1424 • CID 2009:49 (1 November) • HIV/AIDS
H I V / A I D S M A J O R A R T I C L E
Defining Immune Reconstitution Inflammatory
Syndrome: Evaluation of Expert Opinion
versus 2 Case Definitions in a South African Cohort
Lewis J. Haddow,1,2Philippa J. Easterbrook,1,2Anisa Mosam,3Nonhlanhla G. Khanyile,2Raveen Parboosing,4,5
Pravikrishnen Moodley,4,5and Mahomed-Yunus S. Moosa2
1Department of HIV and Genitourinary Medicine, King’s College London, London, United Kingdom; Departments of
Inkosi Albert Luthuli Central Hospital, Durban, South Africa
4Virology, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, and
5National Health Laboratory Services,
reconstitution inflammatory syndrome (IRIS). We measured the level of agreement of 2 published case definitions
(hereafter referred to as CD1 and CD2) with expert opinion in a prospective cohort of patients who were starting
antiretroviral therapy in South Africa.
A total of 498 adult patients were monitored for the first 6 months of antiretroviral therapy. All
new or worsening clinical events were reviewed by ?2 investigators and classified on the basis of expert opinion,
CD1, and CD2. Events were categorized according to whether they were paradoxical or unmasking in presentation.
We measured positive, negative, and chance-corrected agreement (k) with expert opinion for CD1 and CD2, and
reviewed areas of disagreement.
A total of 620 clinical events were recorded, of which, on the basis of expert opinion, 144 (23.2%)
were defined as probable IRIS and 112 (18.1%) were defined as possible IRIS. Of the 144 probable IRIS events,
93 (64.6%) were unmasking in presentation, 99 (68.8%) were associated with dermatological or orogenital disease,
and 45 (31.3%) were associated with tuberculosis or major opportunistic infections. Of the 620 clinical events
recorded, 41 (6.6%) were classified as IRIS on the basis of CD1, and 156 (25.2%) were classified as IRIS on the
basis of CD2. Positive agreement between CD1 and expert opinion was low for both unmasking (17.2%; k p
) and paradoxical events (37.3%; ), mainly because 1 major criterion requires IRIS to be atypical and0.24
k p 0.43
either an opportunistic infection or a tumor, although negative agreement was 198%. In contrast, CD2 had good
positive agreement (175% for most event types), with a k value of 0.75 for paradoxical and 0.62 for unmasking.
CD2 agreed well with expert opinion, with additional clinical events, such as arthropathy and
inflammatory dermatoses, being classified as IRIS and added to CD2. We propose revised case definitions for both
paradoxical and unmasking IRIS.
There is no validated case definition for human immunodeficiency virus–associated immune
Immune reconstitution inflammatory syndrome (IRIS,
or immune reconstitution disease) is a clinical entity
characterized by an excessive inflammatory response to
a preexisting antigen or pathogen and a paradoxical
deterioration in clinical status after initiation of anti-
retroviral therapy (ART) [1–4]. IRIS may present in 2
Received 16 March 2009; accepted 13 June 2009; electronically published 29
Reprints or correspondence Prof. Mahomed-Yunus S. Moosa, Dept. of Infectious
Diseases, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal,
Private Bag 7, Durban 4013, South Africa (firstname.lastname@example.org).
Clinical Infectious Diseases2009;49:1424–32
? 2009 by the Infectious Diseases Society of America. All rights reserved.
different ways: (1) the “paradoxical” worsening of
symptoms of a known disease, either at a new body
site or at the original body site, or (2) the “unmasking”
of an occult opportunistic infection, in which disease
that was not clinically apparent prior to ART manifests
during ART [5, 6]. The spectrum of clinical events is
diverse, with incidence ranging from 10% to 23% of
all individuals who started ART [6–11] and from 8%
to 43% of all individuals with an existing opportunistic
French et al  developed diagnostic criteria to aid
in the differentiation of IRIS from immunodeficiency
disease among patients presenting with an opportu-
nistic infection during ART. These diagnostic criteria
HIV/AIDS • CID 2009:49 (1 November) • 1425
Immune Reconstitution Inflammatory Syndrome
Assessment of Published Case Definitions 1 and 2 of
Case definition 1a
A. Atypical presentation of opportunistic infections or tumors
in patients responding to ART, including
a. Localized disease (eg, lymph nodes, liver, or spleen)
b. Exaggerated inflammatory reaction (eg, severe fever or
c. Atypical inflammatory response (eg, granulomas, suppu-
ration, necrosis, or perivascular lymphocytic inflammatory
d. Progression of organ dysfunction or enlargement of pre-
existing lesions after definite clinical improvement with
pathogen-specific therapy prior to ART and exclusion of
treatment toxicity and new diagnoses
B. Decrease in VL 11 log10copies/mL
1. Increased CD4 cell count
2. Increase in an immune response specific to the relevant
pathogen (eg, DTH response to mycobacterial antigens)
3. Spontaneous resolution of disease without specific antimi-
crobial therapy or tumor chemotherapy with continuation of
Case definition 2b
1. New onset or worsening symptoms of an infection or inflam-
matory condition after start of ART
2. Symptoms not explained by
a. Newly acquired infection
b. Predicted course of previously diagnosed infection
c. Adverse effects of drug therapy
3. Decrease in VL 11 log10copies/mL
aMust have both major criteria A and B, or both major criterion A and any
2 minor criteria.
bMust meet all of the criteria.
ART, antiretroviral therapy; DTH, delayed-type hypersensitivity; VL,
are based on 2 major and 3 minor criteria (Table 1). The first
infection or tumor in a patient responding to antiretroviral
drugs) is essential and must be accompanied by evidence of
either a therapeutic response to ART in the form of ?1 log
load or 2 minor criteria (an increase in the CD4 cell count, a
spontaneous resolution of symptoms, or a measurable patho-
gen-specific immune response). Robertson et al  used a
definition proposed by the AIDS Clinical Trials Group, which
was adapted from a definition proposed by Shelburne et al
. They evaluated 20 cases of IRIS associated with major
opportunistic infections, as defined by the AIDS Clinical Trials
Group, and found a high level of agreement with expert phy-
sicians . The definition comprises 3 essential criteria: (1)
new or worsening infectious or inflammatory symptoms, (2)
?1 log decrease in viral load, and (3) the absence of 3 other
explanations (newly acquiredinfection,predictedcourseofpre-
viously diagnosed infection, and adverse drug effects).
The objective of our prospective cohort study inSouthAfrica
was to measure the level of agreement of 2 published case
definitions of IRIS with expert opinion. We measured their
positive, negative, and chance-corrected agreement with con-
sensus expert opinion and reviewed areas of disagreement.
PATIENTS, MATERIALS, AND METHODS
1–infected patients who started ART during the period from
December 2006 through October 2007 was carried out at 2
clinics in Durban, South Africa. Patients were started on ART
according to South African national guidelines, which require
a nadir CD4 cell count of !200 cells/mL or a World Health
Organization stage 4 disease . All patients underwent pre-
ART assessment using a standardized questionnaire and phys-
ical examination. The data collected included details of recent
symptoms and past medical history. The baseline data thatwere
investigated were as follows: CD4 and CD8 cell counts, viral
load, full blood count, blood chemistry, results of hepatitis B
and C and syphilis serology testing, chest radiograph results,
and results of sputum examination for acid-fast bacilli (if
Ascertainment of clinical events.
were evaluated every 2–4 weeks for 24 weeks, with additional
visits if clinically indicated. Patients were screened at each re-
view for new or worsening symptoms, hospital admission,
death, and liver enzyme elevations (an alanine transaminase
level 12.5 times the upper limit of normal or an alkaline phos-
phatase level 11.75 times the upper limit of normal). Further
evaluations and management of patients were undertaken as
indicated and dictated by available resources. Rashes and skin
A prospective cohort study of adult HIV-
lesions were diagnosed with the support of a dermatologist
(A.M.) and clinical photography. At the time of each event,
CD4 and CD8 cell counts and viral load were measured.
Classification of clinical events by consensusexpertopinion.
All clinical events were evaluated by at least 2 investigators
(L.J.H., M.-Y.S.M, P.J.E., and/or A.M.) to determine a diagnosis
and to determine whether the event was due to IRIS, after
consideration of all clinical features, investigation findings, and
competing explanations. Events were assigned to 1 of 3 cate-
gories: a probable IRIS event indicated that IRIS was the most
likely of possible causes; a possible IRIS event indicated that
IRIS was plausible but that competing explanations were equal
or stronger in likelihood; and non-IRIS event indicated that
there was another diagnosis or that IRIS had been excluded.
Clinical events of probable IRIS and possible IRIS were cate-
gorized according to whether they were paradoxical or un-
masking in presentation.
1426 • CID 2009:49 (1 November) • HIV/AIDS
The following 11 factors were used to weight our decision
in support of an IRIS event or to exclude competing expla-
nations. These factors varied according to the nature of the
1. The underlying pathogen or antigen could exist in the host,
both at the time of starting ART and at onset of the clinical
event (eg, herpes simplex virus or Cryptococcus species); the
pathogen was unlikely to be a newly acquired infection (eg,
acute gastroenteritis or an upper respiratory tract infection).
2. The clinical course of illness was not consistent with the
expected natural history of a preexisting condition.
3. The onset of illness was within 3 months after initiation
4. The patient presented with an unusual or florid presentation.
5. There was a resolution of symptoms without a change in
ART or treatment for the underlying condition; this factor was
used to exclude cutaneous and hepatotoxic drug reactions.
6. The patient’s liver enzyme level was elevated, there was
evidence for a causative pathogen (eg, hepatitis B virus), and
no hepatotoxic drugs were used other than ART.
7. There was confirmation of the presence of a causative
pathogen or antigen.
8. There was no recent cessation of therapy for an ongoing
condition to account for relapse.
9. A drug-resistant infection was excluded as a diagnosis as
a result of drug-sensitivity testing.
10. A diagnosis of newly acquired infection was excluded on
the basis of history; for example, for a case of IRIS associated
with a genitourinary infection, a diagnosis of a new sexually
transmitted infection was excluded on the basis of a history of
sexual abstinence since starting ART.
11. There were similar published cases of IRIS reported in
the scientific literature.
Classification of clinical events by use of published case
Clinical events were further evaluated using the
case definition described by French et al (hereafter referred to
as CD1) and the case definition described by the AIDS Clinical
Trials Group definition (hereafter referred to as CD2) (Table
1) in a blinded fashion by the same investigators, and we as-
signed a classification of IRIS event or non-IRIS event under
each definition. In applying major criterion A of CD1, we
closely adhered to the 4 examples of “atypical presentation”
included in the original definition . Minor criterion 2b of
CD1 (ie, an increase in pathogen-specific immune response)
could not be evaluated in this setting. When considering cri-
terion 2 of CD2 (ie, symptoms not explained by predicted
course of previously diagnosed infection), a self-reported past
medical history was considered sufficient evidence for preex-
Assessment of agreement.
and Cohen’s k statistic for chance-corrected agreement were
determined on the basis of expert opinion, CD1, and CD2.
Possible IRIS and non-IRIS events were considered to be neg-
ative on the basis of expert opinion, for the purposes of cal-
culating agreement. The k value refers to the proportion of
potential agreement that was achieved beyond chance alone:
is considered poor agreement, 0.21–0.40 is consid-
k p 0–0.20
ered fair agreement, 0.41–0.60 is considered moderate agree-
ment, 0.61–0.80 is considered substantial or good agreement,
and 10.80 is considered excellent agreement . Levels of
agreement were calculated separately according to mode of
presentation (paradoxical or unmasking) and organ system
(eg, respiratory or dermatological).
Evaluation of impact of viral load and CD4 cell count on
diagnosis of IRIS.
During initial expert opinion assessment,
results of viral load and CD4 cell count were unavailable for
use in the classification process. We subsequently assessed how
often the results of viral load and CD4 cell count would have
affected the diagnosis based on expert opinion, and how often
viral load affected the diagnosis based on CD1 and CD2.
Approval was obtained from the Uni-
versity of KwaZulu-Natal Biomedical Research Ethics Com-
mittee (23 November 2006; reference E024/06), King’s College
Hospital Research Ethics Committee (15 June 2006), KwaZulu-
Natal Provincial Department of Health (epidemiology unit),
and the management teams of RK Khan and King Edward VIII
Of the 498 adult patients who participated, 375 (75.3%) were
female, with a median age of 35 years (interquartile range
[IQR], 30–41 years), a median CD4 cell count of 106 cells/mL
(IQR, 53–165 cells/mL), and a median viral load of 5.0 log10
copies/mL (IQR, 4.4–5.6 log10copies/mL), and 344 (69.1%)
had World Health Organization stage 3 or 4 disease at the start
of ART. Recent coinfections were common, including tuber-
culosis (102 [20.5%] of 498 patients received antituberculous
therapy at the time of starting ART), genital ulcer disease (154
patients [30.9%] in the past year), herpes zoster infection (126
patients [25.3%] in the past 5 years), chronic diarrhea of un-
known cause (104 patients [20.9%]), hepatitis B virus infection
(39 patients [7.8%] tested positive for hepatitis B surface an-
tigen), and Pneumocystis pneumonia, cryptococcosis, and Ka-
posi sarcoma (!2% of patients for each infection).
Of 498 patients, 25 (5.0%) died, and 21 (4.2%) were lost to
follow-up. During the 24-week follow-up period, there were
620 clinical events. On the basis of expert opinion, 144 clinical
HIV/AIDS • CID 2009:49 (1 November) • 1427
clinical events), and the level of agreement in classification betweencase
definitions 1 and 2 (CD1 and CD2, respectively) and expert opinion. Of
the 620 clinical events diagnosed as IRIS, 144 (23.2%) were diagnosed
on the basis of expert opinion, 41 (6.6%) were diagnosed on the basis
of CD1, and 156 (25.2%) were diagnosed on the basis of CD2. There
were 429 events (69.2%) that were classified as non-IRIS events on the
basis of all 3 assessment methods. Agreement statistics were calculated
using expert opinion as the reference. The k value is Cohen’s k statistic
for chance-corrected agreement.
Venn diagram showing the number of IRIS events (from 620
events (23.2%) were classified as probable IRIS events, and 112
clinical events (18.1%) were classified as possible IRIS events.
Onset of illness occurred within 3 months after start of ART
in 130 (90.3%) of 144 probable IRIS events. Using CD1, only
41 (6.6%) of 620 clinical events were classified as IRIS, and
using CD2, 156 (25.2%) of 620 clinical events were classified
as IRIS (Figure 1). Table 2 lists the diagnoses associated with
IRIS under all 3 case definitions. On the basis of expertopinion,
the most common diagnoses were itchy and/or pustular follic-
ulitis and papular pruritic eruption(39[27.1%]of144probable
IRIS events), tuberculosis (35 [24.3%]), genital ulcer disease
(14 [9.7%]), warts (11 [7.6%]), and herpes zoster infection (9
[6.3%]). Of the 144 probable IRIS events that were based on
expert opinion, 93 (64.6%) were unmasking in presentation,
and 51 (35.4%) were paradoxical in presentation.Thespectrum
of IRIS events based on CD1 and CD2 was similar, with notable
differences being that no cases of itchy folliculitis and/or pap-
ular pruritic eruption were captured as an IRIS event on the
basis CD1; of the 156 CD2-based IRIS events, 8 (5.1%) were
diagnosed as either monoarthropathy or polyarthropathy.
A total of 112 events were classified as possible IRIS using
expert opinion, because of an inflammatory response to a pre-
existing antigen, but other explanations were also plausible.
This situation usually arose when there was insufficient clinical
information to determine whether symptoms were unequivo-
cally worse (31 [27.6%] of 112 possible IRIS events),toconfirm
the underlying diagnosis (29 possible IRIS events [25.9%]), or
to exclude other causes (14 possibleIRISevents[12.5%]).There
were also 34 possible IRIS events (30.4%) for which no caus-
ative organism was identified (6 events associated with vagi-
nal discharge syndrome, 5 events associated with arthropa-
thy, 4 events associated with unexplained abdominal pain, and
4 events associated with fever and lymphadenopathy).
Agreement between expert opinion and existing case
The level of agreement between CD1 and expert
opinion was poor for nonviral mucocutaneous symptoms
( for both paradoxical and unmasking presentations),
k ! 0.10
fair to moderate for viral mucocutaneous disease (k p
) and unmasking presentations of opportunistic in-
fections and other systemic disease (
paradoxical opportunistic infections and/or systemic disease
( ; 75% positive agreement), which was mainly due to
k p 0.74
tuberculosis (positive agreement in 13 of 16 cases [81.3%])
(Table 3). Overall, agreement between expert opinion and CD1
was better for paradoxical than unmasking presentations of
IRIS (37.3% vs 17.2% positive agreement [
and 0.24, respectively).0.43
In contrast, expert opinion and CD2 agreed well for almost
all types of events, except for unmasking viral mucocutaneous
diseases ( ). Overall, positive agreement betweenexpert
k p 0.32
opinion and CD2 was similar for paradoxical (84.3%) and
), and good for
k p 0.43
];P ! .001
unmasking (75.3%) presentations, and k was higher for par-
adoxical (0.75 vs 0.62).
Disagreement between expert opinion and CD1.
events that were diagnosed as IRIS events on the basis of expert
opinion and as non-IRIS events on the basis of CD1, 106
(97.2%) did not meet major criterion A, because the events
were either not “atypical” or not “opportunistic infections or
tumors.” These disagreements commonly included itchy fol-
liculitis and/or papular pruritic eruption (39 events), tuber-
culosis (14 events), genital ulcer disease (11 events), shingles
(8 events), and warts (8 events). Six events were diagnosed as
IRIS on the basis of CD1 but only possible IRIS on the basis
of expert opinion, because the underlying diagnoses were un-
confirmed but were suspected to be tuberculosis (3 events),
tinea (2 events), or cryptococcosis (1 event).
Disagreement between expert opinion and CD2.
31 events that were diagnosed as IRIS events on the basis of
expert opinion and as non-IRIS events on the basis of CD2,
the most common reason for disagreement by CD2 was that
the symptoms could be diagnosed as newly acquired infection,
as warts (6 events), tuberculosis (6 events), genital ulcers (2
events), or stomatitis and/or tinea (2 events).
Forty-three events were diagnosed as non-IRIS events on
the basis of expert opinion and as IRIS events on the basis of
CD2. Of these 43 events, 34 (79.1%) were considered possi-
ble IRIS events, representing 30.4% of all possible IRIS events.
This group included diverse conditions, such as arthropathy (8
Table 2. Categorization of Types of Immune Reconstitution Inflammatory Syndrome (IRIS) Events
Clinical presentation, diagnosis
Consensus expert opiniona
(n p 41
(n p 156
n p 144( events)
n p 112( events)
No. (%) of events of opportunistic infection
or systemic disease (proven or suspected)
Hepatitis B virus infection
No. (%) of events of dermatological, oral, or
Genital ulcers and/or extragenital herpes
Genital and extragenital warts
Itchy, pustular folliculitis, and/or PPE
Seborrhoeic dermatitis and/or psoriasis
Tinea corporis or capitis
STI (proven pathogen)
Other dermatological diseased
Suspected STI syndrome
Parotid lymphoepithelial cysts
No. (%) of events of miscellaneous
99 (68.8) 62 (55.4)14 (34.1) 102 (65.4)
, and case definition 2 (CD2) from the AIDS Clinical Trials Group cited by Robertson et al . PPE, papular pruritic eruption; STD,
sexually transmitted disease; STI, sexually transmitted infection.
aIn addition, there were 364 non-IRIS events (according to expert opinion) caused by upper respiratory tract infection (40 events
[11.0%]), diarrheal illness (27 [7.4%]), deranged liver enzymes (19 [5.2%]), chronic lung disease (18 [4.9%]), headache (17 [4.7%]),
locomotor symptoms (17 [4.7%]), vaginal discharge (16 [4.4%]),peripheralneuropathy(14[3.8%]),gastrointestinalsymptoms(12[3.3%]),
lower respiratory tract infection (12 [3.3%]), genital ulcers (10 [2.7%]), trauma (6 [1.6%]), and miscellaneous causes: preexisting disease
(36 events [9.9%]), new infections (55 [15.1%]), new noninfectious disease (45 [12.4%]), and adverse effects of drugs (20 [5.5%]).
bIncluded cases of self-limiting fever, cough, night sweats, lymphadenopathy, liver enzyme elevation, oranemia,inwhichtuberculosis
and other organisms were sought but no underlying cause was identified.
cSweet’s syndrome is also known as febrile neutrophilic dermatosis.
dOther dermatological included nonspecific dermatitis (3 events), generalized pruritus (2 events),andurticaria (1event),allofunknown
IRIS events were categorized on the basis of consensus expert opinion, case definition 1 (CD1) proposed by French et al
HIV/AIDS • CID 2009:49 (1 November) • 1429
sification of Immune Reconstitution Inflammatory Syndrome (IRIS)
Negative, Positive, and Chance-Corrected Agreement (k) between Existing Case Definitions and Expert Opinion in Clas-
Mode of presentation,a
system and underlying etiology
No. of IRIS
on the basis of
Case definition 1
Case definition 2
Paradoxical or suspected paradoxical
Dermatological, oral or genital (viral etiology)
Dermatological, oral, or genital (nonviral)
TB, OI, systemic, or serious illness
All “paradoxical” events
Unmasking or suspected unmasking
Dermatological, oral, or genital (viral
Dermatological, oral, or genital (nonviral)
TB, OI, systemic, or serious illness
All “unmasking” events
aEvents were assigned to paradoxical (suspected worsening of known disease) or unmasking (suspected new disease) modes of presentation if they were
probable or possible IRIS events under any of the 3 assessment methods. Events that were non-IRIS events under all 3 methods were grouped according to
pre–antiretroviral therapy history; 45 (12.4%) of 364 non-IRIS events were included as both suspected paradoxical and unmasking IRIS events.
bExpert opinion was used as the reference.
OI, opportunistic infection; TB, tuberculosis.
events), dermatitis(7 events),folliculitisand/orpapularpruritic
eruption (4 events), unexplained lymphadenopathy and night
sweats (4 events), and perianal disease (3 events). The arthrop-
athy cases met the first criterion of “new onset or worsening
symptoms of an infection or inflammatory condition” on the
basis of clinical signs of arthritis or an elevated level of C-
Use of Measuring Viral Load and CD4 Cell Count
in Diagnosing IRIS
The viral load and CD4 cell count of a patient were measured
a median of 8 weeks after start of ART (IQR, 4–12 weeks).
Viral load results were available for 519 (83.7%) of 620 events,
and there was a ?1 log reduction in 494 (95.2%) of the 519
events. Diagnosis underexpertopinionwouldhavebeenaltered
because of virological failure in only 5 (3.5%) of 144 events
currently classified as probable IRIS. Eight additional events
(5.6%) of probable IRIS based on expert opinion occurred
without a recorded decrease in viral load: 3 had a !1 log re-
duction in viral load at the time of the event but had a viral
load of !50 copies/mL after 3 months; and 5 had no follow-
up viral-load measurement taken. CD4 cell counts were avail-
able in 595 (96.0%) of 620 events, of which 450 (75.6%) had
at least a 25% increase in CD4 cell count. A documented de-
crease or a !25% increase in CD4 cell count was detected in
32 (22.2%) of 144 IRIS events based on expert opinion.
Of 44 events fulfilling major criterion A of CD1 (Table 1),
40 also met major criterion B (?1 log decrease in viral load),
and 1 met the 2 minor criteria of an increase in CD4 cell count
and spontaneous resolution without change in therapy. There
were no events for which the measurementofpathogen-specific
immunity would have changed the classification. Of 171 events
that fulfilled the first 2 criteria of CD2, 15 (8.8%) were diag-
nosed as non-IRIS events under CD2 either because of a failure
to achieve a ?1 log decrease in viral load at the time of the
event or because of a missing viral load result.
We have evaluated 2 generic published case definitions forIRIS,
in a prospective cohort study of 498 patients who were starting
ART in South Africa. During a 6-month period, there were 620
clinical events, of which 144 (23.2%) were classified as IRIS on
the basis of the consensus expert opinion of our research team.
The first generic case definition of IRIS (ie, CD1)  per-
formed poorly, with a positive agreement of only 24% across
all events (although with a high negative agreement of 99%).
This was mainly due to the poor sensitivity of major criterion
A, which requires IRIS to be “atypical” and either an oppor-
tunistic infection or a tumor. As a result, this definition failed
to capture IRIS events with dermatological, oral, or genitou-
rinary pathology or events resulting from conditions not clas-
sically considered to be opportunistic infections. Because dis-
ease of mucocutaneous sites accounted for 69% of all IRIS
events diagnosed in our study, and for 51% of all IRIS events
in other cohorts [6–10], it is important that any definition of
IRIS is able to capture these types of events. In addition, a
number of clinical syndromes identified in this cohort are not
typically considered as part of the IRIS spectrum but were
supported by existing literature. These include arthropathy
, strongyloidiasis , oesophagitis [9, 29], stomatitis ,
and inflammatory dermatoses [31–34]. It is therefore impor-
1430 • CID 2009:49 (1 November) • HIV/AIDS
Inflammatory Syndrome (IRIS)
Proposed Diagnostic Criteria for Paradoxical and Unmasking Immune Reconstitution
1. Temporal relationship: ART initiation must precede clinical deterioration
2. One of the following:
a. Worsening of an infectious or inflammatory condition that was recognized and ongoing
at the time of ART initiation, following a clinical response to appropriate treatment
b. Deterioration with atypical or exaggerated clinical, histological, or radiologic findings in
terms of severity, character of inflammatory response, rapidity of onset, or localizationa
c. Recurrence of an episodic infectious or inflammatory condition, worse than episodes
within 1 year preceding ART in terms of frequency, severity, or response to therapy
Exclusion of other causes
Worsening not explained by
1. Expected clinical course of underlying condition, given current therapy and the suscepti-
bility profile of the organism
2. Drug toxicity
3. Other infection or inflammatory condition
4. Withdrawal of previously effective therapy
5. Failure of antiretroviral treatment: presumptive, based on either nonadherence or resis-
tance to ART, or confirmed, based on VL assay if available
1. Temporal relationship: ART initiation must precede clinical deterioration
2. New onset of symptoms of an infectious or inflammatory condition after initiation of ARTb
3. Consistent with the presence of preexisting causative pathogen or antigen at the time of
4. Either of the following:
a. Onset within 3 months after initiating ART
b. Atypical or exaggerated clinical, histological, or radiological findings in terms of severity,
character of inflammatory response, rapidity of onset, or localization
Exclusion of other causes
Event not explained by
1. Expected clinical course of another condition
2. Drug toxicity
3. Newly acquired infection, based on clinical history or other evidencec
4. Failure of antiretroviral treatment: presumptive, based on either nonadherence or resis-
tance to ART, or confirmed, based on VL assay if available
aThis criterion may also apply even in the presence of drug-resistant opportunistic infection.
bThe condition may have been asymptomatic prior to ART, or subclinical and undiagnosed after reasonable
cThis may be particularly difficult to exclude for some infections (eg, tuberculosis in high-prevalence settings).
Serological or other evidence of underlying pathogen prior to ART may be sought for infections such as hepatitis
B and C virus infection. In some settings, serological testing for herpes simplex virus, cryptococcosis, or other
organisms may be available.
ART, antiretroviral therapy; VL, viral load.
tant that any IRIS case definition be sufficiently flexible to cap-
ture potential new manifestations of IRIS. Also, subcriterion
d (“[p]rogression of organ dysfunction or enlargement of pre-
existing lesions after definite clinical improvement with path-
ogen-specific therapy”) applies only to paradoxical presenta-
tions and not to unmasking IRIS or infections that may have
an episodic course.
The AIDS Clinical Trials Group case definition (ie, CD2)
adopted by Robertson et al  performed well on both pos-
itive and negative agreement. Events that were notinagreement
with expert opinion but were in agreement with CD2 often
occurred in cases of uncertainty or inconsistency regarding the
underlying diagnosis or clinical course. The second criterion
of CD2 requires that symptoms not be explained by competing
causes. There is an inherent difficulty with any case definition
of IRIS in excluding other causes with certainty, and the ability
HIV/AIDS • CID 2009:49 (1 November) • 1431
to do so is influenced by the availability of clinical expertise
and the quality of diagnostic facilities, especially in resource-
A further shortcoming of CD2 is highlighted by the14 events
that were classified as unmasking IRIS events on the basis of
expert opinion but as non-IRIS events on the basis of CD2.
These events—which did not fulfill the criterion of not being
explained by newly acquired infection—were caused by warts,
tuberculosis, or genital ulcer disease. The justification for cat-
egorizing these events as IRIS under expert opinion came from
subjective factors, including a close temporal relationship be-
tween the start of ART and event onset, rapidity of onset, and
character of the presentation. A provisional definition for un-
masking IRIS as tuberculosis has been proposed; diagnos-
tic features include onset !3 months after start of ART and
“[h]eightened intensity of clinical manifestations” [5, p 521].
The presence of a viral load reduction of at least 1 log10is
a criterion for both existing case definitions, in keeping with
published studies reporting early virological responses on triple
ART: a mean viral load decrease of 1.5 log10copies/mL after 2
weeks of ART ; 30%–42% of patients with !500 copies/
mL after 4 weeks of therapy [36, 37]; and 80% of patients with
a 1 log10decrease by 8 weeks . In our cohort, assessment
of virological and immunological response would have affected
the decision made by expert opinion in only 5 (3.5%) of 144
IRIS events. Only 3 (6.8%) of 44 potential IRIS events under
CD1 and 15 (8.8%) of 171 potential IRIS events under CD2
were rejected on the basis of virological failure or missing viral
load results. We conclude that, although measurement of viral
load may be useful in detecting primary virological failure, it
is not a useful discriminator of IRIS events from non-IRIS
events for most individuals. In addition, we recommend cau-
tion in the use of CD4 cell count criteria for diagnosing IRIS.
Our cohort was an ideal cohort in which to evaluate the
performance of the IRIS case definitions. First, through careful
prospective monitoring, we were able ascertain a wide range
of post-ART clinical events, from mild disease and common
infections to hospitalization and death. Second, the character-
istics of the study population and the relatively limited diag-
nostic facilities can be generalized to other HIV treatment set-
tings in sub-Saharan Africa.
On the basis of these findings, we propose a revised case
definition for IRIS that incorporates elements of both CD1 and
CD2 (Table 4). We suggest separate definitions for unmasking
and paradoxical IRIS, grouped into 2–4 clinical criteria, and
4–5 criteria aimed at excluding competing causes. We propose
that fulfillment of all clinical criteria is essential. There should
ified, following a competent clinical assessment. A label of pos-
sible IRIS may be applied when competing diagnoses have not
been adequately excludedorwhenclinicalassessmentislimited.
Our proposed case definitions are intended to encapsulate
the IRIS events observed in this cohort study in a structured
manner. However, these definitions require evaluation in a
range of clinical and researchsettings,whichmayleadtofurther
refinements. It is likely that clinical case definitions will be
enhanced as data emerge regarding immunopathological cor-
relates of IRIS [38, 39].
We thank all study cohort participants and clinic staff at the ART rollout
sites in RK Khan and King Edward VIII Hospitals; Ntombizethu Sithole,
Queen Zulu, and Skhumbuzo Mzimela for data collection; Fowzia Ibrahim
for statistical advice; Thumbi Ndung’u, Shabashini Reddy, Karen Bishop,
Lorna Madurai, and Photini Kiepiela for laboratory support; and Jaysingh
Brijkumar, Ganasen Manikam Govender, Devilliers Zitha, and Kamalika
Singh for clinical management and logistical support.
British Society of Antimicrobial Chemotherapy
(GA745), Doris Duke Charitable Foundation (2006029), and Medical Re-
search Council UK (G0700530).
Potential conflicts of interest.
All authors: no conflicts.
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