Transcript Tuberculosis and the Immune Reconstitution Inflammatory Syndrome (IRIS) Bob Colebunders Names • Immune reconstitution inflammatory syndrome (IRIS) • Immune restoration disease (IRD) • Paradoxical reactions.

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
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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 ARV’s 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 >38.6°C) 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
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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 ARV’s 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