Tuberculosis and

the Immune Reconstitution

Inflammatory Syndrome (IRIS)

Bob Colebunders

Names
Immune reconstitution inflammatory
syndrome (IRIS)
Immune restoration disease (IRD)
Paradoxical reactions

Pathogenesis
Increased lymphoproliferative response to
mycobacterium antigens in vitro
Restoration of cutaneous response to
Tuberculin
Increased [Il-6], activation markers (CD38)
Associated with TNFA-308*1, IL6-174*G

Incidence TB/IRIS
Europe and USA

Narita et al 36% (Miami, 1998)

Wendel et al 11% (Baltimore 2001)
Breen et al 29% (London, 2004)
Breton et al 43% (Paris, 2004)

Incidence TB/IRIS
Africa
Breton et al: 41%
No cases in TB/DOT study in South Africa (20 patients
only)

India
Kumarasamy et al: IRIS of 15.2 cases per 100 patientyears
Patel et al: TB IRIS more often in patients with active
TB at the start of HAART than in those without active
TB at the start of HAART (11 [8.73] vs. 3 [2.32%],
respectively; p = 0.0489).

Risk factors for TB/IRIS

Starting ARVs within 6 weeks of TB
treatment
Disseminated, extra-pulmonary disease
Low base line CD4 count
Rise in CD4 %
Fall in viral load
High bacillary burden?

Types of TB IRIS
Patient unknown to have TB at the start of
HAART

Patient on TB treatment before or at the

start of HAART

Timing of IRIS
Mean of 15 days after starting HAART
Up to months (years)
Syndrome lasts for 10-40+ days

TB IRIS

TB IRIS

TB IRIS

TB IRIS

TB IRIS

TB IRIS

Prognosis
Breton et al: 16 cases of TB/IRIS: 5 severe
complications
Splenic rupture
Compressive lymphadenopathy
Ureteric obstruction
Narita et al: The study found a 6-fold increased
risk of subsequent TB relapse in patients who
experienced IRIS during early TB treatment.

MRI: TB abscess spinal cord

Cryptococcal meningitis treated with HAART,

bilateral blindness: fundoscopy: bilateral
papiloedema: IRIS?

Differential diagnosis
Side effects of the antiretroviral treatment
Drug fever
TB infection not responding to standard
anti-TB treatment
Other concomitant infection
Failure of HAART (late IRIS)

Proposed criteria for the diagnosis of

IRIS in HIV patients on
antiretroviral therapy
French et al

Major criteria
Atypical presentation of opportunistic
infections or tumours in patients
responding to antiretroviral therapy
Decrease in plasma HIV RNA level by
1log10 copies/mL

Minor criteria
Increased blood CD4 T-cell count after HAART
Increase in an immune response specific to the
relevant pathogen, e.g. DTH response to
mycobacterial antigens
Spontaneous resolution of disease without specific
antimicrobial therapy or tumour chemotherapy
with continuation of anti-retroviral therapy antiretroviral therapy

Suspected TB IRIS: a TB patient who after

starting HAART develops either
New persistent fevers (temperature >38.6C) which last for
more than 1 week without an identifiable source (e.g.,
urine and sputa testing, and other procedures when
clinically indicated) or reason (e.g. an allergic reaction)
or marked worsening or emergence of intrathoracic
lymphadenopathy, pulmonary infiltrates
or worsening or emergence of cervical
adenopathies/abscesses, or worsening of other tuberculous
lesions or manifestations, such as cutaneous peritoneal or
central nervous system (CNS) inflammatory pathology.

Suspected TB IRIS: a patient who after

starting HAART develops TB characterised by
the formation of

Large adenopathies
Abscesses
Miliary TB with large nodules
Cavity formation

Confirmed TB IRIS
Same definition as suspected TB IRIS but
multi drug resistant TB excluded
and
a satisfactory virological response to ART

Diagnostic investigations
AFB may be be present or absent
Viable organisms despite TB treatment
since > 2 months may suggest treatment
failure
Tuberculin skin testing
88% of IRIS negative
33% of non-IRIS negative

Recommendations to prevent TB
IRIS
Exclude TB before starting antiretroviral
therapy
Treat first the TB and start antiretroviral
treatment only once the patient has
clinically improved, is tolerating very well
his TB treatment
Increase awareness about TB IRIS

Treatment recommendations
TB treatment should be continued
Exclude treatment failure
Ensure adequate treatment
Ensure adherence to ATT
Consider drug resistance

Treatment recommendations
Drainage
Adding prednisolone/NSAIDS may be beneficial
Continue HAART in most cases
Consider stopping ARVs if life threatening?

Research questions?
Propose definition of IRIS
Validate clinical definition of IRIS
Incidence of TB IRIS in different populations?
Predictors/risk factors for IRIS?
Morbidity and mortality (cause of early deaths?)
What are the potential long term consequences?

How to diagnose TB IRIS?

What are the clinical manifestations of TB
IRIS in adults and children?
Are there immunological markers or other
simple laboratory parameters that could
help to diagnose TB IRIS?
How useful is it to perform a tuberculin skin
test prior to the start of ARVs and to repeat
it when there is a suspicion of IRIS?

What is the pathophysiology of TB

IRIS (early and late forms of IRIS)?

How to treat TB IRIS?

Corticosteroids (dose, duration)?,
NSAIDs? thalidomide?
Aspiration of abscesses?
Should HAART be stopped? When?
Should the management of early and late
TB IRIS be different?

How to prevent/avoid IRIS?

When is the optimal moment HAART
should be started in a HIV/TB co infected
patient?
TB prophylaxis to avoid IRIS?
Corticosteriod therapy able to prevent the
development of TB IRIS?

Operational issues
How to diagnose TB IRIS clinically at the
primary health level?
When should a health care worker at the
primary health care level refer a patient or
call for advice?

Research methods
Cohort studies
Randomised clinical trials