Immune Reconstitution

Inflammatory Syndrome (IRIS)

Graeme Meintjes
GF Jooste Hospital
University of Cape Town
Wellcome Trust Fellow

Antiretrovirals result in viral suppression and

CD4 recovery and thereby improve immunity
Viral load response

CD4 response

NEJM 1999;341:1865

HAART
Viral suppression
CD4 rise
Restoration of pathogen-specific immunity

Regression or prevention of
opportunistic infections

Inflammatory reactions days to

months after starting HAART

IRIS
Clinical deterioration in the initial period of
immune recovery as a result of these
inflammatory reactions

Wide range of IRIS conditions described

Mycobacteria

Cryptococcus
Histoplasmosis
PCP
Dermatophytes
Candida
Aspergillus
Penicillium
Hepatitis B and C
HSV 1 and 2
HZV
CMV
JC virus
BK virus
Molluscum
Warts
Parvovirus B19
HIV dementia

Toxoplasmosis
Leishmaniasis
Microsporidia
Cryptosporidia

Helminths

Schistosoma
Strongyloides

Bacteria

Other skin conditions

Auto-immune and inflammatory conditions

Viruses

Protozoans

Fungi

TB
MAC
Leprosy
BCG
Other NTM

Bartonella
Acne and folliculitis
Guillain-Barre syndrome
Sarcoidosis
Graves
Peyronies
Rheumatological conditions (SLE, RA, Reiters)
Tattoo pigment and foreign body reactions
Cerebral vasculitis
TTP
LIP

Tumours

KS, lymphoma

Categories of IRIS
Antigen target
Untreated infection

Clinical manifestations
Unmasking IRIS
Inflammatory and atypical presentations

Treated infection

Paradoxical deterioration

Host antigen

Auto-immune conditions

Tumour

Kaposis sarcoma IRIS

Other

Tattoos, sarcoidosis

Unmasking IRIS
Atypical and inflammatory presentations of OIs

Cytomegalovirus uveitis
Mycobacterium avium complex
lymphadenitis

Prevent by diagnosing and treating active OIs

before commencing HAART

Paradoxical and unmasking

TB-IRIS

INSHI consensus TB-IRIS case definitions

Meintjes et al, Lancet Infect Dis 2008

Unmasking TB-IRIS
Subclinical or undiagnosed TB prior to ART
Patients then present few weeks after starting ART with
inflammatory and/or accelerated presentation of TB
Examples
Inflammatory node masses
Pulmonary TB that may mimic bacterial pneumonia
Acute onset
Respiratory failure and systemic inflammatory syndrome

Unmasking TB-IRIS case

Paradoxical TB-IRIS
Recurrent, new or worsening TB
symptoms, signs and/or radiological
findings
Incidence: 8-45%
Typically 1-4 weeks after ART initiation
Fever is the most common manifestation
Usually TB culture negative
Lawn 2005, Shelburne 2005, Breton 2004, Narita 1998, Michailidis 2005,
Ollala 2002, Breen 2004, Kumarasamy 2004

Respiratory distress and stridor due to nodal enlargement

and compression of left main bronchus

Recurrent TB symptoms, worsening of pulmonary infiltrate

and development of new pleural effusion
3 weeks after starting ART

Worsening pulmonary infiltrate and cavitation due to TB-IRIS

Abdominal manifestations

Abdominal symptoms
Granulomatous hepatitis
Splenic involvement
Peritonitis and ascites
Lymphadenitis
Cold abscesses

Splenic abscesses

Hepatic TB-IRIS

RUQ pain, nausea and vomiting

Tender hepatomegaly
Cholestatic LFT derangement
+/- Jaundice
Usually other TB-IRIS
manifestations
Biopsy: granulomatous hepatitis
Can be difficult to differentiate from druginduced hepatitis

4 months treatment for drug-sensitive pericardial TB

Clinically improved, then started ART
3 weeks later presented with fever and hepatomegaly
LFT: Bil 52, CBil 31, Alk Phos 1081, GGT 1468, ALT 82, AST 88
CD4 rise from 64 to 221
Biopsy AFB- and TB culture Case courtesy of Mark Sonderup

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Massive psoas abscess

Severe TB-IRIS
Neurological manifestations
Respiratory failure
Compression of vital structure
Nodal compression of airway
Pericardial tamponade

Abdominal manifestations
with wasting syndrome

11

Neurological manifestations of
TB-IRIS
Meningitis
Tuberculomas
Myeloradiculopathy/Arachnoiditis
Potentially fatal. Neurological sequelae.

Tuberculoma CT

12

TB-IRIS
Risk factors
Shorter interval between TB treatment and
ART initiation
Disseminated TB
Low baseline CD4 and high baseline VL
Vigorous CD4/VL response to ART

Life threatening complications described

but mortality rare among cases in the
literature

Challenges in diagnosis
No diagnostic test; diagnosis of exclusion
Drug resistance

ALTERNATIVE DIAGNOSIS
Bacterial infections
Fungal infection
PCP
NTM
Lymphoma
Kaposis sarcoma

10% in Cape Town cohort of

TB-IRIS suspects had
MDR
or Rifampicin monoresistance

DRUG REACTION
Drug fever vs TB-IRIS fever
Hepatic involvement

13

PARADOXICAL TB-IRIS CLINICAL CASE DEFINITION

1)

2)

Antecedent requirements:
TB diagnosis fulfils WHO case definition
Initial response to TB treatment

Clinical criteria (at least 1 MAJOR or 2 MINOR), within 3 months of ART:

MAJOR - New or worsening nodes/abscesses, radiological features,
CNS TB or serositis

MINOR - New or worsening constitutional symptoms, respiratory

symptoms or abdominal pain

3)

Exclusion of alternative explanations

Corticosteroids for TB-IRIS

Anecdotal evidence of efficacy
Most guidelines recommend steroids for
life threatening TB-IRIS
Side effects
Herpes reactivations, Kaposis sarcoma

If patient has MDR, steroids hazardous

Most IRIS is self-limiting
Do the benefits of steroids outweigh the risks
in patients with mild and moderate TB-IRIS?

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Randomized Placebo-controlled Trial of

Prednisone for the TB-Immune Reconstitution
Inflammatory Syndrome

Graeme Meintjes1,2, Robert J Wilkinson1,2,3,4, Chelsea

Morroni1, Dominique Pepper1,2, Kevin Rebe1,2, Molebogeng
Rangaka1, Tollulah Oni1,3, Gary Maartens1
1. University of Cape Town, 2. GF Jooste Hospital, 3. Imperial College London, 4.
National Institute for Medical Research (UK)

Study Design
Hypothesis: 4 week course of prednisone would reduce
morbidity without excess adverse events
Study drug
Prednisone or placebo, randomized, double-blind
1.5mg/kg for 2 weeks then 0.75mg/kg for 2 weeks

Follow up assessments at 1, 2, 4, 8 and 12 weeks

Open-label prednisone at physician discretion if clinical
deterioration/relapse
Predefined primary endpoint*
Cumulative number of days hospitalized and outpatient
therapeutic procedures counted as 1 additional day
*Trial registered: http://www.controlled-trials.com/ISRCTN21322548/maartens

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Case Definition

Prior to ART

Microbiologic, histologic or very strong clinical evidence of TB

Initial improvement during TB treatment
Infecting strain of M. tuberculosis susceptible to rifampicin (if result available)
Receiving TB treatment when ART initiated

Within 3 months of initiating ART

New or recurrent TB-related symptoms

Presence of 1 following TB manifestations

Lymph node enlargement

Cold abscess
Serous effusion
Radiographic pulmonary infiltrate

No other opportunistic disease to explain clinical deterioration

Exclusion criteria

Age < 18 years

Pregnancy
Prior ART exposure
Kaposis sarcoma
Uncontrolled diabetes mellitus
Prior adjunctive corticosteroid therapy for this TB episode
Immediately life threatening TB-IRIS
Neurological involvement
Respiratory failure
Airway compression

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287 screened (June 2005 - December 2007)

Alternative diagnosis = 44
Did not fulfill case definition = 65
Exclusion criterion = 55
Unwilling/unable to consent = 13
110 enrolled

55 placebo arm

55 prednisone arm

2 died
6 defaulted (1 LTF)
3 discontinued study drug
6 rifampicin resistance

3 died
0 defaulted
1 discontinued study drug
4 rifampicin resistance

Baseline characteristics
Placebo
arm

Prednisone
arm

P-value

Age (median, years)

31.6

31.5

0.82

Gender

32F; 23M

38F; 17M

0.23

Previous TB

10

15

0.26

WHO stage 4

33

29

0.44

Duration TB treatment to ART (median, days)

43.5

66

0.02

Duration ART to IRIS (median, days)

10

14

0.21

CD4 prior to ART (median, cells/L)

48

56

0.15

CD4 at enrollment (median, cells/L)

109

138

0.07

Hospitalized at enrollment

19

14

0.30

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Primary endpoint
Cumulative number of days hospitalized and outpatient
therapeutic procedures (counted as 1 additional day), ITT analysis

Placebo
arm
N = 55

Prednisone P-value
arm
N = 55

Total days hospitalized

463

282

Total number outpatient procedures

28

24

Cumulative primary endpoint (median, IQR)

3 (0-9)

0 (0-3)

0.04

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Ultrasound score demonstrated no differences at week 2 or 4

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Adverse events
Placebo
arm

Prednisone
arm

P-value

Death on study

(4%)

(5%)

0.65

Corticosteroid side effects

while on study drug*

(5%)

(15%)

0.11

Infections while on study

drug

17 (31%)

27 (49%)

0.05

Severe infections**

0.40

(7%)

(4%)

* Included BP > 140/90, oedema, hyperglycaemia, hypomania,

acne, Cushingoid features, gastritis symptoms
** WHO stage 4 or invasive bacterial infection

Conclusions

Prednisone reduced days of hospitalization and outpatient procedures

combined
Consistent benefit, maximal in first 4 weeks, across a range of
secondary outcome measures
Symptom score
Karnofsky performance score
Radiology score
C-reactive protein
Benefit shown despite crossovers to open label prednisone, that may
have reduced observed effect size
No excess of steroid side effects or severe infections
For some patients, 4 weeks appeared to be too short
Exclusion of rifampicin resistance and alternative diagnoses is critical

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Suggested management
of paradoxical TB-IRIS
Counsel regarding risk
Continue ART and TB therapy
Consider steroids when alternative diagnosis
excluded and especially if:

Respiratory failure
Airway compression
TBM / tuberculomas
Severe reaction

Some recommend interrupting ART if lifethreatening

Cryptococcal IRIS

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Manifestations of Cryptocccal-IRIS
Most commonly manifests as culture-negative
relapse of meningitis symptoms with raised ICP.
In up to 30%
May present with
other features
eg. cryptococcomas,
encephalitis,
lymph node involvement

Cryptococcal Meningitis IRIS

Patient diagnosed with CM
Started on treatment and improves

Starts ART
Days to months later (median 28 days)

Develops meningitis symptoms again

Typically fungal culture negative

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MRI demonstrating hydrocephalus and marked periventricular, brainstem

and meningeal enhancement

Suggested management of CM
relapse on HAART

Exclude Fluconazole resistance if possible

Consider additional diagnosis (esp. TBM)
Serial lumbar punctures if ICP raised
Consider steroids
Continue ART

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Cutaneous manifestations of
IRIS
Important to differentiate from drug rash
HSV and HZV reactivations more common
after HAART started
Usually respond to standard therapy

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Rapid enlargement of warts upon commencing HAART

Molluscum contagiosum: increase in number of lesions on HAART

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Case
36 year old woman, failing first line ART
(VL = 350 000 and CD4 = 120)
Switched to AZT, ddI, Kaletra
Developed facial rash

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28

 Diagnosis?
Management?

Management
Doxycycline 100mg daily
Good response

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Acne IRIS
Immune response to Propionebactreium
acnes in hair follicles
Important to differentiate from drug
reaction
Papular pruritic eruption (PPE) may also
worsen with IRIS

Kaposis sarcoma IRIS

Incidence 10/150 (7%)
Manifestations
Enlargement of lesions
New lesions
Inflammation, oedema, pain

Visceral KS IRIS may be life threatening

Progression of pulmonary KS, airway
obstruction
Bower, J Clin Oncology, 2005

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Uganda

Martin, CROI 2009

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PATHOGENESIS OF IRIS
High antigen burden
Enhanced pathogen-specific immunity
HAART shifts balance from Th-2 to Th-1
cytokine response resulting in exacerbation of
pro-inflammatory responses
Lack of regulation of the recovering immune
system

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