Download IRIS - HAIVN

Immune Reconstitution
Inflammatory Syndrome
(IRIS)
HAIVN
Harvard Medical School AIDS
Initiative in Vietnam
1
Learning Objectives
By the end of this session, participants
should be able to:
 Define and differentiate between the
two forms of Immune Reconstitution
Inflammatory Syndrome (IRIS)
 Identify the etiological agents and
syndromes of IRIS
 Explain TB/IRIS interaction
 Explain how to manage IRIS
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IRIS - Definition (1)


IRIS = Immune Reconstitution
Inflammatory Syndrome
IRIS: occurrence of symptoms of a
new or recurrent OI:
• after the initiation or change of ARV
therapy
• with evidence for immune restoration
such as increased CD4 or decreased
viral load
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IRIS - Definition (2)

A pattern of diseases presenting
soon after the initiation of ARV:
• Typically, in the first 2-12 weeks
• Less common after many months of ART

Results from rapid restoration of
pathogen specific immune responses
to opportunistic infections
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Two Forms of IRIS
Paradoxical Reaction
 IRIS in patients
already receiving
therapy for an OI at
the time at which ART
is initiated, leading to
clinical deterioration of
the disease
Unmasking IRIS
 IRIS may trigger the
presentation of an OI
that was sub-clinical
prior to ART
Both forms of IRIS result from the rapid return of
the immune response after ART initiation
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IRIS – Pathogenesis
IRIS is secondary to immunological
changes after ARV:
 Rapid and potent suppression of HIV
viremia
AND

Abundant microbial antigen promotes a
greater immune response when it
encounters suddenly increased
numbers of functionally active immune
cells
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IRIS - Clinical Presentations



The inflammatory response causes
the unexpected worsening of the
patient’s condition
Often there is no detectable evidence
of the underlying pathogen
Mycobacterium Tuberculosis
accounts for at least 1/3 of all IRIS
events in developing countries
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What Are Common Pathogens
that Cause IRIS?

All infections have been reported to
cause IRIS:
Mycobacteria TB, MAC, BCG in children
Fungal
Cryptococcosis, PCP,
Histoplasmosis, Penicilliosis
Viral
CMV, VZV, HBV, HCV
Parasites
Strongyloides, Cryptosporidium
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IRIS - Risk Factors (1)




Low CD4 count (< 50) before
starting ARV
Rapid reduction in HIV viral load with
ARV
High pathogen load at the beginning
of ARV (i.e. starting ARV therapy in
the setting of an active OI)
Higher number of prior OIs
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IRIS - Risk Factors (2)
Antigens of opportunistic
pathogens:
•Active infection
•Subclinical infection
•Non-viable
organisms
Genetic Factors
IRIS
CD4 T-cells < 50/mm3
•High pathogen load
•Immune dysregulation
IRIS – TUBERCULOSIS
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Introduction




Worsening of signs and symptoms of TB in
patients being started on ARV
Occurs in up to 1/3 of patients
More frequent when ARV is started within
2 months of beginning TB treatment
Two kinds of TB IRIS:
Paradoxical
Reaction
worsening of TB symptoms in a
patient on TB treatment
Unmasking TB
new symptoms of TB in a patient not
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yet on TB treatment
IRIS - Unmasking TB (1)
Unmasking TB IRIS has 3 main characteristics
Characteristic
Shown through:
Subclinical or
unapparent TB at the
start of ART
• Insufficient clinical symptoms to
justify TB treatment
• Normal Chest X-ray
• Negative TB screening and
sputum AFB smears
Good response to
ART
• Adequate adherence
• Decreased viral load
TB appears within
first 6 months of ART
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IRIS - Unmasking TB (2)

Risk of unmasking IRIS can be reduced
by:
• TB screening in all patients
• Careful evaluation for presence of other
OIs before starting ART

Consequences of unmasking IRIS can
be reduced by:
• Close follow-up during first few months
after ART is started
• Prompt diagnosis and treatment of OIs
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IRIS TB - Paradoxical Reaction (1)
Patient on TB therapy at start of ART:
 Has an initial clinical response to TB
treatment, then:
 Develops new or recurrent symptoms
or signs of TB
and
 Has adequate adherence to ARV and
TB treatment
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IRIS TB - Paradoxical Reaction (2)

Rule out new OI or drug-resistant TB:
• Chest X ray/Ultrasound: worsening or
new lesions
• Good virological response
• Clear exclusion of other conditions:




TB treatment failure
Other OI
Malabsortion
Drug reactions
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IRIS TB - Paradoxical Reaction (3)
Case definition:
1 major clinical criterion or 2 minor clinical criteria
 New/enlarging lymph nodes, cold abscesses or
other focal tissue involvement
 New/worsening radiological features of TB
Major
Criteria  Breakthrough TB meningitis or new/enlarging
focal CNS lesion
 New or worsening serositis
 Constitutional symptoms (fever, night sweats)
Minor
 Respiratory symptoms (cough, dyspnea)
Criteria
 Abdominal pain and/or hepatomegaly
 Resolution of clinical and/or radiological findings
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without change in TB treatment
What Is the Optimal
Timing for Starting ART
When TB Is Diagnosed?
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Concerns: Early or Late ART
Early ART





High pill burden
Co-toxicity
Adherence
challenge
PK interactions
TB-associated
IRIS
Late ART




Progressive
immuno-deficiency
Higher risk of HIVassociated
morbidity
Risk of death
Less rapid
resolution of TB
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When Should ART Be Started in
Patients with TB?


Some important studies (SAPIT,
CAMELIA, STRIDE) have recently
tried to answer this question
Researchers found that:
• IRIS is more common with earlier ART
initiation BUT
• Risk of death from TB-IRIS < risk of
death from delaying treatment of AIDS
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Initiation of ART for TB Patients with
CD4 Count Available
CD4
250 – 350
Cells/mm3
<250
Cells/mm3
Start TB therapy first
>350
Cells/mm3
Management
Assess for ART after:
• intensive phase
or
• completion of TB
treatment
Start ART after
completion of intensive
phase of TB therapy
If patient is at
clinical stage 4,
ART can be
started after
patient tolerates
TB drugs
(between 2 to 8
weeks of TB
treatment)
Start ART as soon as possible, after the
patient tolerates the TB drugs (between 2 to
21
8 weeks of TB treatment)
What are Possible Differential
Diagnoses for IRIS TB?

For IRIS-TB Paradoxical reaction:
• Side effects of ARV, such as drug fever
• TB infection not responding to
treatment


Resistant TB
Poor adherence to TB treatment
• Other HIV or non-HIV related infections
IRIS is a diagnosis of exclusion!!!
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Challenges in Diagnosis


No diagnostic test
Diagnosis of exclusion
The differential diagnosis is broad,
especially in advanced HIV patients
•
•
•
•
ADDITIONAL
DIAGNOSIS
Bacterial infections
Fungal infections
NTM infections
Malignancies
DRUG
RESISTANCE
DRUG
REACTION
• Drug fever vs.
TB-IRIS fever
• Hepatic
involvement23
IRIS Management
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IRIS – Management (1)
Most cases of IRIS can be easily
managed by:
 Continuing therapy against the
primary opportunistic pathogen
 Continuing ART
 Anti-inflammatory agents
 Providing reassurance to the patient
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IRIS – Management (2)

Corticosteroids might be necessary in
case of severe symptoms:
• Worsening of meningeal, cerebral or
mediastinal disease with compression of
vital structures
• Severe pain
• Prolonged fever

In case of life-threatening forms of
IRIS, stopping ARV temporarily should
be considered
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CASE STUDY
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Case 1: Son, Male, 29 Years Old (1)
Baseline:
 HIV + in March
2006
 Sputum AFB
+++
 CD4: 64 mm3
 TB treatment:
RHEZ
BASELINE
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Case 1: Son, Male, 29 Years Old (2)
Week 8:
 Improved
clinical and
radiological
status
 Maintenance
TB therapy: EH
 Start ARV:
d4T+3TC+NVP
WEEK 8
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Case 1: Son, Male, 29 Years Old (3)
After 1 months on
ARV and 3 months
of TB treatment:
 The patient was
hospitalized due
to:
• high fever
• cough
Week 12
WEEK 12
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Case 1: Son, Male, 29 Years Old (4)
BASELINE
WEEK
8
WEEK
12
What is the differential diagnosis?
• IRIS TB “Paradoxical reaction”
• Resistant TB
• Another OI
• Adherence problems
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Case 2: Hung, Male, 30 Years Old (1)



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Sputum AFB ++
CD4: 15 mm3
Peripheral
lymph nodes <
1 cm
CXR: minor left
hilar and
aortopulmonary
lymphadenopat
hy
TB treatment:
RHEZ
Baseline
Case 2:
Hung, Male, 30 Years Old (2)


Start ARV
(d4T/3TC/NVP) after
8 weeks of TB
treatment
After 4 week on ARV
(week 12 of TB
treatment):
• Peripheral and
mediastinal lymph
nodes increased size
LN
Week 12
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Case 2: Hung, Male, 30 Years Old (3)

What is the diagnosis?
• IRIS “paradoxical reaction”

What is the treatment?
•
•
•
•
Continue TB treatment
Continue ARV
Aspirate lymph nodes
Give steroids (indicated because of risk
of tracheal compression)
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Key Points

IRIS is caused by a
return of the
immune response to
antigens of
opportunistic
pathogens
• Subclinical infections:
Unmasking
• Treated infections:
Paradoxical


Typically presents after
2-12 weeks of ART
Diagnosis of exclusion
• Rule out adherence
problems, new OIs

Treatment consists of:
• OI therapy
• ART
• Anti-inflammatory
therapy
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Thank you!
Questions?
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