Immune Reconstitution and ‘‘Unmasking’’ of
Tuberculosis during Antiretroviral Therapy
Stephen D. Lawn1,2, Robert J. Wilkinson3,4,5, Marc C. I. Lipman6, and Robin Wood1
1The Desmond Tutu HIV Centre, Institute for Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town,
Cape Town, South Africa;2Clinical Research Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical
Medicine, London, United Kingdom;3Mycobacterial Immunology, Institute of Infectious Disease and Molecular Medicine, and Department
of Medicine, University of Cape Town, Cape Town, South Africa;4Division of Medicine, Imperial College London, London, United Kingdom;
5National Institute for Medical Research, London, United Kingdom; and6Department of HIV Medicine, Royal Free Hospital, London,
Tuberculosis (TB) is the most common opportunistic disease in HIV-
infected patients during the initial months of antiretroviral therapy
(ART) and presents a great challenge to ART programs in resource-
limited settings. The mechanisms underlying development of TB in
this period are complex. Some cases may represent progression of
undiagnosed subclinical disease present before starting ART, em-
phasizing the importance of careful screening strategies for TB. It
has beensuggestedthat progression in suchcasesis due toimmune
reconstitution disease—a phenomenon in which dysregulated res-
toration of pathogen-specific immune responses triggers the pre-
sentation of subclinical disease. However, whereas some cases have
existing case definitions for IRD, many others do not. Moreover,
since ART-induced immune recovery is a time-dependent process,
active TB may develop as a consequence of persisting immunodefi-
a spectrum of complex interactions between mycobacterial burden
range of effects of ART includes (1) shortening of the time for sub-
clinical TB to become symptomatic (a phenomenon often referred to
as ‘‘unmasking’’), (2) increased rapidity of initial onset of TB symp-
toms, and (3) heightened intensity of clinical manifestations. We
to all cases of TB presenting during ART and that ‘‘immune reconsti-
tution disease’’ be used to refer to the subset of ART-associated TB
overtly inflammatory disease.
Keywords: HIV; tuberculosis; antiretroviral; immune reconstitution;
Since the mid-1990s, availability of antiretroviral therapy (ART)
has transformed the prognosis of HIV-infected people living in
high-income countries and more recently in resource-limited set-
tings (1, 2). Through suppression of HIV replication, ART permits
both quantitative and functional reconstitution of the immune
system (3, 4), thereby reducing the risk of new opportunistic
infections and neoplasia (1, 5). However, an appreciable (albeit
diminished) risk of opportunistic infection persists during ART,
especially during the first few months of treatment. Tuberculosis
(TB) is the most frequent of these both in high-income and
resource-limited settings (6–15).
Although heightened clinical vigilance may, in part, account
for increased ascertainment of cases of TB during the initial
months of ART, several different mechanisms may also underlie
the temporal distribution of cases. ART-induced immune recov-
ery occurs gradually over time and so active TB may develop in
some patients as a consequence of persisting immunodeficiency.
Conversely, restoration of pathogen-specific immune responses
during treatment may cause subclinical TB to manifest or be
‘‘unmasked’’ (16–19). Of these latter cases, there is debate as to
whether some or all of these should be termed ‘‘immune recon-
stitution disease’’ (IRD); clarity on this issue is needed.
The burden of TB during early ART is particularly great in
resource-limited settings where this presents a major challenge
in treatment programs (9). Management of these two diseases
requires concurrent use of two multidrug regimens, with associ-
ated high pill burden, overlapping toxicity, and pharmacokinetic
interactions (20). Furthermore, patients with incident TB during
ART have increased mortality risk and may be a source of TB
transmissionwithin ART clinics(9,21).Understandingtheunder-
lying mechanisms will facilitate development of preventive and
therapeutic strategies. In this article, we consider how ART-
induced immune recovery is likely to mediate a range of effects
on both the timing and manifestations of active TB.
BURDEN OF TB DURING EARLY
A number of reports have described the incidence of TB in
patients receiving ART in high-income countries (12–15). The
largest of these is a study of European and North American
cohorts that included over 17,000 patients with a median baseline
CD4 cell count of 280 cells/ml (12). The prevalence of TB at base-
line was not known but the incidence rate was 1.3 cases per 100
person-years during the first 3 months of ART (12). Beyond this
time point, the risk of TB decreased sharply (Figure 1A).
As might be expected, incidence rates of TB are substan-
tially higher in ART cohorts in sub-Saharan Africa and other
resource-limited settings (7, 9–11, 22). For example, in a com-
munity-based ART cohort in South Africa with a median base-
line CD4 cell count of 96 cells/ml, prevalent TB (disease either
newly diagnosed or in patients already receiving treatment) was
reported among 25% of all patients at baseline (9). Despite the
(Received in original form September 5, 2007; accepted in final form January 16, 2008)
S.D.L. and R.J.W. are funded by the Wellcome Trust, London, UK, with grant
numbers 074641 and 072070, respectively. R.J.W. is funded in part by the
National Institutes of Health through a CIPRA grant (1 U19AI53217-01) and an
RO1 grant (A1058736-01A1).
Correspondence and requests for reprints should be addressed to Stephen D.
Lawn, M.D., Desmond Tutu HIV Centre, Institute of Infectious Disease and
Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio
Road, Observatory 7925, Cape Town, South Africa. E-mail: email@example.com
Am J Respir Crit Care Med
Originally Published in Press as DOI: 10.1164/rccm.200709-1311PP on January 17, 2008
Internet address: www.atsjournals.org
Vol 177. pp 680–685, 2008
high yield of prevalent TB detected during pre-ART screening
of all patients with suggestive symptoms, the rate of incident TB
in the first 3 months of ART was nevertheless extremely high at
23 cases per 100 person-years (Figure 1B). All cases had new
onset of symptoms after initiation of ART and therefore rep-
resented true incident disease. The risk of TB decreased steeply
during the first year of ART (Figure 1B) and was strongly asso-
ciated with improving immune status (9).
ROLE OF IMMUNODEFICIENCY
Patients accessing ART programs in resource-limited settings
typically have advanced immunodeficiency (2) and therefore
have very high TB incidence rates just before commencing
ART. An exceptionally high rate in excess of 50 cases per 100
person-years has been reported in African patients with World
Health Organization clinical stages 3 and 4 disease in the pre-
ART era, for example (23). In cohorts in which incidence rates
are so high, active but ‘‘subclinical’’ TB is likely to be present in
a proportion of patients at any given point in time. This could
either progress to symptomatic disease or remain undiagnosed
until death of the patient.
Post mortem studies of patients who died with HIV/AIDS
support the supposition that rates of subclinical TB are high in
Africans with advanced HIV infection; occult disseminated TB
has been detected in up 54% of cadavers (24, 25). Furthermore,
in studies in which HIV-infected patients in southern Africa were
actively screened for TB, high rates of culture-proven pulmonary
disease have been detected despite the absence of suggestive
symptoms (26–29). In the absence of a standard definition for
subclinical TB, the proportions reported by such studies will
therefore vary according to the criteria used. However, the fact
that the World Health Organization’s DOTS (directly observed
tigation of symptomatic patients is problematic and most sub-
clinical disease is likely to remain undetected pre-ART.
The limited sensitivity of TB diagnostic tests when applied to
patients with advanced immunodeficiency further compounds
poor TB case-finding in patients preparing to start ART. Sputum
smear microscopy, for example, which is the mainstay of TB di-
agnosis in much of the developing world, typically detects less
than 50% of active pulmonary disease in those with HIV in-
fection (9, 27, 30). Thus, a proportion of the TB presenting during
early ART may simply reflect failure of diagnosis of suspected
cases before treatment initiation. This burden will vary between
settings according to the intensity of screening and diagnostic
We suggest that subclinical TB among patients entering
ART programs provides much of the reservoir of infection that
fuels the high rates of symptomatic TB presenting during early
ART. Because ART-induced immune recovery is time depen-
dent, some of these cases may progress to symptomatic disease
during early ART in the context of persisting immunodeficiency.
In addition, rates of latent Mycobacterium tuberculosis infec-
tion and new exogenous infection are also very high in high-
TB-prevalence settings (31, 32); these may also progress and
contribute to the burden of active disease during early ART.
ROLE OF IRD
Having discussed the role of immunodeficiency, we now con-
sider IRD as a further important potential mechanism in the
presentation of TB (33–35). IRD (also known as immune recon-
stitution inflammatory syndrome or IRIS) is believed to be
caused by dysregulated recovery of pathogen-specific immune
responses during the initial months of ART. This leads to de-
velopment of unusual and overtly inflammatory disease, most
commonly in association with chronic viral, mycobacterial, and
invasive fungal infections (33–36).
TB-associated IRD presents in two principal ways. The most
common form occurs in patients with TB receiving effective
treatment who subsequently start ART; ART-induced immune
recovery results in the deterioration of the clinical manifesta-
tions of TB. This has been reported to occur in 8 to 43% of
patients with TB starting ART (35, 37–42). In the context of this
review, however, the second form of TB IRD is the more
relevant. Here, recovery of host immune responses triggers the
clinical presentation or ‘‘unmasking’’ of previously subclinical
TB during the early months of ART (33–35). It seems likely that
these two types of IRD may be related phenomena, but
immunologic studies to support this assertion are lacking.
Reports of TB IRD causing presentation of TB after ART
initiation are relatively few (16, 18, 19, 43, 44), the clearest
example being that reported by Goldsack and colleagues (19).
In this report, a 41-year-old African with advanced HIV in
London commenced ART. Two weeks later, he presented again
with rapid-onset fever, breathlessness, and hypoxia. Although
his chest radiograph was normal before treatment, a repeat ra-
diograph revealed florid miliary shadowing that was microbio-
logically proven to be TB. The onset of this complication was
temporally associated with a rapid immunologic and virologic
response to ART. The patient developed adult respiratory dis-
tress syndrome, requiring mechanical ventilatory support, but
he subsequently had a good response to anti-TB drugs and ad-
junctive corticosteroid therapy. An appropriate diagnosis of TB
during first 3 months of antiretroviral treatment (ART) and the sub-
sequent rapid decrease. Data are from (A) cohorts in low-TB-burden
countries in Europe and North America (data are from Reference 12)
and (B) a community-based ART program in Cape Town, South Africa,
where the burden of TB is very high (data are from Reference 9). Power
trend lines are shown. PY 5 person-years.
Graphs showing the high incidence of tuberculosis (TB)
Pulmonary Perspective 681
IRD was made, which is entirely consistent with similar cases
we have seen in South Africa.
Breen and colleagues in London, United Kingdom, described
a series of 19 cases of incident TB during ART and hypothesized
that the presentation of 13 of these cases may have been attrib-
utable to IRD (16). The rationale for this was largely based on
the temporal distribution of cases; 13 early-onset cases were
clustered within the first 4 months of ART and many of these had
a marked inflammatory response and systemic illness. Also, a
paradoxical reaction after initiation of anti-TB therapy was ob-
served in eight (62%) of the early cases compared with none of
the late-onset group (16).
In agreement with the report by Breen and colleagues,
workers in Uganda speculated that IRD was also the cause of
the large number of new cases of TB diagnosed during ART in
their setting (18). In a further report from the same country, all
cases of incident TB during the first year of ART were de-
scribed by the authors as being due to IRD (45). Park and
coworkers reported from South Korea that 82% of new TB
events occurring during the first year of ART (either new TB
cases or paradoxical reactions at a new disease site) were
attributable to IRD (17).
Evaluation of the role of IRD among cases of incident TB
during ART is hindered by the lack of a diagnostic test or
a clinical case definition specific to this condition. Importantly,
however, the existing literature indicates that, for a diagnosis of
IRD to be made, either the clinical manifestations and/or the
clinical course of disease should be atypical and be consistent
with an exaggerated, overtly inflammatory host response (34, 35,
46). Our own clinical experience gained during several studies of
TB during ART in South Africa (7, 9, 42), however, is that most
cases of TB diagnosed in the initial months of ART have typical
clinical presentations. Only a subset of such cases present with
unusual, overtly inflammatory manifestations that would be con-
sistent with a clear diagnosis of IRD. Moreover, in high-TB-
burden settings, it cannot be reasoned that the timing of onset of
TB during the first months of ART is particularly unusual. Thus,
in the context of the existing literature on IRD, it would appear
appropriate to use the term IRD to refer to some but not all cases
of incident TB during the initial months of ART.
HYPOTHESIS: A SPECTRUM OF EFFECTS OF IMMUNE
RECOVERY ON TB PRESENTATION
Thus far, we have considered contrasting reasons why TB may
present during early ART, with TB developing in the context of
persisting immunodeficiency or TB presenting as TB IRD. How-
ever, we suggest that these represent opposing ends of a spec-
trum of important effects of ART-induced immune recovery on
Because immunopathologic host responses to M. tuberculosis
are central to the clinical presentation of TB, we suggest that
development of symptoms at a given anatomic site is a function
of two key parameters: the mycobacterial antigen burden and
the intensity and quality of the associated host inflammatory
response. It is the interrelationship between these that is likely
to determine the threshold for symptom onset and to affect the
timing and severity of cases of TB presenting during early ART.
The supposition that high mycobacterial load is a risk factor
for TB IRD is strongly suggested by two observations: first, the
risk of IRD is greater the earlier ART is started during anti-TB
therapy when the residual mycobacterial burden is high; second,
the risk of TB IRD is increased in those with disseminated TB
(35, 38, 42). Considerable improvements in immune function
occur during the initial weeks of ART in most ART-naive
patients living in resource-limited settings, even in those with
the lowest baseline CD4 cell counts (47–49). Thus, the potential
for cases of TB presenting in this period to be modified by
changes in immune function is substantial. We suggest that im-
mune recovery has three principal effects on the progression of
subclinical TB to symptomatic disease, namely the timing of
onset, the rapidity of initial symptom onset, and the overall in-
tensity of clinical manifestations.
Timing of Onset
In an HIV-infected patient with a certain level of immune func-
tion, symptoms of TB are likely to develop at a given anatomic
site once the mycobacterial burden that is sufficient to trigger
host inflammatory responses has been reached (Figure 2A). If
ART is initiated, however, TB-specific immune function in-
creases rapidly (49, 50), and this would have the effect of rapidly
lowering the threshold for symptom development (Figure 2B).
This process may be augmented by immune-mediated liberation
of mycobacterial antigen, further enhancing immune responses.
In patients with subclinical TB, this would cause TB to manifest
much sooner than would otherwise have occurred in the absence
of ART (Figure 2B). In effect, the initiation of ART may serve
as a therapeutic challenge that unmasks subclinical disease,
triggering the presentation of TB. This accelerated progression
Figure 2. (A) A hypothetical graph showing the rising burden of Myco-
bacterium tuberculosis over time at a given anatomic site in an HIV-infected
patient with advanced immunodeficiency (shown as a linear rise over
time for simplicity). Symptom onset occurs when the mycobacterial
load rises to a level at which the host inflammatory responses are trig-
gered (symptom threshold). With poor immune function, the symp-
tom threshold is reached at time t1. (B) If the patient were to have
started antiretroviral therapy (ART), tuberculosis-specific immune func-
tion would increase rapidly and the threshold for development of symp-
toms would correspondingly decrease. As a result, symptoms would
develop much earlier soon after the initiation of ART (time t2).
682 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINEVOL 1772008
to symptomatic TB would result in the temporal clustering of
cases in the initial 3 months of ART as observed in Figure 1 and
in the report by Breen and colleagues (16).
Rapidity of Onset
In patients with advanced immunodeficiency, TB often has a
fairly insidious onset. In contrast, however, our clinical impres-
sion is that, in cases of TB presenting during the initial weeks of
ART, the initial onset of symptoms is often unusually rapid.
This is consistent with the speed with which antimycobacterial
immune responses recover during early ART (49, 50).
Intensity of Clinical Manifestations
When immune recovery causes unmasking of subclinical TB,
the severity of clinical manifestations at a given anatomic site is
likely to depend on the interrelationship between two main
variables: the mycobacterial antigen load and the rate, intensity,
and quality of immune recovery (Figure 3). In those in whom
immune function remains very poor, TB is likely to remain
subclinical despite an increasing mycobacterial load. Those
patients with an intermediate rate of immune recovery would
tend to develop clinical disease with a relatively ‘‘normal’’ pre-
sentation. In contrast, we propose that patients with dysregu-
lated immune recovery are the ones most likely to develop
unusual and severe manifestations that characterize IRD. This
would be most pronounced in those with a high mycobacterial
load (Figure 3). Within this model, therefore, only a proportion
of patients in whom ART causes the unmasking of TB in the
initial months of ART would fulfill existing case definitions for
IRD. With a disease that is as heterogeneous in its clinical pre-
sentation as TB, it will clearly be difficult to develop a robust
case definition for these cases.
CLINICAL AND PROGRAMMATIC IMPLICATIONS
The high early burden of TB during ART highlights the funda-
mental problem of how to efficiently screen for TB among
patients preparing for ART. The less adequate the pre-ART
screening processes, the greater the burden of TB is likely to be
after starting treatment. Optimal screening strategies need to be
defined; it is possible that all patients entering ART programs in
resource-limited settings should ideally undergo culture-based
screening for TB regardless of the presence or absence of symp-
toms. The major need to upgrade laboratory facilities and ex-
pand availability of culture-based diagnosis in resource-limited
settings has been recognized and more sensitive tools for TB
diagnosis at the point of care are desperately needed (30).
Although screening for TB among patients with advanced
HIV-associated immunodeficiency is difficult, ART may para-
doxically serve as a useful diagnostic tool, serving to unmask
occult disease. Research is needed to determine the relative
merits of delaying initiation of ART to permit full culture-based
investigation for TB versus starting ART without delay if there
is no initial evidence of TB. Because few of the cases of un-
masking TB have increased clinical severity and yet delays in
ART initiation may be associated with high mortality risk in this
setting (51), we would not advocate a strategy of deferring ART
while waiting for TB culture results in all patients.
Many in the field agree that management of those with
moderate or severe TB-associated IRD should include cortico-
steroids (33–35). Pending the results of a randomized controlled
trial in South Africa, however, the only evidence for this comes
from case reports and expert opinion. In view of the seemingly
normal clinical presentations of the large majority of cases of
unmasking TB presenting in the initial months of ART, how-
ever, it seems likely that most patients who develop TB during
early ART are unlikely to require adjunctive immunomodula-
tory therapy. On the basis of the same premise, there may be
little merit in a strategy of using corticosteroids as prophylaxis
against unmasking TB in high-TB-burden settings. Potential
benefits, if any, may well be restricted to a small minority of
patients and could be outweighed by adverse events (52).
Finally, it has been speculated that the unmasking of TB
during the early months of ART may contribute to the overall
burden of TB in resource-limited countries where ART is being
rolled out (16). This is of course true and is an inevitable conse-
quence of hundreds of thousands of lives being saved by ex-
panding access to ART. However, the longer term burden of
TB during ART (rather than that occurring in the initial months
of treatment) is much more important with regard to TB control
at the population level (9, 49, 53).
CONCLUSIONS AND SUGGESTED TERMINOLOGY
Using data and clinical experience from both low- and high-TB/
HIV-burden countries, we propose that a spectrum of mecha-
nisms underlies the development of TB during the first 3 months
of ART. Much of this disease is likely to represent progression
of subclinical TB that was present before ART initiation, either
due to persisting immunodeficiency or due to unmasking during
ART-induced immune recovery. The spectrum of effects of im-
mune recovery on TB presentations in this period may include
shortening of the time to development of symptoms (unmasking
TB), increasing the rapidity of the initial onset of symptoms
of TB, and increasing the intensity of clinical manifestations.
These effects are likely to depend on the antigen load and the
rate and intensity of immune recovery. Much remains to be
learned from studies of the immunologic mechanisms underly-
ing these phenomena.
Because it is presently not possible to clinically distinguish
the underlying disease mechanisms, we suggest that cases of TB
presenting during the initial months of immune recovery might
collectively be referred to as ‘‘ART-associated TB.’’ To refer to
Figure 3. Progression of subclinical disease to symptomatic tubercu-
losis (TB) during early antiretroviral therapy (ART). This hypothetical
conceptual diagram shows the interrelationship between Mycobacte-
rium tuberculosis antigen load, rate, and intensity of immune recovery
during early ART and the resulting clinical presentation of TB (plot area)
in patients with subclinical TB at the time of ART initiation. Most cases
of incident TB present with relatively ‘‘normal’’ clinical features, and TB
immune reconstitution disease (TB IRD) forms only a subset of incident
TB cases. TB IRD is most likely in patients with high antigen burden and
dysregulated immune recovery, leading to development of exagger-
ated and overtly inflammatory manifestations of TB.
the phenomenon whereby immune recovery triggers the presen-
tation of TB, we suggest the term ‘‘unmasking’’ disease be used.
Finally, in agreement with the existing literature, we suggest
that only the subset of patients with exaggerated and overtly
inflammatory manifestations of TB should be referred to as
IRD. To enable case definitions for unmasking TB and TB IRD
to be derived, further immunologic and clinical studies are
needed to better characterize these phenomena.
Conflict of Interest Statement: None of the authors has a financial relationship
with a commercial entity that has an interest in the subject of this manuscript.
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