TB-Associated Immune Reconstitution
Inflammatory Syndrome (IRIS)
John W. Wilson, MD
Associate Professor of Medicine
Division of Infectious Diseases
Mayo Clinic, Rochester MN
Mayo Clinic Center for Tuberculosis
Wisconsin TB Summit; April 24, 2014
©2013 MFMER | slide-1
TB-IRIS: General concepts
• The paradoxical worsening of signs, sx’s and/or
radiologic features of TB after starting
antiretroviral therapy (ART) for HIV infection
• In setting of initial clinical improvement after
starting TB-drug therapy
• Incidence of TB-IRIS in HIV(+) patients is
variable = 8-43%
• Can occur in HIV (-) patients as well, but less
common
• E.g. CNS tuberculomas, cervical LNs
Thorax 2004. 59:704-707
Clin Infect Dis 2006. 39:1709-12
©2013 MFMER | slide-2
Immunologic Reconstitution Inflammatory
Syndrome (IRIS): principles - I
Associated with increased functional
immunologic & inflammatory responses
- Examples:
a. HIV (+) patient: Recovery of CD4 T-cells after
recent start of antiretroviral therapy (HAART, ART)
b. Leukemia, BMT patient: Recovery of neutrophils
after myeloablative chemotherapy or
hematopoietic stem cell transplantation (HSCT)
engraftment
c. Solid organ trnplt pt: Reduction in pharmacologic
immunosuppressive therapy
©2013 MFMER | slide-3
Immunologic Reconstitution Inflammatory
Syndrome (IRIS): principles - II
IRIS results from a rapid restoration of pathogen
specific immune responses to opportunistic
infections – causing either:
a. The deterioration of a treated infection via
worsening symptoms, or
b. The new presentation of a previously
subclinical infection
Inflammatory response also augmented by
increased MTB antigen loads released by dead
or dying bacilli (Antivir Therap 2005, 10:417-22)
©2013 MFMER | slide-4
Immunologic Reconstitution Inflammatory
Syndrome (IRIS): principles -III
• Timing of IRIS onset:
• During the first few months of ART
• Generally sooner after myeloablative neutrophil
recovery
• IRIS can be associated with a wide array of
pathogens - examples:
•
•
•
•
M. tuberculosis
Cryptococcus neoformans (e.g. meningitis)
Herpes viruses
IRIS not always limited to HIV (+) pts – e.g.:
• Invasive filamentous fungal diseases (heme)
©2013 MFMER | slide-5
IRIS common with other HIV-associated
opportunistic infections
Meta-analysis of immunologically advanced HIV
(+) pts developing IRIS after starting ART:
• 13,100 pts among 54 cohort studies
Incidence of IRIS s/p ART start:
•
•
•
•
•
•
Cytomegalovirus (CMV) – 37.7%
Cryptococcus meningitis – 19.5%
PML – 16.7%
Tuberculosis 15.7%
Herpes zoster – 12.2%
Kaposi's sarcoma – 6.4%
Müller et al. Lancet Inf Dis 2010;10:251-61
©2013 MFMER | slide-6
CNS VZV–IRIS (non-TB)
• 37 yo HIV (+) woman with VZV lesions - T7
dermatome
• Treated with acyclovir 6 weeks prior to admission
• HAART was initiated 2 weeks PTA
• Double vision was followed by severe weakness in her legs
1–2 days PTA
Post el at. Am J Neuroadiol. 2013 Jul;34(7):1308-18
©2013 MFMER | slide-7
IRIS common with other HIV-associated
opportunistic infections - II
Deaths in patients developing IRIS:
• 20.8% in pts with cryptococcal meningitis
• 3.2% pts in pts with TB
• Lower CD4 counts at time of ART start – associated
with high risk of IRIS
• Especially when CD4 < 50 cells/uL
Müller et al. Lancet Inf Dis 2010;10:251-61
©2013 MFMER | slide-8
Distinguishing between:
1 - TB-associated IRIS and
2 - ART-associated TB
Meintjes et al. Lancet Infect Dis 2008; 8: 516–23
©2013 MFMER | slide-9
Diagnosing TB-associated IRIS
• *No single laboratory or confirming test for TB-IRIS
• IRIS is a clinical diagnosis – based on
• Timing of TB and/or HIV therapies and case definitions
• Clinical signs, pt. symptoms with supportive radiologic studies and
laboratory information
• Underlying risk & predisposing patient factors towards IRIS (e.g. low
CD4 before starting ART)
• Must exclude other diagnoses including:
• Other opportunistic or community-based infections
• Negative tissue stains, cultures, PCR; serologies, etc. for
alternative pathogen(s)
• Aseptic causes of inflammation
• Malignancies
• Other processes
©2013 MFMER | slide-10
Symptoms and Clinical findings of TB-IRIS
- can be quite variable - I
• Clinical examples:
• New or recurrent fever (may be most
common)
• New or recurrent cough
• New or worsening lymphadenopathy
• New skin lesions
• New soft tissue abscess
• New or recurrent seizure (e.g. CNS
tuberculoma)
©2013 MFMER | slide-11
Symptoms and Clinical findings of TB-IRIS
- can be quite variable - II
• Radiologic examples:
• New intraabdominal adenopathy
• New pulmonary infiltrate
• *Worsening CXR infiltrate → can still
be IRIS; but must r/o drug-resistant
TB or non-TB cause
• New pleural effusion
©2013 MFMER | slide-12
Paradoxical TB-associated IRIS
36 yo HIV (+) pt; baseline
CD4 of 39 cells with
culture (+) pulmonary TB
A. Cervical LN
enlargement (1 week
after starting ART)
B. Chest wall cold
abscess
C. Right psoas abscess
(CT scan)
D. Worsening cough with
sputum AFB staining
(+); but culture (-)
Meintjes et al. Lancet Infect Dis 2008; 8: 516–23
©2013 MFMER | slide-13
Presentations of miliary TB-IRIS after
starting HAART
A.
B.
Miliary Pulmonary
TB
C. Cerebral
tuberculomas with
meningeal TB
D. Choroid tubercles
Sharma et al. Indian J Med Res 135, May 2012, pp 703-730
©2013 MFMER | slide-14
Presentations of miliary TB-IRIS after
starting HAART
Sharma et al. Indian J Med Res 135, May 2012, pp 703-730
©2013 MFMER | slide-15
Timing of TB-IRIS onset
• Generally presents within the first 3 months
• Usually within the first 2 months or even first
few weeks after starting ART
Bangkok, Thailand:
167 patients
21 (12.6% developed TBIRIS)
Journal of Infection (2006) 53:357-63
©2013 MFMER | slide-16
Case definition for paradoxical TB-IRIS
- 3 components to case definition:
A. Antecedent requirements
Both of the 2 following requirements must be met:
1. Diagnosis of TB: the TB diagnosis was made before starting ART and this should fulfil WHO criteria for diagnosis of smear-positive
PTB, smear-negative PTB or extrapulmonary TB
2. Initial response to TB treatment: the patient’s condition should have stabilized or improved on appropriate TB treatment before ART
initiation – e.g. cessation of night sweats, fevers, cough, weight loss. (Note: this does not apply to patients starting ART within 2 weeks
of starting TB treatment since insufficient time may have elapsed for a clinical response to be reported.)
B. Clinical criteria
The onset of TB-IRIS manifestations should be within 3 months of ART initiation, re-initiation, or regimen change because of treatment
failure.
Of the following, at least 1 major criterion or 2 minor clinical criteria are required:
Major criteria
1. New or enlarging lymph nodes, cold abscesses or other focal tissue involvement – e.g. tuberculous arthritis
2. New or worsening radiological features of TB (found by chest X-ray, abdominal USS, CT or MRI)
3. New or worsening central nervous system TB (meningitis or focal neurological deficit – e.g. caused by tuberculoma)
4. New or worsening serositis (pleural effusion, ascites, or pericardial effusion)
Minor criteria
1. New or worsening constitutional symptoms such as fever, night sweats, or weight loss
2. New or worsening respiratory symptoms such as cough, dyspnea, or stridor
3. New or worsening abdominal pain accompanied by peritonitis, hepatomegaly, splenomegaly, or abdominal adenopathy
C. Exclude alternative explanations for clinical deterioration
1. Failure of TB treatment due to TB drug resistance
2. Poor adherence to TB treatment
3. Another opportunistic infection or neoplasm (it is particularly important to exclude an alternative diagnosis in patients with smearnegative PTB and extrapulmonary TB where the initial TB diagnosis has not been microbiologically confirmed)
4. Drug toxicity or reaction
Lancet Infect Dis 2008;8(8):516-523
©2013 MFMER | slide-17
ART-associated TB
“Unmasking” tuberculosis-associated IRIS
48 yo HIV (+) pt; baseline
CD4 of 10 cells with dry
cough (no sputum
collected)
A. Baseline CXR clear
B. 10 days after starting
ART – (+) fever and
worsening productive
cough. Sputum (+)
AFB
The rapid development of
pulmonary symptoms and
infiltrated attributed to the
‘unmasking of TBassociated IRIS
Chest wall cold abscess
Meintjes et al. Lancet Infect Dis 2008; 8: 516–23
©2013 MFMER | slide-18
Case definition for ART-associated TB
- 3 components to case definition:
1. Patient is not receiving TB treatment when
ART is started
• Active TB has not yet been diagnosed (when ART started)
2. Active TB is diagnosed after ART has been
started
3. Diagnosis of TB should meet WHO criteria for
AFB smear (+), smear ()-) or extrapulmonary
TB
Lancet Infect Dis 2008;8(8):516-523
Case Rep Infect Dis. 2013; 2013:1-7
©2013 MFMER | slide-19
Presentations of ART-associated TB
- “unmasking” IRIS
• Pulmonary TB most common
• Other sites periodically encountered:
• Spinal TB
• Spondylodiscitis
• Paraspinal abscess(s) – in up to 50% cases
• Psoas abscess
• AFB stains and cultures may be positive – e.g.
• Sputum – pulmonary source
• Needle aspiration
• Tissue biopsies
Case Rep Infect Dis. 2013; 2013:1-7
©2013 MFMER | slide-20
Risk factors for TB-associated IRIS
development in HIV (+) pts:
• Baseline low CD4 cell count (e.g. CD4 < 100 cells/uL)
• Rise in CD4 count with effective ART during first 3
months of therapy
• Disseminated TB (extrapulmonary TB)
• More common in advanced HIV (+) pts
• Earlier start of ART
• Balancing potential reductions in AIDS-related mortality risk vs.
IRIS morbidity & mortality risks
• No effect on IRIS
• Latent TB infection (much lower MTB load) - ↓↓ risk (if any)
• Type if ART therapy used
Michailidis et al. Antivir Therap 2005, 10:417-22
©2013 MFMER | slide-21
Associations between pre-ART clinical and laboratory
characteristics with subsequent TB-IRIS events
Narendran et al. PLoS One. 2013; 8(5): e63541
©2013 MFMER | slide-22
Pre-ART plasma levels of IL-6 or CRP distinguish
individuals at higher risk for TB-IRIS
Narendran et al. PLoS One. 2013; 8(5): e63541
©2013 MFMER | slide-23
Not every HIV-TB pt with low CD4 cell
counts develops TB-IRIS
Reasons for such discordance among patients is
not overly clear - examples:
a. Complex interplay of immune responses and/or
severity of immunosuppression
b. Inter-patient genetic predisposition
• E.g. humoral immune response – abnormalities in IL-12
and IFN-γ
c. Higher MTB bacilli burden; antigen load
• E.g. rise of antigen release after treatment started
d. Anatomic location of MTB infection
e. Other??
©2013 MFMER | slide-24
When to start HIV antiretroviral therapy
(ART) in patient with active TB?
Considerations:
Curr Opin HIV AIDS. Jan 2010; 5(1): 61–69
©2013 MFMER | slide-25
Early vs. Late introduction of ART
CAMELIA study (Cambodia)
• Patients who had CD4 counts <200 cells/mm3
were randomized to initiate ART at 2 wks or 8
wks after start of TB treatment.
• Enrolled pts with advanced HIV disease,
median CD4 of 25, low BMI, high rates of
disseminated TB
• Compared with ART started at 8 wks, ART
started at 2 wks resulted in a 38% reduction in
mortality (P = 0.006)
N Engl J Med. Oct 20 2011;365(16):1471-1481
©2013 MFMER | slide-26
Early vs. Late introduction of ART
CAMELIA study (Cambodia)
• However, pts starting ART earlier (at 2 weeks)
had a higher incidence of IRIS (36%) compared
to pts starting ART at 8 weeks (16%)
• Most frequent IRIS findings:
•
•
•
•
Progressive adenopathy
Fever
Abdominal pain
HSM
• TB-assoc. IRIS was very manageable
• Low mortality (3.9%)
Laureillard et al. AIDS 2013, 27:2577–2586
©2013 MFMER | slide-27
CAMELIA Trial:
Kaplan–Meier estimates
of occurrence of TBassociated IRIS by
study arm
Laureillard et al. AIDS 2013, 27:2577–2586
©2013 MFMER | slide-28
The ACTG 5221 (STRIDE) trial
• Multinational study, randomized ART-naive patients with
confirmed or probable TB and CD4 counts <250
cells/mm3
• Earlier (<2 weeks) ART or later (8–12 weeks) ART
• Overall rates of mortality and AIDS diagnoses were not
different between the earlier and later arms – However:
• Higher rates of IRIS were seen in the earlier ART
arm
• A significant reduction in AIDS or death was seen in
the subset of patients with CD4 <50 cells/mm3 who
were randomized to the earlier ART arm
Havlir et al. N Engl J Med. Oct 20 2011;365(16):1482-1491
©2013 MFMER | slide-29
Basic TB and HIV Treatment Principles –
Summary (DHHS)
• All HIV-infected patients with diagnosed active TB
should be started on TB treatment immediately (AI)
• TB has the priority in timing
• All HIV-infected patients with diagnosed active TB
should be treated with antiretroviral therapy (ART) (AI)
• Timing of starting ART depends upon patient factors,
including:
a. CD4 count
b. Clinical severity of HIV disease
2013 DHHS Guidelines for the Use of Antiretroviral Agents
in HIV-1-Infected Adults and Adolescents http://aidsinfo.nih.gov/guidelines on 4/14/2014
©2013 MFMER | slide-30
Basic TB and HIV Treatment Principles –
Summary (DHHS) – II
• In pts with CD4 counts <50 cells/mm3, ART should be
initiated within 2 weeks of starting TB treatment (AI)
• In pts with CD4 counts ≥50 cells/mm3 who present with
clinical disease of major severity (e.g. low Karnofsky
score, low body mass index, low Hgb, low albumin,
organ system dysfunction, etc), ART should be initiated
within 2 to 4 weeks of starting TB treatment
• Strength of this recommendation varies on the basis of CD4
cell count:
• CD4 count 50 to 200 cells/mm3 (BI)
• CD4 count >200 cells/mm3 (BIII)
2013 DHHS Guidelines for the Use of Antiretroviral Agents
in HIV-1-Infected Adults and Adolescents http://aidsinfo.nih.gov/guidelines on 4/14/2014
©2013 MFMER | slide-31
Basic TB and HIV Treatment Principles –
Summary (DHHS) – III
• In pts with CD4 counts ≥50 cells/mm3 who do not have severe
clinical disease, ART can be delayed beyond 2 to 4 weeks of
starting TB therapy but should be started within 8 to 12 weeks of
TB therapy initiation.
• The strength of this recommendation also varies on the basis of CD4
cell count:
• CD4 count 50 to 500 cells/mm3 (AI)
• CD4 count >500 cells/mm3 (BIII)
• In all HIV-infected pregnant women with active TB, ART should be
started as early as feasible, both for maternal health and for
prevention of mother-to-child transmission (PMTCT) of HIV (AIII)
• In HIV-infected patients with documented MDR- or XDR-TB, ART
should be initiated within 2 to 4 weeks of confirmation of TB drug
resistance and initiation of second-line TB therapy (BIII)
2013 DHHS Guidelines for the Use of Antiretroviral Agents
in HIV-1-Infected Adults and Adolescents http://aidsinfo.nih.gov/guidelines on 4/14/2014
©2013 MFMER | slide-32
The End
Questions?
©2013 MFMER | slide-33