This document discusses immune reconstitution inflammatory syndrome (IRIS) in patients with HIV. It provides background on IRIS, defines the two types (paradoxical and unmasked), and lists risk factors. It then discusses the pathology of IRIS and various pathogens that can cause central nervous system IRIS, including PML, cryptococcal meningitis, VZV, CMV, and mycobacteria. Specific details are provided on the clinical manifestations and imaging findings of PML-IRIS and cryptococcal meningitis-IRIS.

1. DR. VIJAY PRAKASH HAWA
SR NEUROLOGY
GOVT.MEDICAL COLLEGE,
KOTA

2. With the advent of combination antiretroviral
therapy (cART) in 1996,
reports of atypical presentations of well-described
opportunistic infections following induction of
antiretroviral therapy began to appear in the
medical human immunodeficiency virus (HIV)
literature.
Jacobson et al., 1997 lancet 349; 1443-1445
Race et al., 1998 lancet 351: 252-255

3. In 2000, the term immune reconstitution
syndrome was used to describe the cART-associated
inflammatory syndrome following reconstitution of
CD4+ T-cell lymphopenia in HIV-seropositive patients
with new or previously unrecognized opportunistic
infections.
Behrens et al., 2000; Immunobiology 202: 186-193
An alternate term, immune restoration
disease, was introduced nearly a year later to
describe the same clinical syndrome

4. The term ‘IMMUNE RECONSTITUTION
INFLAMMATORY SYNDROME’ (IRIS)
was defined at the Annual Meeting of Infectious
Disease Society of America in San Francisco, by
a group of researchers at Baylor University and
continues to be the most widely used term to
date
Shelburne et al., 2002 ;Medicine Baltimore 81;213-227

5. Handbook of Clinical Neurology, Vol. 152 (3rd series) The Neurology of HIV
Infection

6. Two types of clinical manifestations of IRIS:
(1) PARADOXIC IRIS
(2) UNMASKED IRIS.

7. •PARADOXIC IRIS
clinical scenarios where an opportunistic infection is known to
be present prior to immune reconstitution, and on reversal,
the patient experiences a worsening of the known
opportunistic infection along with a robust inflammatory
response.
Also known as DELAYED IRIS
•UNMASKED IRIS
clinical scenarios where an opportunistic infection was not
known to be present, i.e., asymptomatic, but was
“unmasked” during immune reconstitution whereby the
immune response to the pathogen makes its symptomatic.
Also known as SIMULTANEOUS IRIS

9. The risk factors for the development of IRIS
1) The patient being HAART-naïve, which allows a more
intense inflammatory response to develop
2) The patient being severely immunocompromised with very
low CD4 counts (50 cells per cubic millimeter) at the
initiation of ART
3) High pre-HAART HIV-1 RNA levels
4) falling HIV-1 RNA levels in response to HAART initiation,
especially when this fall occurs rapidly and results in
significant level
reductionsandwhenittakesplacewithin90daysoftheintroducti
on of HAART
Contd...

10. 5) rising CD4 counts after initiation of HAART,
especially later in the course of therapy after falling
HIV-1 RNA levels have resulted in an initial
redistribution of memory CD4 lymphocytes
6) OI or the patient on treatment for OI when HAART
is initiated,especially within a month of the OI
diagnosis, because the increased antigenic burden
evokes a more robust inflammatory response
7) resumption of HAART after an interruption
8) younger age

11. 9) male sex
10) genetic factors that alter the clearance of the pathogen
(such as with herpesviruses or mycobacteria) or enhance
the immune response to it via polymorphisms in cytokine
genes
Shelburne SA, Visnegarwala F, Darcourt J, et al. Incidence and risk factors for immune reconstitution
inflammatory syndrome during highlyactiveantiretroviraltherapy.AIDS2005;19:399–406

12. PATHOLOGY OF IRIS
The incidence of IRIS changes with each host pathogen and its unique influence
on the immune system – for instance,
Mycobacterium tuberculosis and Cryptococcus neoformans have far higher
rates of IRIS, even in the non-HIV population, than their classic counterpart HIV
opportunistic infection Toxoplasma gondii
 Mechanism of action of the immune system in IRIS pathology is less clear
and multiple theories have been proposed.
A majority favor a CD4+ T-cell mediated pathway to explain the aberrant
immune response in IRIS

13. Several animal models have been created to attempt to identify the
mechanisms underpinning IRIS pathophysiology, many supporting the role of
dysregulated CD4+ and CD8+ T-cell cascades .
Newer mouse models have also looked at the role of checkpoint inhibitors,
such as programmed cell death protein 1 (PD-1) in IRIS. PD-1 is expressed on
both B and T cells, and is involved in establishing immune tolerance.
In humans, it is upregulated in chronic viral infections, marking “immune
exhaustion”of the T cells to the host pathogen.
Interestingly, one mouse model found that, although PD-1 is involved in the
susceptibility to opportunistic infections, its expression did not alter the
development of IRIS.
PATHOPHYSIOLOGY
Animal models for IRIS
Mutnal et al., 2013 journal of neuroinflammation 10;98

15. The interplay between CD4+ and CD8+ T cells in IRIS is complex, and can be
challenging to interpret based on the initial characteristics of the host prior to
immune reconstitution ,as well as nature of the infecting organism itself.
Take, for example, the animal model of Pneumocystis jiroveci pneumonia-
induced IRIS in T-cell deficient RAG2 knockout mice. After immune
reconstitution with wild-type lymphocytes, there was a prominent CD4+ T-cell-
mediated IRIS in the lungs with a relative absence of a CD8+ T-cell response .
The absence of a CD8+T-cell response also reflected a reduction in the CD8+
regulatory T-cell response (CD25+FoxP3+) and in this model it was presumed
that the interferon-gamma receptor modulated the CD4+T-cell-driven IRIS by
promoting the upregulation of regulatory or suppressor CD8+ T cells.
Pathology of CNS IRIS

16. Th1-driven immune responses were upregulated and
major histocompatibility complex class II expression on
microglia was significantly increased in animals receiving
donor T-cell transfers compared to HSV-1-infected animal
controls, suggesting a CD4+ T-cell-driven response.
•This finding is consistent in the literature and across
several IRIS animal models.
However, both CD4+ and CD8+ appear to play critical
roles in CNS IRIS and it is likely that the immune response
is influenced by the nature of the CNS pathogen itself
during IRIS.

18. Recent evidence suggests a role for CD8+ T cells in IRIS
pathology.
 dysregulated CD4+ T-cell-driven response point to the fact that
decrease theCD4/CD8T-cell ratio due toa differential expression of
unbound alpha 4 integrin on the cell surface between the two
subsets of T cells cause excessive inflammation in IRIS.
 Case series of IRIS after cART have demonstrated predominant
CD8+ T-cell infiltration in the brain parenchyma, both in cases of
IRIS associated with opportunistic infections and in cases of IRIS
with HIV encephalitis.
.
Rushing et al., 2008; J Neuropathol exp neurol ;67: 819-827
Johnson and Nath, 2014 curr opin HIV AIDS:9 ; 572-578

19. Pooled cumulative incidences in various studies are
calculated by specific disease processes in patients with
previously confirmed AIDS-defining illnesses.
Those IRIS incidences are as follows:
1. 37.7%, cytomegalovirus retinitis;
2. 19.5%, cryptococcal meningitis;
3. 16.7%,PML
4. 15.7%,tuberculosis;
5. 12.2%,herpeszoster; and
6. 6.4%, Kaposi’s sarcoma
Muller M, Wandel S, Colebunders R, et al.Lancet Infect Dis 2010;10:251–61

20. •While IRIS can affect any organ in the body, such as
the lungs, liver, and lymph nodes,it uncommonly
targets the CNS, where it has an incidence ranging
from only 0.9 to 1.5% .
•
•Nevertheless, when CNS-IRIS develops, it can have a
serious impact on patient morbidity and mortality.
•Mortality rates can range from 5% upto 15%
McCombe JA, Auer RN, Maingat FG, et al.Neurology 2009;72:835–41

21. At autopsy or at brain biopsy, the typical pathology in
CNS-IRIS has been characterized by a CD8+ T-
cell lymphocytosis with CD8+T cells found in a perivascular and
even in a parenchymal location, leading to encephalitis.
 The relative paucity of CD4+T cells in the brain despite arising
peripheral CD4 cell count in patients on HAART has led to postulate that
the underlying etiology responsible for IRIS is a dysregulated
CD8+/CD4+ lymphocyte ratio

22. COMMON PATHOGENS ASSOCIATED WITH
CNS-IRIS
1. PML- IRIS
2. CRYPTOCOCCAL MENINGITIS-IRIS
3. VZV CNS-IRIS
4. CMV-IRIS: Vitritis and Encephalitis
5. Candida Meningoencephalitis-IRIS
6. Mycobacteria TYPICAL AND ATYPICAL
7. TOXOPLASMOSIS

23. PML- IRIS
 INCIDENCE 18% (may extend upto 50 %) of PML-IRIS in
HIV+patients on HAART.
 the robust inflammatory response that typifies PML-IRIS
may be seen any time between 1 week and 26 months after
HAART initiation, but most commonly at 3 months due to the
restoration of T-cell function peaking at this time.
 This wide time range in which PML-IRIS may develop has
been postulated to be related to the initial redistribution in
the first several weeks of pre-existing memory T-cells followed
1 month to 4 years later by the proliferation of naïve T-cells.

24.  PML-IRIS is characterized by the development of contrast
enhancement of the PML lesions as well as mass effect and
increased high FLAIR/T2 signal due to interstitial edema
.Usually occurring within 1–2 months of HAART (though they
can occur up to 2 years), patchy white matter lesions with
multiple areas of nodular enhancement on MR imaging can be
seen, which can respond to steroids.
 Untreated PML typically presents as white matter lesions,
often subcortical, low on T1WI, and high on FLAIR and T2WI
(due to the myelin destruction), without mass effect and
without contrast enhancementwith no diffusion restriction
centrally(but only peripherally at the active site of lesion
expansion with cytotoxic edema)
DIFFERENCE IN NEUROIMAGING

25. •The white matter lesions can be confined to the posterior
fossa.
•The peripheral enhancement of the white matter lesions
and perivascular spaces has been related to their
infiltration by CD8 + T-cells, sometimes accompanied by
macrophages and CD4 + T-cells.
• However, not all patients with HIV-associated PML-
IRIS demonstrate contrast enhancement of the PML
lesions. Contrast enhancement may be seen in only 56%
of patients

29. •PML-IRIS can be fulminating and lead to patient
death.
• In these patients increase in the number and size
of the lesions, all of which enhanced compared with
the pre-HAART MR imaging.
•Biopsy showed both demyelinating lesions as well
as severe inflammation with massive T-cell
lymphocyte and macrophage infiltration without
JCV detection.

30. •At autopsy, an acute perivenous leukoencephalitis
was found, mostly comprised of CD8+ lymphocytes
without detectable Jc virus in those specific areas.
•However,areas of abundant JC virus with active
PML inflammatory lesions and perivascular and
parenchymal infiltration by T lymphocytes were
also found.
• While CD8+ lymphocytes were in abundance,
CD4+ lymphocytes were absent.

31. •The patient’s death with PML-IRIS was thought
then to be related to a dysregulation of the
immune response with an imbalance in the
CD8+/CD4+ T-cell ratio.
•The marked infiltration of CD8+ T-cell
lymphocytes into the brain parenchyma was not
matched by a sufficient enough CD4+T-cell
lymphocyte response.
This led to a perivenous
leukoencephalitis as well as an aggravation of the
JCV infection.

32. In a study, one consisting of 54 patients with PML-
IRIS, the patients who fared worse, having shortened
survival rates (2.5 weeks versus 8.5 weeks) and
increased mortality,
were those whose pre-existing PML worsened
after HAART initiation, who developed IRIS earlier
on, and who had higher MR imaging lesion loads,
compared with those patients who developed IRIS
simultaneously with PML.
.
Tan K, Roda R, Ostrow L, et al. PML-IRIS in patients with HIV
infection:clinicalmanifestationsandtreatmentwithsteroids.Neurology
2009;72:1458–64

33. Increased survival in this same report was
associated with earlier and more prolonged use of
steroids as well as contrast enhancement on
imaging studies.
87.5% of those patients with a good outcome
demonstrated lesional contrast enhancement on
either CT or MR imaging versus 80% with poor
outcome whose imaging demonstrated no
contrast enhancement

34. CRYPTOCOCCAL MENINGITIS-IRIS
Cryptococcus neoformans is an organism that can cause
infection frequently seen inassociation with IRIS.
Cryptococcal-IRIS can be manifested in many different
ways—as lymphadenitis, pneumonitis, cryptococcal
meningitis, or cryptococcomas—and can result in
considerable morbidity and mortality.
 In CM-IRIS, mortality rates have ranged between 8% and
30%.
BicanicT,MeintjesG,RebeK,etal J Acquir Immune Defic Syndr 2009;51:130–34

35. How to differentiate CM-IRIS from CM
1. There was a trend for those patients developing CM-IRIS to
have a higher fungal burden at the end of >7 days of initial
treatment with amphotericin B.
2. pre-ART serum cryptococcal antigen level was 4 times
higher in those developing CM-IRIS.
3. lower tumor necrosis factor ,vascular endothelial growth
factor, granulocyte-macrophage colony–stimulating factor,
and granulocyte colony–stimulating factor .
4. higherlevels of interleukin 4 and interleukin 17
5. increasing levels of D-dimer and C-reactive protein

36.  Initiating antiretroviral therapy within 1–2 months of the
diagnosis of CM and CD4 counts below 11 cells/mm3 as well as
higher baseline HIV RNA levels have also been viewed as risk
factors for CM-IRIS.
In neuroimaging before the advent of HAART,
leptomeningeal enhancement in CM was uncommon in
patients with AIDS because those individuals were unable to
mount a sufficient inflammatory response.
Because of a restoring immune system, CT or MR imaging
can demonstrate leptomeningeal enhancement,which can be
accompanied by a communicating hydrocephalus in CM-IRIS.

38. The findings of linear perivascular enhancement in the
sulci and new meningeal or choroid plexus enhancement
have been shown to be imaging indicators of CM-IRIS.
While distention of the Virchow-Robin spaces manifested
as highT2/FLAIR signal, particularly in the basal ganglia, and
gelatinous pseudocysts have been imaging features of
cryptococcal meningitis in both the pre- and post-HAART
era, enhancement of these Virchow-Robin spaces appears
characteristic of CM-IRIS as does secondary involvement of
the brain parenchyma characterized by areas of high
T2/FLAIR signal , restricted diffusion, and parenchymal
enhancement.

39. •Higher organism burden in the CSF at disease onset
in CM-IRIS has also been reported to be associated
with elevated intracranial pressure.
This elevated intracranial pressure is due to the
blockage of CSF pathways and arachnoid villi by the
production of greater amounts of mucoid material,by
the higher number of organisms, and by the greater
reactivity to the cryptococcal antigens.

40. • A lumbar drain or ventriculostomy is often
necessary to combat the increased mortality (25%)
with elevated intracranial pressure and delay for 1
month the institution of HAART in these patients
who develop cryptococcal meningitis
•.
• Treatment with amphotericin B and flucytosine for
2 weeks and fluconazole for 8 weeks has been
suggested in this setting.

42. VZV CNS-IRIS
 VZV vasculopathy affecting either large or small vessels leading to
infarcts in the brain has been reported in the setting of CNS-IRIS, but it is
said to be rare.
The rash typical of herpes zoster was evident in only 54% of the
immunosuppressed patients versus 68% in those with an intact immune
system.
 For the diagnosis of VZV vasculopathy, there was a greater sensitivity
for the detection of VZV IgG in the CSF (93.33%) than for the PCR
detection of VZV DNA in the CSF (30%).
This detection of the IgG antibody was even higher in the
immunocompromised population(100%) as was the detection of CSF
pleocytosis (82% versus 58%).

43. Neuroimaging clues to the diagnosis of VZV-IRIS included
leptomeningeal enhancement in the spinal subarachnoid spaces
as well as patchy spinal cord enhancement at sites of high T2
signal intensity along with intracranial leptomeningeal
enhancement and patchy peripheral high FLAIR signal and
enhancement in the adjacent parenchyma along with vasculitis
and infarcts.
The avid enhancement was likely due to the robust
inflammatory response caused by IRIS.
 Vascular beading, and multifocal infarcts are also seen in
CMV-IRIS.
Nagel MA, Cohrs RJ, Mahalingam R, et al. Neurology 2008;70:853–59

46. CMV-IRIS: Vitritis and Encephalitis
In a study 63% of patients with CMV retinitis and
HAART developed an “immune recovery virtritis”
after 10 months. The CMV retinitis was inactive,
though this vitritis can also occur in patients with
active retinitis as well.
It is due to a transient inflammatory reaction in the
vitreous in patients with AIDS with CMV retinitis on
antiretroviral therapy.
Karavellas MP, Lowder CY, MacDonald C, et al. Arch Ophthalmol 1998;116:169–75

47.  In an HIV+ patient noncompliant to antiretroviral therapy
and to treatment ,CMV encephalitis developed, characterized
by both typical and atypical imaging features.
In typical MR imaging findings of ventriculitis or even
solitary focal mass lesions are found.
In atypical MR imaging widespread multifocal areas of
restricted diffusion and faint solid or peripheral enhancement
in both the supra and infratentorial compartments are seen.
 Periventricular and corpus callosum white matter can be
involved as well as subcortical white matter and the basal
ganglia, brain stem, and cerebellum.

48. Candida Meningoencephalitis-IRIS
Usually present as unmasked IRIS
Patient generally have no symptoms of meningitis
or have submeningitis and patient deteriorates after
starting HAART and in Autopsy of these patients
revealed pathology due to IRIS with a meningitis due
to Candida organisms as well as a vasculitis related
to CD8+ T-cell lymphocytic infiltration.
BerkeleyJL,NathA,PardoCA. J Neurovirol 2008;14:267–76

49. Inflammatory changes in the basilar meninges were
accompanied by extensive destruction of all the wall layers of
the basilar artery by the inflammatory process with a
predominance of lymphocytes along with some plasma cells
and multinucleated giant cells. Numerous microinfarcts were
found in the brain stem with vacuolization.
Because the high mortality rates in candida meningitis have
been reported to be reduced with treatment to 10%–30%,
diagnosis of this infection, which can simulate on CSF profile
TBmeningitis, is critical so that treatment can be
initiated,especially before beginning HAART.

50. Mycobacteria:
Atypical Mycobacterial CNS-IRIS
As the most commonly occurring bacterial infection in patients
with AIDS, MAC would be expected to commonly involve the
brain.
 However, brain involvement by MAC is actually rare but,
when present, is characterized by a granulomatous
inflammation and by lymphocytes and macrophages aggregated
in a perivascular location.
 Also rarely occurring is MAC-related CNS-IRIS despite the
fact that MAC is frequently identified as a pathogen causing IRIS
outside the CNS with pulmonary disease and lymphadenitis

51. Mycobacterium Tuberculosis:
 IRIS occurs in approximately 16% of patients with
AIDS with TB and antiretroviral therapy, of whom 3%
die.
In fact, TB is reported to be the infection
most commonly associated with IRIS extracranially
and usually occurs within 2 months of antiretroviral
therapy when not involving the CNS.
•As for TB-associated CNS-IRIS, the incidence is said
to be low.

52. • In a study by Pepper et al, it was reported in 12% of 190
patients with paradoxical TB ,a condition in which
antitubercular treatment precedes antiretroviral therapy. Of
these 23 patients with neurologic TB-IRIS and coinfection with
HIV-1, meningitis was found in 8; tuberculoma, in 7; meningitis
and tuberculoma, in 5; and radiculomyelopathy, in 3 .
•The heightened inflammatory response against the M
tuberculosis antigens in patients with paradoxical TB-IRIS
result in new or worsening radiologic findings, including
tuberculous abscesses, tuberculomata, meningitis, and
hydrocephalus.

53. •It is evident, then, when comparing the 3 different cohorts:
namely patients with CNS TB without HIV coinfection with
those with CNS TB with HIV co-infection with those with CNS
TB with HIV co-infection and IRIS, that there are many
similarities, with numerous overlapping clinical and imaging
findings.
• although some investigators have suggested that meningeal
enhancement and a communicating hydrocephalus in a patient
with antitubercular and antiretroviral therapy should point to a
diagnosis of TB-CNS-IRIS.
these imaging findings are not exclusive to this group of
patients, even if some authors have reported them more
commonly in the IRIS cohort.

54. (A)Communicating hydrocephalus
with transexudation of CSF
(B)avid and diffuse enhancement of
the leptomeningeal spaces
compatible with meningitis
After starting HAART and ATT
(C)Persistent hydrocephalus, and new
enhancing parenchymal lesions
(D)tuberculomas
After 6 months of therapy
(E)& (F) reveals a marked decrease in
edema and in the ventricular size and
resolution of the tuberculomas

55. Toxoplasma Encephalitis–IRIS
It is much less frequently seen.
When one compares the imaging appearance in HIV+ patients with
toxoplasma encephalitis without IRIS with those with IRIS, the
similarities stand out.
Focal enhancing parenchymal mass lesions with edema are seen in
both groups.
1 report suggesting an uncharacteristic finding of a speckled
enhancement pattern in addition to the more typical focal ring
enhancement.
 pathologic response is a induced granulomatous inflammatory
response
Pfeffer G, Prout A, Hooge J, et al. Biopsy-proven immune reconstitution syndrome in a patient with AIDS and cerebral
toxoplasmosis. Neurology 2009;73:321–22

56. CNS-IRIS WITHOUT ORGANISMS
Neuro-IRIS without Coinfection
 Following HAART an exaggerated immune response can
occur to an antigenic stimulus when the immune system is
being restored even in the absence of an infectious agent and
even at long time intervals after the initiation of HAART.
In various case studies shows aseptic meningitis,
Tumefactive Inflammatory CNS Demyelinating Disease and
Fulminating Leukoencephalopathy in hiv + patients after
starting HAART.
.

57. The Possible pathophysiology is that the rapid
recovery of circulating CD4+ cells following HAART
could induce IRIS by triggering a CD8+ lymphocytic
T-cell response against antigens, leading to
leptomeningitis,vasculitis,or cerebritis.
When that response is aimed against the peripheral
nervous system,a peripheral nerve inflammatory
demyelinating disease may develop. A Guillain-Barre´
syndrome occurring after HAART initiation is
documented in a casr report

58. IRIS MANAGEMENT
 The mainstay of treatment is to control the
inflammation since inflammation can cause
bystander damage to the brain .
 Since IRIS occurs in the context of an
underlying infection, the flipside of controlling
the inflammation is that the infection may
become unchecked and thus cause harm.

59. When an effective antimicrobial agent is available for treating
the underlying infection like cerebral toxoplasmosis and
cryptococcal meningitis can be effectively treated with
antibiotics, hence the inflammation can be treated with
corticosteroids once the antibiotics have been initiated.
The same is true of In HIV-infected patients without
opportunistic infections but with HIV CNS escape, the cART
needs to be optimized to use drugs with increased CNS
penetration.

60. When antimicrobials are not available for treating
theunderlyinginfection:
For patients with PML, currently there is no
effective antiviral agent available, hence the mainstay
of defense is the immune system.
 In these patients, some caution is necessary when
anti-inflammatory drugs are used.

61. If the inflammation is substantial and pressing on
vital structures and has substantial mass effect
 course of corticosteroids may be beneficial.
Here the goal is not to totally obliterate the
inflammation but rather to temper the response, since
the cytotoxic T cells are needed to control the viral
infection.

63. FUTURE DIRECTIONS
Specific immune modulators
Ideally we need drugs that would preserve the
immune responses directed against the microbial
pathogen but downregulate the bystander effects on
the surrounding brain tissue.
This can only be accomplished if we develop a better
understanding of the underlying pathophysiologic
mechanisms that mediate these immune responses.

64.  However, for some infections such as cryptococcal infection
we need to develop better mechanisms to clear the antigen
from the CNS, since current fungicidal agents may kill the
pathogen but the antigen may remain in the CNS and
intrathecal space for months,thus driving the immune
response
In HIV-infected patients, where the inflammation is
triggered by the Tat protein(Trans-Activator of Transcription)
despite the use of adequate cART,
agents need to be developed that will block the production of
Tat or antagonize its effects on the HIV long terminal repeat
and thus drive it along protein degradation pathways.

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66. 7) Jacobson et al., 1997 lancet 349; 1443-1445
8) Race et al., 1998 lancet 351: 252-255
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67. THANK YOU