Immune reconstitution inflammatory syndrome (IRIS) describes paradoxical worsening of preexisting infections after initiating antiretroviral therapy in HIV patients. It occurs as a result of the rapid recovery of CD4+ T cells, which mount inflammatory responses against pathogens. Common types of IRIS include TB, cryptococcosis, and CMV. Symptoms vary by pathogen but may include fever, lymphadenitis, and worsening pulmonary infiltrates. While usually self-limiting, corticosteroids may be used for severe cases. Prevention strategies include earlier HIV diagnosis and optimizing treatment of opportunistic infections prior to initiating ART.

1. IMMUNE RECONSTITUTION
INFLAMMATORY SYNDROME
Dr. Navin Adhikari
Internal Medicine Resident

2. DEFINITION
The term "immune reconstitution inflammatory syndrome"
(IRIS) describes a collection of inflammatory disorders
associated with paradoxical worsening of preexisting infectious
processes following the initiation of antiretroviral therapy
(ART) in HIV-infected individuals.
Synonyms
• Immune recovery disease
• Immune reconstitution disease
• Immune reconstitution syndrome
• Immune restoration disease
• Immune rebound illness
• Steroid-withdrawal disease
• Immuno restitution disease
• Immune response reactions

3. RISK FACTORS
• Low CD4+ T-cell count when ART is initiated
• Disseminated infection
• a short time interval between treatment of the infection and
commencement of ART.
• Integrase strand transfer inhibitor (INSTI)-based regimens –
due to faster reduction in HIV viral load.

4. PATHOGENESIS
Occurs as a result of recovery of CD4+ T count which occurs biphasically.
Rapid increase occurs during first 3 to 6 months of ART.
• Due to increase in numbers of CD45RO+ memory T cells
• Decreased lymphocyte apoptosis and simultaneous redistribution from
peripheral lymphoid tissues into circulation.
Slower increase of predominately naive CD4+ T cells (CD45RA+, CD62L+)
• Due to expansion of T cell clones produced by thymus prior to its age-
related functional decline - secondary to thymopoiesis
• ART –> Rapid increase in CD8+ T lymphocytes also -> memory CD8+ cells
subsequently decline and are replaced by naive CD8+ T lymphocytes ->
total numbers of CD8+ T lymphocytes eventually stabilize
Accompanied by: increased in vitro lymphocyte proliferation responses, and
pathogen-specific delayed hypersensitivity reaction

5. TYPES
Paradoxical IRIS: manifest as a worsening of previously
diagnosed disease.
Examples: TB, Cryptococcosis, Kaposi sarcoma and herpes
zoster.
Unmasking IRIS: manifest as the appearance of a previously
undiagnosed disease
Examples: Mycobacterium avium complex

6. EXAMPLES OF IRIS

8. Diagnosis
• IRIS should be considered only when the presentation cannot
be explained by a new infection, expected course of a known
infection or drug toxicity.
• IRIS is diagnosis of exclusion. Following condition should be
excluded
a. active OIs
b. treatment failure
c. side-effects of ARVs and
d. ARV resistance

9. Features required to make the diagnosis:
• The presence of AIDS with a low pretreatment CD4 count
(often less than 100 cells/microL).
• A positive virologic and immunological response to
antiretroviral therapy .
• The absence of evidence of drug-resistant infection, bacterial
superinfection, drug allergy or other adverse drug reactions,
patient noncompliance, or reduced drug levels due to drug-
drug interactions or malabsorption.
• The presence of clinical manifestations consistent with an
inflammatory condition.
• A temporal association between ART initiation and the onset
of clinical features of illness.

10. DIFERENTIAL DIAGNOSIS
• Progression of initial opportunistic infection (OI) due to
antimicrobial resistance or nonadherence to prescribed drug
regimens.
• New OI.
• Drug toxicity (Eg. Abacavir hyersensitivity)

11. Similar Paradoxical inflammatory
syndromes in other Conditions
• Treatment for tuberculosis or lepromatous leprosy
• Corticosteroid withdrawal.
• Discontinuation of antitumor necrosis factor alpha therapy.
• Recovery of neutropenia after cytotoxic chemotherapy.
• Withdrawal of immunosuppression in transplant recipients
infected with Cryptococcus neoformans.
• Engraftment of stem cell transplantation .

12. CLINICAL FEATURES

13. TB-IRIS
• M. tuberculosis is the most common pathogen involved in
IRIS.
• Most TB-IRIS develops within the first 3 months after the
initiation of ART.
• After initiation of ART, paradoxical iris evedent by recurrent,
worsening, or new clinical or radiologic manifestations of TB
develop.
• Common manifestations include fever, enlargement of lymph
nodes, and worsening radiographic pulmonary infiltrates.

14. • Tracheal compression by intrathoracic lymph nodes or
massive pleural effusions can cause life-threatening dyspnea.
• Respiratory failure as a result of worsening pulmonary
infiltrates and acute respiratory distress syndrome have
occasionally been reported.
• Neurologic TB-IRIS accounted for 12% of cases of paradoxical
TB-IRIS. Meningitis, tuberculoma, or both were the most
common manifestations.
• TB-IRIS may cause granulomatous hepatitis, typically with
tender hepatomegaly and cholestatic liver function
derangement.

15.  Pulmonary TB :
• Fever
• Malaise
• Weight loss
• Worsening respiratory
symptoms
• Transient worsening of
radiographic abnormalities (
new parenchymal opacities
and progressive intrathoracic
lymph node enlargement )
• Severe respiratory
compromise
• Adult respiratory distress
syndrome.
 Extrapulmonary TB :
• Worsening lymphadenitis
• New pleural effusions
• Reappearance of fever with
new infiltrates
• Expansion of preexisting
intracranial tuberculomas
• Changes in ability to respond
to tuberculin proteins

16. NTM-IRIS
• Atypical manifestations of Mycobacterium avium complex
(MAC) disease in patients who were on zidovudine
monotherapy suggested that IRIS may be a complication of
ART.
• Unmasking disease is most common.
• Manifestsas fever, night sweats, and lymphadenitis.
• Peripheral lymphadenitis may suppurate and sometimes
cause chronically discharging fistulas to the skin.
• Pulmonary and thoracic disease usually causes cough that is
sometimes associated with chest pain.

17. • Microscopic examination of biopsy material or aspirates from
affected tissues often reveals mycobacteria, but these may
not be cultured.
• In HIV-seropositive children vaccinated with bacille Calmette-
Guérin (BCG), a BCG-associated lymphadenitis with or without
abscess formation may develop after starting ART.
• Leprosy-associated IRIS is usually manifested as unmasking of
previous subclinical Mycobacterium leprae infection, with a
borderline and type I reactional state.

19. CRYPTOCOCCOSIS IRIS
• Presents as recurrence of previously treated cryptococcal
meningitis.
• Unmasking inflammatory reactions are also reported.
• The time of onset of C-IRIS varies from 4 days to around 3
years after initiation of ART.
• In addition to recurrent meningitis, the central nervous
system (CNS) features of C-IRIS include intracranial
cryptococcoma or abscesses, spinal cord abscesses,
recalcitrant raised intracranial pressure, optic disc swelling,
cranial nerve lesions, dysarthria, hemiparesis, and
paraparesis.
• Extracranial manifestations of C-IRIS include lymphadenitis,
eye disease, suppurating soft tissue lesions, and pulmonary
disease that may include cavitating or nodular lesions

20. • In cryptococcal meningitis, cerebrospinal fluid with white
blood cell counts of 25 cells/µL or less and protein levels of 50
mg/dL or less are associated with the development of C-IRIS.
• CSF profiles at paradoxical C-IRIS may show an increased
white blood cell count and an increased opening pressure of
greater than 25 cm H2O, but these features overlap
significantly with those observed in patients with non–IRIS-
related relapses of cryptococcal meningitis.

21. Pneumocystosis-IRIS
• It is usually characterized by fever, cough, dyspnea, chest
discomfort, and patchy alveolar infiltrates on the chest
radiograph
• In some patients, organizing pneumonia develops.
• This condition is relatively rare, occurring in less than 5% of
patients treated for PJP prior to ART.

22. Cytomegalovirus IRIS
• Eye disease is the most common manifestation of IRIS
associated with cytomegalovirus infection.
• Retinitis usually develops during the first few weeks of ART as
a paradoxical worsening of treated retinitis or as a new
manifestation of CMV retinitis.
• Previously treated CMV infection is the most common cause
of immune recovery uveitis (IRU), which results from the
restoration of an immune response against residual CMV
antigens in the eye.
• It may develop up to 21 months after ART is commenced
• Clinical manifestations vary in severity from a transient
vitreitis to persistent uveitis, papillitis, cystoid macular edema,
and detachment of epiretinal membranes.

23. PML-IRIS
• Progressive multifocal leukoencephalopathy (PML) occurs
when cellular immune responses fail to control JCV infection
of oligodendrocytes and astrocytes.
• ART is effective in some patients, presumably because it
enhances cellular immune responses against JCV antigens.
• ART may also result in a paradoxical worsening of established
PML or in unmasking of subclinical JCV infection and
appearance of PML for the first time.
• The median time at onset is 7 weeks on ART, and most cases
occur within the first 3 months but very occasionally as late as
26 months.

24. Management
• IRIS is generally self-limiting, and interruption of ART is rarely
indicated.
• Patient may need to be reassured in the face of protracted
symptoms to prevent discontinuation of or poor adherence to
ART.
• Anti-inflammatory therapy should not be given routinely but
be reserved for patients with severe inflammation,
particularly when it is life-threatening, or with significant
symptoms.
• Corticosteroid therapy is used most often, but its
effectiveness may vary from one type of IRIS to another.

25. • A randomized controlled trial in South Africa demonstrated
that corticosteroids (prednisone 1.5 mg/kg/day for 2 weeks,
then 0.75 mg/kg/day for 2 weeks) are a safe and effective
treatment option for paradoxical TB-IRIS.
• Corticosteroid therapy in HIV patients who are already very
immunodeficient should be started only after weighing all
considerations
• Corticosteroid therapy for IRIS affecting the eye should be
supervised by an ophthalmologist.

26. PREVENTION
• Earlier HIV diagnosis and initiation of ART before a decline of
the CD4 count to below 200 cells/ mm3
• Improved screening for OIs before initiating ART, especially TB,
cryptococcal disease and CMV
• Optimal management of OIs before initiating ART.
• Delaying the introduction of ART so that the OI can be fully
treated.
• in cryptococcal meningitis, ART should be deferred for 5
weeks, as earlier initiation increases the risk of death; and in
tuberculosis, ART should be deferred until 8 weeks (except if
the CD4 count is < 50 cells/mm) to prevent IRIS.

27. • However, randomized controlled trials demonstrated that for
patients with HIV-associated TB and CD4+ T-cell count less
than 50 cells/µL, the survival benefit of starting ART within
the first 2 weeks of TB therapy outweighs the risk for IRIS and
other adverse events.
• A randomized controlled trial demonstrated that the risk of
paradoxical TB-IRIS could be reduced by 30% in high-risk
patients (CD4+ T-cell count ≤100 cells/µL) with HIV-associated
TB starting ART by prescribing prednisone for the first 4 weeks
of ART (40 mg daily for 2 weeks then 20 mg daily for 2 weeks).

28. PROGNOSIS
• highly variable because of differences in the extent of the
infection
• Most cases of IRIS are self-limited, and outcomes are usually
good
• Mortality and hospitalization rates are particularly high when
TB-IRIS or C-IRIS affects the CNS
• Mortality rates of 53% have been reported for paradoxical
PMLIRIS and 31% for unmasking PML-IRIS. Furthermore,
patients who survive PML-IRIS may have neurologic sequelae
such as hemiparesis or seizure.
• Lymphadenitis resulting from TB-IRIS11 or NTM-IRIS may
exerience recurrent relapses

29. REFERENCES
• Goldman-Cecil_Medicine_2-
Volume_Set_26th_Edition_by_Lee_Gold
• Uptodate 2021
• Mandell, Douglas, and Bennett's Principles
and Practice of Infectious Disease