INVITED REVIEW SERIES:
UNRAVELLING THE MANY FACES OF COPD TO OPTIMIZE ITS CARE AND
OUTCOMES
SERIES EDITORS: GREGORY G KING AND DON SIN
HIV and COPD: a conspiracy of risk factors
UMESH G. LALLOO,1 SANDY PILLAY,1 ROSIE MNGQIBISA,1 SABEER ABDOOL-GAFFAR2 AND
ANISH AMBARAM3
1
Durban University of Technology, 2Kingsway Hospital, and 3Gateway Private Hospital, Durban, South Africa
ABSTRACT
Chronic obstructive pulmonary disease (COPD) is
an under recognized complication of HIV infection. It
is estimated that up to 25% of HIV infected people
may have COPD. HIV is associated with COPD as a
result of a complex interplay of multiple factors
such as pulmonary inflammation, recurrent pulmonary
infections especially tuberculosis (TB), increased
cigarette smoking, socio-economic status, childhood
respiratory illnesses and industrial and environmental
exposures; each of which are risk factors for COPD in
their own right. COPD presents at an earlier age in
people with HIV infection. There are over 35 million
people living with HIV, and most people infected with
HIV live in developing regions of the world where they
are faced with multiple risk factors for COPD and
suboptimal access to health care. TB is the commonest
infectious complication of HIV, and HIV infected
persons often experience multiple episodes of TB.
Cigarette smoking is increasing in developing countries
where the greatest burden of TB and HIV is experienced.
Cigarette smoking is associated with increased risk of
TB and may be associated with acquisition of HIV
infection and progression. It is not clear whether non-
infectious pulmonary inflammation persists in the lung
when immune reconstitution occurs. Prevention and
control of HIV infection must be part of the multiple
interventions to reduce the global burden of COPD. A
multidisciplinary approach, including behavioural
science is required to address this challenge. It presents
research opportunities that should be driven by the
pulmonology community.
Key words: chronic obstructive pulmonary disease, human
immunodeficiency virus, infections, smoking, tuberculosis.
Abbreviations: ART, active antiretroviral treatment; BMI, body
mass index; COPD, chronic obstructive pulmonary disease; DLCO,
diffusing capacity of carbon monoxide; FEV1, forced expiratory
volume in 1 s; FVC, forced vital capacity; HIV, Human
Correspondence: Umesh G Lalloo, Durban University of Technology,
19 Copperstone Lane, Mount Edgecombe Country Club, 4302,
Durban, South Africa. E-mail: umeshlalloo@gmail.com
Received 16 August 2015; invited to revise 1 September 2015;
revised 7 February 2016; accepted 15 March 2016.
© 2016 AsianPacifi
2016 Asian Pacific Societyof
c Society ofRespirology
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immunodeficiency virus; MDR-TB, multi-drug-resistant tuberculosis;
TB, tuberculosis; XDR-TB, extensively drug resistant tuberculosis.
INTRODUCTION
Chronic obstructive pulmonary disease (COPD) affects
an estimated 329 million people and is the third leading
cause of death globally.1 While most information about
the epidemiology comes from high-income countries,
it is known that almost 90% of COPD deaths occur in
low-income and middle-income countries and that,
with the expansion of tobacco use, the disease affects
men and women almost equally.2 In a review of COPD
in major developed countries, the prevalence ranged
from 0.2–37%, varying according to population and
classification methods; prevalence and incidence were
highest in men over 75 years of age and mortality
ranged from 3 to 111 deaths per 100 000 with increasing
mortality among women.3
The prevalence in Africa has been poorly studied
and compounded by varying classification and
diagnostic methods.4
Whilst cigarette smoking is the leading cause of
COPD, there are numerous other causes of COPD,
which are shown in Figure 1. HIV infection has
emerged as an important cause of COPD. Most of the
people living with HIV reside in developing regions of
the world and are also subject to low socioeconomic
standards of living and infections. Cigarette smoking
is also increasing in these poorer regions of the world
as multinational tobacco companies’ shift their
marketing to these regions.5 HIV infection has
become a chronic disease with the advent and wide-
spread use of highly active antiretroviral treatment
(ART).6 As a result of this, many people with HIV
are living longer and will be subject to long term
complications of the disease and its treatment.7 It
should not be surprising therefore that non-AIDS
defining conditions now account for the majority of
deaths in people with HIV and that the causes of
mortality will equate to the non-HIV infected
counterparts.8 ART is known to be a risk factor for
development of chronic diseases such as cardiovascular
disease, dyslipidaemias and osteoporosis. Development
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doi: 10.1111/resp.12806
2 and COPD: a conspiracy of risks
HIV
of the chronic conditions may be as a direct result of
ART or due to long term exposure to HIV.9 Some
studies have suggested that COPD is one of the
chronic conditions linked to ART.10
Further, HIV infection is associated with an in-
creased risk of many pulmonary diseases that are
established causes of COPD.11 It is apparent that these
factors conspire to cause and aggravate COPD in HIV
infected people. This review will discuss the asso-
ciation of HIV infection with COPD.
THE GLOBAL BURDEN OF HIV
At the end of 2013, there were 35 million people living
with HIV with 15 countries, the overwhelming majority
in Sub-Saharan Africa, housing 75% of all infected
people.12 It is estimated that more than half of people
living with HIV have not been tested and only two
out of every five infected people are receiving ART.13
Less than a quarter of infected children are on ART.
New infections are increasing in some parts of the
world with trends in the Middle East and North Africa
—where incidence rates have increased by 31%—are
of special concern.14 South Africa remains the hotspot
for HIV infection. While South Africa’s rapid scale-up
of their ART programme is admirable, the country still
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Figure 1 Chronic obstructive pulmonary
disease and HIV—a complex interplay of
risk factors.
bears the largest burden of HIV—18% of the world’s
HIV population—and 58% of the HIV-infected people
still do not have access to ART.15 In addition, recent
indications are that risky sexual behaviour is increasing
in the country. India accounts for 51% of the AIDS
deaths in Asia, while ART coverage is only 36%. Western
Europe and North America recorded an increase in new
infections of 6% in 2013.16
Fortunately, new HIV infections continue to decline
in most parts of the world—a decrease of 38%
between 2001 and 2013 with a rapid decline of 13%
between 2010 and 2013 alone.16 New infections
among children dropped by 58% between 2002 and
2013, with the provision of ART to pregnant women
having averted an estimated almost 1 million vertical
transmissions since 2009.16 By the end of 2013, 13
million people were accessing ART: almost half of
these people having received this treatment between
2010 and 2013—largely attributable to South Africa’s
ART programme—accounted for a third of this
increase.15 The provision of ART has averted an
estimated 7.6 million deaths since 1995—death due
to AIDS has declined by 35% between 2005 and
2013.16 This means that these individuals will live
longer and have longer exposure to risk factors for
COPD such as the effects of ART and HIV infection,
cigarette smoking and pollution
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HIV and COPD: a conspiracy of risks
BURDEN OF TB IN HIV
TB is the commonest infection in HIV infection in the
developing regions. People with HIV have a 10% annual
risk of developing active TB compared with a 10%
lifetime risk in non-HIV infected.17 Pulmonary TB is
established as a risk factor for COPD.18,19 It is not
uncommon for HIV-infected persons to develop
multiple episodes of active TB.17 Globally, an estimated
9 million people developed TB in 2013, resulting in 1.5
million deaths in that year.16 More than half of this
disease burden is borne by Southeast Asia and the
Western Pacific regions with India alone accounting
for 24% of incident TB.16 Although, the incidence of TB
continues to fall at a rate of 1.5% per annum since
2000 and TB mortality has dropped by 45% since 1990,
it is unlikely that all three Millennium development
goals of reducing incidence, prevalence and mortality
will be achieved globally.20 TB remains the leading cause
of death among people living with HIV globally. About
13% of those who developed TB in 2013 were HIV
infected with Africa bearing the brunt of this burden,
accounting for four out of every five HIV/TB co-infected
cases and deaths.16 Up to 80% of people presenting with
active TB are HIV co-infected in high TB-burden
countries such as South Africa.21 Globally, 3.5% of new
and 20.5% of previously treated cases of TB were
estimated to have had drug-resistant TB (MDR-TB) in
2013—an absolute number of 480 000 in that year. About
9% of these cases are believed to be extensively drug
resistant TB (XDR-TB). The majority of XDR-TB cases
in South Africa are HIV co-infected.22 The mechanisms
of TB and COPD are beyond the scope of this review.
ESTIMATION OF BURDEN OF CHRONIC
OBSTRUCTIVE PULMONARY DISEASE IN
HIV
It has been demonstrated that HIV-infected smokers
had a significantly higher rate of COPD compared with
uninfected smokers.23 Indeed, one report noted a 16%
prevalence of emphysema in post-mortem specimens
of non-smoking HIV-infected people, which is excep-
tionally higher than the HIV-uninfected population.24
This suggests that HIV is an independent risk factor
for COPD.25
In the pre-ART and early ART era, the pulmonary
manifestations of HIV were dominated by infectious
complications.26 As longevity in HIV improved, there
has been a wide shift in the presentations of the
pulmonary complications of HIV disease.26 The ageing
HIV-infected population has longer exposure time to
HIV. Widespread implementation of ART has meant
that the number of people with HIV achieving survival
rates similar to their non-HIV-infected counterparts.27
It is not certain whether long term suppression of
HIV infection is associated with pathophysiological
changes in the lungs, similar to that of ex-smokers with
COPD. The pulmonary secretions of ex-smokers with
COPD have demonstrated increased neutrophils and
inflammatory markers independent of infections.28
Longer survival is also associated with longer exposure
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to cigarette smoking and other factors associated with
HIV. HIV-associated COPD has become more com-
mon with an increase since pre-ART.29 Several studies
have demonstrated that ART is a predictor of airway
obstruction even when other factors like age and
smoking were adjusted for.9–11
Many initial estimates of the COPD prevalence in HIV
were flawed by diagnoses based on ICD-9 codes or self-
reported symptoms without having measured pulmonary
function directly. Diaz and colleagues found that 23% of
HIV-infected smokers without a history of pulmonary
infections had emphysema compared with only 2% of
control subjects matched for age and smoking.30
A study from the Veteran’s Aging Cohort Study
reported that HIV-infected subjects were approximately
50 to 60% more likely to have COPD than HIV-
uninfected subjects after adjusting for differences in
age, smoking, race/ethnicity and other potential con-
founders such as injection drug use and alcohol abuse.31
HIV-infected individuals, known to have risk behaviours
such as smoking, may represent another population
with an increased susceptibility to COPD.23,32 It is
estimated that 75% of HIV-infected people have smoked
at least 100 cigarettes in their lifetime.33 Additionally, HIV
infection has been associated with a high degree of
accelerated emphysema and airway obstruction.23
HIV infection is also independently associated with
an increased odds ratio of acute exacerbations of
COPD.34 This is in part due to variability in treatment
access as well as variability in disease manifestation
based on immune status.
Little is known about the association of HIV and
COPD in Sub-Saharan Africa.4 Not only does this
region have the highest burden of disease, it also has
the weakest health systems. Estimates of COPD vary
between 4 and 25%, reflecting the range of populations
studied, inconsistent diagnostic criteria and variable
methods as well as methodological quality.35 Added
to this is the unaccounted for contribution of biomass
fuels, air pollution and sequelae of TB.
Since the widespread use of ART, several cross-
sectional studies have documented a high prevalence
of airflow obstruction in HIV.9,10 There are associations
between COPD and risk factors such as cigarette
smoking, previous opportunistic infections, markers
of HIV infection and ART use. Older age, number of
pack years smoked, previous bacterial pneumonia and
the use of ART appear to be independent risk factors,
but this has not been consistently demonstrated.36 In
a cohort of 98 HIV-infected patients with a prevalence
of airflow obstruction on spirometry of 13.6%, only age
and number of pack years were associated with airflow
obstruction but not ART use. Interestingly, previous
Pneumocystis infection was associated with COPD.37
Despite the greatest burden of HIV in Sub-Saharan
Africa, there is a paucity of data on spirometry in HIV
infected individuals from this region.
In fact, the actual burden of COPD in Africa has not
been systematically studied.38 A study using the inter-
nationally accepted method of post-bronchodilator
spirometry diagnosis performed in Uganda revealed a
prevalence of 16.2%, with no significant gender
difference and with 31% of men and 74% of women
being non-smokers.39 All were exposed to biomass
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smoke, which appears to be an important risk factor in
low income countries, explaining the high prevalence in
women and younger people—women in these settings
were found to spend 3–5 h/day in poorly ventilated
kitchens using biomass fuel for cooking. The highest
prevalence of COPD was found in the Burden of
Obstructive Lung Disease (BOLD) study in South Africa,
which was the only population-based study and the
only study to use post-bronchodilator spirometry.40
The high-COPD prevalence seen in this study reflects
the high prevalence of smoking, other airborne
exposures and history of previous tuberculosis in this
study population. The link between infection and airflow
obstruction remains an under researched subject. The
effect of viral infections, pneumonia and TB on airflow
obstruction remains poorly defined in a population with
a high prevalence of HIV infection. Additionally, the high
levels of poverty have many confounding aetiological
factors associated with COPD development, viz. prenatal
and postnatal exposures, nutritional deficiencies, low
BMI and low education levels which may put adults at
risk of developing COPD at an earlier age.41 Other studies
have found associations between indoor air pollution
and the development of airflow obstruction. The
widespread use of biomass fuels for cooking in rural
households may be important to this important yet
poorly understood risk factor in HIV infected people.42,43
Another factor that may contribute to COPD in HIV is
rapid urbanization and industrialization, which is
associated with increased occupational dust exposure
and greater access to disposable income with ante-
cedent increase in tobacco smoking.
The Strategic Timing of AntiRetroviral Treatment
(START) study, an international study on immediate
versus deferred ART in HIV in persons with CD4 counts
above 500 cells/mL has a nested study measuring
spirometry in the cohorts under study.44 This study
has found a prevalence of COPD of 6.8% at baseline
in 1026 ART naive participants from 80 countries.
Almost half of these were lifetime nonsmokers.
Nevertheless smoking was still significantly associated
with COPD in this baseline analysis. This prospective
trial will provide longitudinal data on COPD in HIV
and the impact of ART.
PATHOPHYSIOLOGY OF CHRONIC
OBSTRUCTIVE PULMONARY DISEASE IN HIV
Analysis of bronchoalveolar lavage fluid of people with
HIV infection has demonstrated that the lung is in an
‘inflammatory’ state even in the absence of pulmonary
infections.45 Both the HIV infection per se and the asso-
ciated immune responses have been implicated in the
pathogenesis of COPD. People with HIV infection have
a number of associated factors that may also con-
tribute to this increased risk of developing COPD, viz.
a high prevalence of smoking, recurrent respiratory
tract infections, recreational drug use and a lower
socio-economic status. The pathogenesis of COPD is
therefore multifactorial and complex.46–48 Up to 21%
of HIV infected patients have an obstructive ventilatory
defect, and a reduction in diffusing capacity for carbon
monoxide is seen in over 50% of these patients.46
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Prior to introduction of ART, lung function impair-
ment was worse with more advanced HIV disease,
and abnormally low diffusing capacity was the most
prominent finding.46 One of the largest studies before
the ART era to document this was from the Pulmonary
Complications of HIV Infection Study Group.36 In this
study, the spirometric measurements the forced expi-
ratory volume in 1 s (FEV1) and forced vital capacity
(FVC) were 10–15% lower than healthy populations
and the HIV-infected participants had a lower per-
centage of predicted mean diffusing capacity of carbon
monoxide (DLCO), and this association was driven
predominantly by reduced DLCO in patients with lower
CD4 cell counts. The low DLCO was thought to be due
to HIV-related inflammation or infection and was
associated with advanced HIV disease. Some studies
documented pulmonary function and radiographic
abnormalities that seemed to be independent of
opportunistic infections; with one study reporting
a 15% prevalence of radiographic emphysema in
HIV-infected people without a history of opportunistic
infection.23 Emphysema was an important determinant
of low diffusion capacity.49 HIV infected people there-
fore had a high prevalence of respiratory symptoms
such as cough, shortness of breath and dyspnoea on
exertion, which was seen even in individuals without a
history of pulmonary infections, accelerated airway
obstruction and small airway disease and increased
emphysema.50 Risk factors for respiratory symptoms in
the pre-ART era were smoking, illicit drug use, low
CD4 counts and pulmonary infections.36
There are a number of hypotheses regarding the
pathogenesis of COPD in HIV. These include the high
prevalence of risk behaviour in the HIV infected popu-
lation as well as HIV-related ART related factors.10,36
The associated risk behaviours as outlined earlier pro-
bably interact with the other factors and increase the risk
of HIV-associated COPD particularly as these patients
survive longer and hence experience longer exposure to
HIV, smoking and illicit drug use.24
Pneumocystis pneumonia (PCP) has been linked to
the development of COPD in HIV-infected patients.37
Pneumocystis infection leads to accelerated declines in
FEV1, FEV1/FVC and DLCO beyond that attributable to
ageing and smoking.51 It has been suggested that the
HIV stimulates an inflammatory response in the lung,
which is conducive to the development and progression
of COPD, viz. increases in CD8+ lymphocytes (which
produce Interferon Gamma), activation of alveolar
macrophages and upregulation of expression of matrix
metalloproteinases.37
HIV-infected individuals also have altered systemic
and lung oxidant/antioxidant balance with increases
in oxidant levels and decreases in anti-oxidant levels,
and resultant pulmonary damage.37 This imbalance is
accentuated by cigarette smoking.
There is also evidence that HIV infected persons may
have an increased susceptibility to apoptosis. It has
been proposed that apoptosis, oxidative stress and
inflammation work in concert to promote COPD.37
It has also been proposed that ART may also be a risk
factor in the development of COPD.37 The mechanism
linking ART and COPD are unknown but may be due
to the direct effects of ART, an increased inflammatory
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HIV and COPD: a conspiracy of risks
response secondary to restoration of the immune system
after ART, or a possible development of auto-immunity.
Some studies have shown that uncontrolled HIV
infection is associated with an increased risk for COPD,
and HIV disease control might be associated with a
reduction in COPD risk.52 Obstructive lung disease
has been associated with high viral load but not CD4
cell count in one study.53
In a recent study, radiographically documented em-
physema severity correlated with nadir CD4 cell counts
<200 cells/uL and elevated soluble CD14 levels—this
highlights potential mechanisms linking HIV with
emphysema.54
The mechanism for ART related COPD is suspected
to be direct or as a result of restoration of immunity
with renewed response to subclinical infections or
suspected modified immune inflammatory response
(modified IRIS), which stimulates pulmonary inflam-
mation in response to colonizing pathogens resulting
in airway obstruction.24 Streptococcus pneumonia,
Haemophilus influenza and PCP have been implicated
in the non-HIV infected population in COPD patho-
genesis. It has been suggested that the persistence of
these organisms or HIV itself might form a nidus for
chronic inflammation after starting ART that results
in COPD. It is suggested that initiation of ART can
produce a reaction similar to IRIS, which might result
in chronic inflammation due to subclinical infections.
Organ specific autoimmunity has been demonstrated
as a complication of ART. Autoimmune conditions
seem to increase after ART initiation and generally
occur 6 months post-ART initiation.55 The suscep-
tibility to autoimmunity during immune restoration
in patients on ART and the autoimmune pathogenesis
of COPD suggest that autoimmune mechanism may be
a factor in HIV related COPD. The mechanism for
autoimmunity is thought to be as a result of release of
naïve T cells 6 months after ART initiation.56 These
autoreactive cells are likely to be activated in the
setting of infection or ART. T regulator cell production
is impaired during ART, which might lead to decreased
ability to suppress autoimmunity.
HIV AND AGEING IN COPD
While effective ART has enabled people living with HIV
to live longer and has led to a decrease in the likelihood
of AIDS-defining illnesses among people ageing with
HIV, HIV-associated non-AIDS conditions are more
common in individuals with chronic HIV infection.
These conditions include cardiovascular disease, lung
disease (COPD), certain cancers, neurocognitive disea-
ses and infections such as hepatitis C. The longer life
expectancy has led to an increased risk of age related
illness attributed both to natural ageing and acce-
lerated cellular senescence caused by HIV. Data
directly linking immune activation and senescence
with HIV-associated COPD is limited currently, but
indirect links from studies of ageing and inflammation
in COPD in the HIV-uninfected population support
the association between ageing and HIV-associated
COPD.57 The hypothesis that HIV-associated COPD
occurs as a consequence of accelerated cellular ageing
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is also supported by the fact that inflammatory dys-
function, a hallmark of HIV-associated senescence,
plays a central role in the pathogenesis of COPD.58
Immune-mediated inflammatory pulmonary cell da-
mage and resultant accelerated alveolar epithelial cell
senescence may contribute to HIV COPD. Liu et al.
showed that HIV-associated COPD may be as a result
of accelerated ageing in this population and that
accelerated cellular senescence is associated with the
increased risk of COPD59
DISCUSSION
The association of COPD with HIV is becoming increa-
singly obvious as epidemiologic evidence continues to
accumulate. The challenge in this respect is the
application of medical science to study COPD in
regions where the burden of HIV is the greatest but
are resource limited.
The greatest burden of HIV is in Africa and Asia, which
are resource limited regions. The majority of people with
HIV have a low socio-economic status which is a risk
factor for acquisition and progression of HIV. Cigarette
smoking is increasing in these regions. HIV is a risk factor
for pulmonary TB and other pulmonary infections.
People living in resource limited regions are also exposed
to industrial and environmental pollution as a result of
uncontrolled industrialisation. These regions also bear
a disproportionate burden of TB and other pulmonary
infections that contribute to or cause COPD. Smoking
is an independent risk factor for TB and pneumonia.
TB and other infections accelerate the progression of
HIV. The widespread implementation of ART means that
survival with HIV is prolonged. This increases the
exposure to smoking and other occupational and
environmental pollutants. Silica dust exposure in the
mining industry is associated with COPD. Silicosis
increases the risk of developing TB. Using South Africa
as a case study, HIV and TB are very common among
gold miners as is silica dust exposure and silicosis. The
migrant labour practice in the mines results in large
numbers of ex-miners returning to their homes carrying
the burden of HIV, TB, silica dust exposure and smoking.
All these conspire to increase the burden of COPD.
The natural history of COPD in people with HIV is
unclear and complex because of the interaction of
multiple risk factors. Whether the treatment of COPD
in these people is the same as with smoking related
COPD needs to be determined in clinical trials that
include these patients. Notably most, if not all, current
COPD treatment trials exclude HIV co-infection by
design. As the burden of people with HIV and COPD
continues to increase due to longer survival, it will be
necessary to understand the nuances required to treat
these patients. COPD treatment trials should include
HIV infected people and permit subset analyses.
The thrust of the public health approach must be
preventive in nature. Efforts to reduce the spread of
HIV, control and prevent TB, increase smoking cessa-
tion, reduce occupational and environmental pollu-
tion and exposure to burning of biomass fuel must be
strengthened through global programmes.13
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6 and COPD: a conspiracy of risks
HIV
Research into the unique pathophysiology of HIV
associated COPD is necessary, especially to unders-
tand the inflammatory milieu in the lung with and
without ART.
The Authors
U.G.L. is a pulmonologist in private practice, research professor and is
the principal investigator of the US National Institutes of Health Adult
AIDS Clinical Trials Group Clinical Research Site in Durban. His
research interests include HIV, TB and obstructive lung diseases.
S.P. is an HIV clinician, researcher and primary care practitioner
affiliated with the Enhancing Care Foundation, an institute of Durban
University of Technology. He is an investigator in various therapeutic
clinical trials, and his research interests include HIV, TB and behaviour
change. R.M. is an HIV clinician, researcher and principal investigator
of clinical trials in HIV and TB, mentor and teacher affiliated with the
Enhancing Care Foundation, an institute of Durban University of
Technology. She has strong research interests in HIV and TB and its
complications. S.A.-G. is a Pulmonologist in Private practice and the
recent past president of the SA Thoracic Society. He is the Chair of
the South African Thoracic Society COPD Guideline committee.
A.A. is a pulmonologist in private practice. His research interest
includes multi-drug resistant Tuberculosis and Sarcoidosis. He is
principal investigator in several pharmaceutical company sponsored
COPD studies.
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