JAC

antiviral
Journal of Antimicrobial Chemotherapy (2006) 57, 167–170
doi:10.1093/jac/dki444
Advance Access publication 14 December 2005

Immune reconstitution inflammatory syndrome:

more answers, more questions

Samuel A. Shelburne1, Martin Montes1 and Richard J. Hamill1,2*

1
Department of Medicine, Section of Infectious Diseases, Baylor College of Medicine, 1 Baylor Plaza,
Houston, TX 77030, USA; 2Department of Medicine, Section of Infectious Diseases (111G),

Downloaded from https://academic.oup.com/jac/article/57/2/167/804639 by guest on 05 December 2021

Michael E. DeBakey Veterans Affairs Medical Center, 2002 Holcombe Boulevard,
Houston, TX 77030, USA

The institution of highly active antiretroviral therapy (HAART) in HIV-infected patients restores protective
immune responses against a wide variety of pathogens and dramatically decreases mortality. In a subset of
patients receiving HAART, immune reconstitution is associated with a pathological inflammatory response
leading to substantial short-term morbidity and even mortality. The past several years have seen marked
advances in our clinical understanding of the immune reconstitution inflammatory syndrome (IRIS), but
many questions remain. This article summarizes recent data on clinical risk factors for the development of
IRIS. A consistent finding from multiple groups is that IRIS develops in a substantial percentage of HIV-
infected patients who have an underlying opportunistic infection and receive HAART. As the use of HAART
stands to markedly increase over the next several years, optimal care of patients receiving HAART will need
to incorporate monitoring for and treating complications of IRIS.

Keywords: HIV, HAART, paradoxical reaction, restoration

Introduction Historical view of IRIS in HIV- and

non-HIV-infected patients
The development of highly active antiretroviral therapy (HAART)
has markedly improved the outlook for patients infected with HIV.1 While recognition of IRIS did not become widespread until after
While the receipt of HAART engenders protective immune the introduction of HAART in the mid-1990s, prior to this point
responses against a wide variety of pathogens, for some patients there was ample appreciation that improvement in immune func-
a profound, pathological inflammatory reaction ensues targeted at tion could result in pathological inflammation. The so-called para-
either subclinical or previously recognized microbes.2–4 The doxical responses were well described among non-HIV-infected
inflammatory response can result in a spectrum of presentations patients treated for Mycobacterium tuberculosis (MTB)
ranging from clinical worsening of a treated opportunistic infection infection.21 Clinical worsening in these patients following initi-
(OI), atypical appearance of an unrecognized OI to even autoim- ation of anti-MTB therapy had been attributed to a reversal of
mune disorders such as Graves’ disease.5–7 A multitude of names the immunosuppression that MTB infection induces and was
have been applied to these situations including immune restoration associated with conversion of MTB skin tests from negative to
disease and immune reconstitution inflammatory syndrome positive.21 Inflammatory reactions during treatment are also rou-
(IRIS).2–5 tine in patients infected with Mycobacterium leprae.22 Finally,
Most of the original descriptions of IRIS consisted of case recovery of immune cells following bone marrow transplantation
reports or case series of small numbers of patients.8–10 More or chemotherapy has been clearly associated with clinical deteri-
recently, numerous groups have published cohort studies regarding oration for some patients.23
incidence, risk factors and timing of onset of IRIS among patients That such inflammatory responses might occur among HIV
receiving HAART.11–20 These investigations have provided the patients was first recognized when zidovudine monotherapy res-
required information for clinicians treating HIV-infected patients, ulted in atypical, localized presentations of Mycobacterium avium
but much uncertainty remains. Moreover, the dearth of patholo- intracellulare (MAI) infection.24 The introduction of HAART
gical data means that our understanding of the mechanisms of IRIS was quickly followed by numerous reports of patients in whom
remains at a rudimentary level. recovery of immune responses led to clinical worsening.8,10,25
.............................................................................................................................................................................................................................................................................................................................................................................................................................

*Corresponding author. Tel: +713-794-7835; Fax: +713-794-7045; E-mail: richard.hamill@med.va.gov

.............................................................................................................................................................................................................................................................................................................................................................................................................................

167
Published by Oxford University Press 2005
 Leading article
Initially, the induction of immunity engendered by HAART was
most clearly demonstrated in the case of hepatitis B virus infection
where serial antibody measurements could be correlated with
the clinical course.10 The measurement of pathogen-specific res-
ponses using delayed hypersensitivity testing or more advanced
T-cell techniques demonstrated that IRIS often occurred in the
setting of a measurable increase in immune response to an
underlying OI.20,26
Movement to define IRIS
A major obstacle to quality research on IRIS has been the difficulty
in establishing a definition. The problems in developing a clinically
useful definition included the wide variety of underlying OIs asso-
ciated with IRIS, the need to incorporate both unmasking of clin-
ically silent infections and worsening of previously diagnosed OIs,
and the difficulty in establishing that a new microbial process or
drug toxicity was not the cause of a particular patient’s clinical
presentation. Despite the complexities, several definitions of IRIS
have been utilized (Figure 1), each incorporating the general con-
cept that cases of IRIS need to have an inflammatory component
occurring in the setting of immune reconstitution that cannot be
explained by drug toxicity or a new OI.4,5,16,17 As noted below,
falling HIV-1 RNA levels rather than rising CD4+ cell counts may
be a more sensitive finding during IRIS, and therefore has assumed
a more prominent role in some definitions.4,13
Systematic investigation of IRIS
As a workable definition of IRIS has evolved, studies have moved
from case reports and case series to more systematic investigations
that have shed insight on incidence, risk factors and clinical
presentations.12–20 All of the studies have come from single cen-
tres, and the majority have chosen to focus on those patients
assumed to be at the highest risk for developing IRIS, i.e. patients
who initiate HAART following the diagnosis of a specific OI.
Therefore, the relative percentages of OIs that underlie IRIS in
all patients initiating HAART are not clear. In the three studies
that have examined a cohort of all patients receiving HAART, the
• HIV-positive
• Receiving HAART
o Decrease in HIV-1 RNA level from baseline
o Increase in CD4+ cells from baseline (may lag
HIV-1 RNA decrease)
• Clinical symptoms consistent with inflammatory process
• Clinical course not consistent with:
o Expected course of previously diagnosed OI
o Expected course of newly diagnosed OI
o Drug toxicity
Figure 1. Proposed criteria for the diagnosis of IRIS.5 IRIS, immune recon-
stitution inflammatory syndrome; HAART, highly active antiretroviral therapy;
OI, opportunistic infection.
168
majority of IRIS cases have been associated with underlying viral
infections (cytomegalovirus, herpes simplex virus, varicella-zoster
virus, and hepatitis C virus) and mycobacteria (either MAI or
M. tuberculosis).12,14,18 Given that the prevalence of specific
AIDS-related OIs is quite distinct based on locale, it is likely
that similar geographical variance will be observed in IRIS cases.
When systematic investigations of IRIS are examined, the per-
centage of patients developing IRIS and the timing of IRIS onset
following HAART initiation have been surprisingly similar. For
patients with an underlying OI, between 15 and 45% of patients
developed IRIS with the majority of cases presenting within
60 days of initiating antiretroviral therapy.13,15,16,19,20 When all
patients receiving HAART were analysed, between 15 and 25%
of patients developed IRIS, with most cases again occurring in the
first 3 months of therapy.12,14,18 The reproducibility of the results
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generated by the various investigations is demonstrated by the
remarkably similar finding that in two different studies the incid-
ence of developing IRIS in patients co-infected with MTB was 15.1
and 15.2 per 100-patient-years of HAART.13,15
While the timing of symptoms and percentages of patients has
been quite similar across multiple studies, establishing reprodu-
cible risk factors at baseline for the development of IRIS has been
more elusive. In two studies where all patients initiating HAART
were examined, having a lower CD4+ T-lymphocyte count prior to
starting HAART was associated with subsequent development of
IRIS.12,14 Such an association makes sense in that lower CD4+
counts increase the likelihood of having dissemination of a microbe
with which a restored immune system can react following initiation
of antiretroviral therapy. Perhaps not surprisingly, when patients
who already had a documented OI were studied, baseline CD4+
counts were not predictive of developing IRIS, probably due to the
low starting values for all members of the cohort.13,15–17,19 The
predictive values of baseline HIV-1 RNA levels have also been
examined with one study finding an association and another finding
a trend (P = 0.07) towards higher HIV-1 RNA levels in patients
who developed IRIS after initiating HAART.13,16 Finally, multiple
studies have looked at whether the occurrence of IRIS is related to
the duration between initiating treatment for an underlying OI and
starting HAART. While four studies have found that initiating
HAART in closer proximity to starting therapy for an OI does
increase the risk of developing IRIS, other investigations have
not found such a relationship.13,15–17,19,20
In addition to baseline characteristics, investigators have also
focused on the relationship between response to therapy and the
development of IRIS. Given that the vast majority of adherent
patients respond to HAART in terms of rising CD4+ cell counts
and falling HIV-1 RNA levels, trying to discern differences in
response to therapy among patients who do or do not develop
IRIS depends heavily on sample size. For example, in one study
where a total of 47 patients were examined, the rise in CD4+ count
from baseline was 99 cells/mm3 among patients who developed
IRIS and 35 cells/mm3 for those who did not, but the difference
was not statistically significant (P = 0.07).16 In contrast, when
180 patients were studied a rise in CD4+ cells after 90 days of
therapy was statistically associated with the development of
IRIS.13 Interestingly, in this cohort the change in CD4+ cells
over the first 3 months of HAART was not associated with IRIS
suggesting that longer time periods of observation may be needed
to detect immunological changes associated with IRIS. Import-
antly, a rapid fall in the HIV-1 RNA level during the first 3 months
of therapy was highly associated with the development of IRIS.
 Leading article
This finding suggests that clinicians suspicious of IRIS shortly
after the initiation of HAART should be more attentive to the
change in HIV-1 RNA levels rather than CD4+ counts when
using response to therapy as a criterion for diagnosing IRIS.
Taken together, the data generated by many independent invest-
igators is beginning to clarify our clinical picture of IRIS. Patients
at highest risk for developing IRIS after starting HAART are those
with low baseline CD4+ counts or with an underlying OI, two
scenarios that are directly related. Most cases of IRIS can be expec-
ted to occur within the first few months of initiating therapy. A
brisk immune recovery, in terms of rising CD4+ counts, seems to be
associated with IRIS development, although the CD4+ rise may not
occur until well after a dramatic fall in HIV-1 RNA levels. Import-
antly, we still lack a definitive answer on whether initiating anti-
retroviral therapy in close proximity to starting treatment for an OI
increases the risk of subsequent development of IRIS. Also, all
IRIS treatments have been anecdotal in nature, which precludes any
recommendations about therapy. Finally, the aforementioned stud-
ies suffer from their retrospective nature. Ongoing prospective
studies may be able to clarify some of the outstanding issues.
Pathological basis of IRIS
To understand the immunopathogenesis of IRIS it will be crucial to
elucidate the intrinsic dynamics of immune cell recovery after
initiation of HAART. The numerical increase in circulatory
CD4+ T-cells has been well described, but much remains to be
learned about the characteristics, specificity and function of these
cells. Initial descriptions showed that activated memory cells
(CD4+CD45RO+) account for the early incremental phase of
CD4+ cell recovery following effective HAART.27 Recovery of
lost responses to specific antigens also occurs during this early
phase, probably because of cellular redistribution rather than a
de novo specific CD4+ cell proliferation since naive activated
CD4+ T cells (CD4+CD45RA+CD62L+) do not recover until
after several months of therapy. The nature and strength of this
antigen-specific immune response may be responsible for at least
the early-onset cases of IRIS.28
Whether IRIS is the result of a response to a high antigen burden,
an excessive response by the recovering immune system, exacer-
bated production of pro-inflammatory cytokines or a lack of
immune regulation due to inability to produce regulatory cytokines
remains to be determined.7 Disease susceptibility genes for specific
subsets of IRIS have been identified including TNFA-308*2 with
mycobacterial disease and HLA-B44 with herpesvirus-related
IRIS.29,30 In addition, a CD4+ T-cell subset known as T-regulatory
cells (CD4+CD25+FoxP3+) have an intrinsic ability to down-
regulate immune responses and may play a role in the pathogenesis
of IRIS.31 These T-regulatory cells are susceptible to HIV infec-
tion32 and their numbers are also decreased in AIDS.33 Studies on
T-regulatory cells in tuberculosis-related IRIS are in progress.
Conclusions
Clinicians treating patients with AIDS need to be aware that
HAART-engendered immune recovery may result in pathological
inflammation in a subset of patients. Vigilance needs to be espe-
cially high during the first several months of therapy when the
incidence of IRIS peaks, but cases continue to occur even after
1 or 2 years of therapy. Despite making large strides in the past
169
JAC
antiviral
several years on many aspects of IRIS, important questions remain.
Further systematic investigations, especially in the areas of patho-
genesis and treatment, are required to optimally care for IRIS
patients.
Acknowledgements
Support for this work was provided by a National Institutes of Health
Mentored Clinical Investigator Award (K12 RR17665) to S. A. S
and in part by the Department of Veterans Affairs.
Transparency declarations
None to declare.
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