstruction. Computed tomographic scans were
performed in three of these patients and revealed bul-
lous changes, pointing to a possible link between HIV
infection and emphysematous pulmonary tissue destruc-
tion [19]. The same authors, in a population with no
history of pulmonary infection but with diminished dif-
fusing capacity of the lung for carbon monoxide (DL,
CO) (< 72% predicted), found CT evidence of emphy-
sema in 50% of cases [20]. In another study of 55
patients with AIDS, radiological evidence of emphysema,
bullous lesions or cysts was found in 42% of cases and
was associated with a history of pulmonary infection in
70% of cases [21]. During routine CT studies prior to
initiation of primary PCP prophylaxis, signs of
emphysema were found in 31% of cases [22]. A study
published in 2000 compared lung function in 114 HIV-
infected patients (enrolled between 1994 and 1997) and
44 uninfected controls matched for age, sex and smok-
ing status [23]. The authors confirmed the higher inci-
dence of emphysema associated with HIV infection
(15% versus 2%, p = 0.025). The difference seemed to be
even more marked among smokers. However, it should
be noted that fewer than 10% of these patients, studied
between 1994 and 1997, were receiving HAART.
Several studies have shown abnormal CO diffusion in
HIV-infected patients, but the exact origin of this
abnormality has not been determined. Diaz et al.[20]
found that diffusion impairment in HIV-infected
patients was associated with loss of capillary blood
volume (Vc) and not with an alteration of the mem-
brane component (Dm). This suggests that the decline
in TL, COis not related to infiltration of the alveolar
space or interstitium but rather to vascular abnormal-
ities or emphysema. Reduced carbon monoxide transfer
factor (TL, CO) values were observed outside the context
of respiratory tract disease [24,25], and also during the
acute phase of PCP [16,26-28]. The reduction in DL, CO
appears to be significantly more marked in patients with
CD4 cell counts below 200/mm3 [29] and to correlate
with more rapid progression to AIDS [25]. It may be
linked to pulmonary inflammation related to immuno-
deficiency. In some patients, the reduction in DL, COcan
also be related to undiagnosed HIV-related pulmonary
hypertension [30].
Before the widespread use of HAART, several observa-
tions showed connections between COPD and HIV. Par-
ticular, emphysematous and bullous diseases have been
described in young patients. Respiratory tract infections
(opportunistic or not) were very common during this
period and may had played a major role in the patho-
genesis of COPD. As morbidity and mortality were
essentially due to AIDS at that time, the impact of
obstructive lung disease was not well known.
COPD-HIV interaction in the HAART era (Table 2)
The impact of HAART on respiratory disorders can be
envisaged from different angles. On the one hand,
assuming that HIV has inherent pathogenicity for the
respiratory tract, HAART could prevent COPD by inhi-
biting viral replication. It could also prevent COPD by
reducing the frequency of opportunistic infections and
their long-term consequences.
On the other hand, the increase in life expectancy
among HIV-infected patients, who have a high preva-
lence of smoking, could lead to an increase in the inci-
dence of COPD. Nevertheless, no increase in the
prevalence of airway obstruction has been observed
among HIV-infected patients in recent years.
Raynaud et al. Respiratory Research 2011, 12:117
http://respiratory-research.com/content/12/1/117
Page 3 of 8

Page 4

In 2006, a prospective observational study comparing
1014 HIV-infected patients with 713 uninfected controls
enrolled between 2001 and 2002 was published [31].
The prevalence of COPD was determined from coding
data (International Classification of Diseases, ninth revi-
sion (ICD-9)) and also from a self-assessment in
response to the question: “Has a doctor ever told you
that you had a chronic lung disease (emphysema,
asthma, chronic bronchitis, or chronic obstructive lung
disease)?” In univariate analysis, based on the coding
data, the prevalence of COPD was identical in the two
populations; in contrast, the self-assessment suggested
that the prevalence of COPD could be higher in the
HIV-infected patients (15% vs 12%, p = 0.04). Indeed,
multivariate analysis identified HIV infection as an inde-
pendent risk factor for COPD (Figure 1) [31]. The lack
of spirometric measurements and the failure to take into
account environmental and occupational exposures are
the main limitations of this study. Another study of a
cohort of 867 HIV-infected patients showed that smok-
ing was associated with an increase in respiratory
symptoms; cough and dyspnea were found in 44% of
smokers and 25% of non-smokers control [32].
A more recent prospective observational study exam-
ined the prevalence and risk factors of respiratory symp-
toms and airway obstruction in a population of 234
HIV-infected patients. The median CD4 count was 371
cells/mm3(interquartile range 3 - 1368). A majority of
patients were on HAART (83%). The duration of disease
was 8 years among HAART users and 10 years among
patients not using HAART. The prevalence of airway
obstruction was 6.8% [33]. One year later, in a cross-sec-
tional study, 167 HIV-infected patients had PFT [34].
The median CD4 count was 479 cells/mm3(interquar-
tile range 22 - 1390). A majority of patients were on
HAART (80.7%). The median disease duration was 13
years (range 0.1-27). Irreversible airway obstruction was
found in 21% of this population. Age, cumulative smok-
ing history, a history of bacterial pneumonia, intrave-
nous drug use and HAART were independent risk
factors for bronchial obstruction (Figure 2) [33,34]. In
contrast, a cross-sectional study establishing a link
Table 2 Main published studies on COPD-HIV interaction in the HAART era
Year of
publicationAuthor
reference
First Study
period
Type of
study
Focus Number
of
patients
Main findings
2005Crothers K
[32]
1999-
2000
Observational
study
prospective
cohort
Respiratory
symptoms
867Smoking associated with increase in respiratory symptoms;
cough and dyspnea found in 44% of smokers and 25% of
non smokers
2006Crothers K
[31]
2001-
2002
Observational
study
Prospective
Case-control
Cohort
COPD
(self-assessment and
coding data)
1014
(713
controls)
Self-assessment: prevalence of COPD significantly higher in
HIV-infected patients (15% vs 12%, p = 0.04); HIV infection =
independent risk factor for COPD
2009George MP
[33]
2003-
2004
Observational
study
Prospective
Respiratory
symptoms.
airway obstruction
234Prevalence of airway obstruction: 6.8%. Age, pack-years,
history of bacterial pneumonia and HAART = independent
risk factors for airway obstruction
2009Morris A
[43]
NRObservational
study
Prospective
Pneumocystis
colonization and
airway obstruction
42Colonization by Pneumocystis jirovecii (26% of cases)
associated with increase in airway obstruction and sputum
metalloprotease (MMP 12) levels
2010Drummond
MB [36]
1988-?Observational
study
Prospective
Cohort
Case-control
Respiratory
symptoms.
Airway
obstruction
288
(686
controls)
Prevalence of airway obstruction: 15.5%. No influence of HIV
status
2010 Cui Q [35] NRObservational
study
Prospective
Respiratory
symptoms.
Airway obstruction
119No acceleration of FEV1decline relative to published data for
general population
2010Gingo RM
[34]
2007-
2009
Cross-
sectional
analysis
Airway obstruction167 64% of patients had impaired diffusion.
21% of patients had irreversible airway obstruction.
Irreversible airway obstruction was independently associated
with HAART, pack-years smoked and intravenous drug use.
2011 Crothers K
[37]
1999-
2007
Observational
study
prospective
Cohort
Case-control
Coding data 3707
(9980
controls)
HIV-infected patients more likely to have diagnoses of COPD
(20.3 per 1000 person-years versus 17.5 per 1000 person-years
- p < 0.001).
Raynaud et al. Respiratory Research 2011, 12:117
http://respiratory-research.com/content/12/1/117
Page 4 of 8

Page 5

between cumulative smoking and FEV1in 120 HIV-
infected patients (-2.1% of FEV1 per 10 pack-years)
found a similar loss of FEV1in HIV-infected smokers by
comparison with published data for smokers in the gen-
eral population [35]. However, this was a cross-sectional
study, excluding a formal assessment of rates of FEV1
decline. In a cohort of IV drug users, the prevalence of
airway obstruction was 15.5% overall and did not differ
according to HIV status [36]. In this study, 54.6% of
patients reported HAART use (median CD4 count 322
cells/mm3(interquartile range 177 - 503)) and the
others had a median CD4 count of 321 cells/mm3
(interquartile range 178 - 497). HIV status was not
associated with chronic cough and sputum production
either, but HIV-positive individuals reported moderate-
to-severe dyspnea (MRC dyspnea grade ≥ 2) more fre-
quently (OR 1.50, 95%CI: 1.08-2.09). DL, COand CT-
scan were not available in this study, preventing from
assessing the role of emphysema. Conversely, hemoglo-
bin levels were slightly but significantly lower in HIV+
subjects, which could contribute to explain the higher
frequency of dyspnea.
More recently, Crothers et al. assessed pulmonary dis-
eases in a large cohort of 3707 HIV-infected patients
(65% on HAART; median CD4 count 264 cells/mm3
(interquartile range 108 - 151)) [37]. This cohort was
demographically matched to 9980 HIV-uninfected
patients. Pulmonary conditions were diagnosed based on
ICD-9 codes (International Classification of Diseases,
ninth revision). HIV infection was independently asso-
ciated with a significantly higher risk of COPD (20.3 per
1000 person-years versus 17.5 per 1000 person-years; p
< 0.001). Among HIV-infected subjects, the incidence of
COPD was lower in patients on HAART (65% of the
population studied) and in patients with baseline HIV
RNA levels below 400 copies/ml [37].
Factors underlying COPD-HIV interaction (Figure 3)
Several factors are involved in the COPD-HIV interac-
tion. Some are directly linked to HIV infection, others
relate to its complications (colonization by Pneumocystis
jirovecii, Pneumocystis jirovecii pneumonia, bacterial
pneumonia, etc.) and its treatment. Other risk factors
such as smoking and IV drug use are also more frequent
in the HIV-infected population.
A possible role of HIV itself in the onset of COPD is
supported by data on the pathophysiology of COPD.
HIV infection causes intense pulmonary infiltration by
Figure 1 Predictors of COPD (OR with 95%CI) for some of the
risk factors identified (using ICD-9 codes) in multivariate
analysis as independently associated with a diagnosis of
chronic airflow obstruction, among 1014 HIV-positive and 713
HIV-negative US veterans [31].
Figure 2 Predictors of COPD (OR with 95%CI) for risk factors
independently associated with airflow obstruction, diffusion
impairment, both, and symptoms in a cohort of 167 HIV-
infected subjects [34]. Age/10 y: age in ten-year periods. Smoking/
10 pack-years: smoking per ten pack-years.
Figure 3 Factors underlying COPD-HIV interaction and their
evolutions between pre-HAART era (blue circles) and HAART
era (white circles).
Raynaud et al. Respiratory Research 2011, 12:117
http://respiratory-research.com/content/12/1/117
Page 5 of 8