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Immune Reconstitution
Inflammatory Syndrome (IRIS)

Project Prashiksha - Online Training of ART Medical Officer 2023

 Session Objectives
By the end of the session the participants will be able to:

• Understand IRIS and its diagnostic criteria

• Review the categories and types of IRIS

• Explain the clinical spectrum and differential diagnosis of IRIS

• Review case studies to understand types of IRIS

• Discuss management and prevention of IRIS

Project Prashiksha - Online Training of ART Medical Officer 2023

 IRIS: Definition

“The worsening of signs and symptoms due to known infections, or the

development of disease due to occult infections within 6 weeks to 6
months after initiating ART; with an increase in CD4 count”

Refer: National Guidelines for HIV Care and Treatment, National AIDS Control
Programme, Care Support, and Treatment services, India: 2021

Project Prashiksha - Online Training of ART Medical Officer 2023

 Criteria for Diagnosing IRIS
• HIV positive
• Receiving ART
o Decrease in HIV-1 RNA level from baseline
o Increase in CD4 cells from baseline
• Clinical symptoms consistent with inflammatory process
• Clinical course NOT consistent with:
o Expected course of previously diagnosed OI
o Expected course of newly diagnosed OI
o Drug toxicity

Source: Samuel A. Shelburne, Martin Montes and Richard J. Hamill Journal of Antimicrobial Chemotherapy,
Source: (2006) 57, 167-170.

Project Prashiksha - Online Training of ART Medical Officer 2023

 Criteria for Diagnosing IRIS
Required Criteria Supportive Criteria
Worsening symptoms of inflammation / Increase in CD4 cell count of >25
infection cells/mm3
Biopsy demonstrating well formed
Temporal relationship with starting granulomatous inflammation or unusually
antiretroviral treatment exuberant inflammatory response
Symptoms not explained by newly
acquired infection or disease or the
usual course of a previously acquired
disease
>1-10 log⃰ decrease in plasma viral load

Source: Robertson et al, Clinical Infectious Diseases Journal, 2006; 42:1639-46

⃰ A log change: in powers of 10
Project Prashiksha - Online Training of ART Medical Officer 2023
 Pathogenesis of IRIS
• Improved Cell Mediated Immunity with restoration of both memory and naïve CD4
cells

• Increased CD4/CD8 cells detect hidden pathogens which were ignored with deficiency
of immunity previously

• Result in inflammatory process at the area of occult / sub-clinical infections

• Usually improves with control of inflammation and specific treatment

• This may produce nonspecific symptoms such as fever or in some cases a paradoxical
worsening of pre-existing symptoms of infective or non-infective conditions

Project Prashiksha - Online Training of ART Medical Officer 2023

 Infectious IRIS
• Mycobacteria • Histoplasma capsulatum
o Mycobacterium tuberculosis • Hepatitis B Virus
o Mycobacterium Avium Intra- • Hepatitis C Virus
cellulare Complex (MAC)
• Progressive multifocal
o Mycobacterium leprae
leukoencephalopathy (PML)
• Cytomegalovirus
• Parvovirus B 19
• Herpes viruses
• Molluscum contagiosum & genital
• Cryptococcus neoformans warts
• Pneumocystis jiroveci • Strongyloides stercoralis & other
parasitic infestations
• Toxoplasma gondii

Project Prashiksha - Online Training of ART Medical Officer 2023

 Non-Infectious Causes of IRIS

Autoimmune IRIS Other Rare Manifestations

• Rheumatoid arthritis • AIDS-related lymphoma

• SLE • Guillain-Barre’ syndrome

• Graves disease • Lymphoid interstitial pneumonitis

• Autoimmune thyroid disease

• Sarcoid IRIS

• Granulomatous reactions

Project Prashiksha - Online Training of ART Medical Officer 2023

 Quiz-1

Question: In the national programme, IRIS is defined as “The worsening of signs

and symptoms due to known infections, or the development of disease due to
occult infections within 6 weeks to 6 months after ART initiation, with a fall in CD4
count.
This statement is True or False?
A. True
B. False

Answer- B

Project Prashiksha - Online Training of ART Medical Officer 2023

 Factors Associated with IRIS

• Lower CD4 counts (below 100 cells/mm3) at ART initiation

• Lower CD4:CD8 ratio at ART initiation
• Higher HIV RNA at ART initiation
• Rapid initial fall in HIV viral load due to ART
• The shorter interval between OI therapy initiation and ART initiation
• Severe TB disease, especially high pathogen burden
• Male sex
• Younger age
• Genetic susceptibility

Source: National Guidelines for HIV Care and Treatment, National AIDS Control Programme, Care Support, and
Treatment services, India: 2021

Project Prashiksha - Online Training of ART Medical Officer 2023

 Onset of IRIS

• The temporal association between the commencement of ART (or change from a
previously failing regimen) and the development of an unusual clinical
phenomenon often provides a strong clue to the diagnosis of IRIS

• Typically, IRIS occurs within 2 to 12 weeks of the initiation of ART, although it may
present later (usually between 6 weeks to 6 months)

Source: National Guidelines for HIV Care and Treatment, National AIDS Control Programme, Care
Support, and Treatment services, 2021

Project Prashiksha - Online Training of ART Medical Officer 2023

 Clinical Spectrum of IRIS

• Heterogeneous

• Onset: early or delayed

• Atypical symptoms

• Generalised or localised

• Varying severity

• Infectious agents / site of infection

• Non infectious disorders

Project Prashiksha - Online Training of ART Medical Officer 2023

 Patterns of IRIS

• Tuberculosis : 68.8%

• Herpes Zoster : 12.5%

• Cryptococcal meningitis : 9.4%

• Toxoplasmosis : 6.3%

• Bacterial Pneumonia : 3.1%

Source: Huruy K et al Japanese Journal of Infectious Diseases 2008; 61:205-8

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 Patterns of IRIS: Indian Observation

Manifestation Pts %
Tuberculosis 42 61.8
PCP 10 14.7
Crypto. Meningitis 8 11.8
CMV Retinitis 4 5.9
Toxoplasmosis 2 2.8
PML 1 1.5
Hepatitis 1 1.5
Total IRIS Observed: 68 Total 68 100

Source: Bhrushundi M Mishra P, Nagpur, India, International AIDS Conference 2006

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 Patterns of IRIS-TB: Indian Observation
Pleural Effusion Abdominal TB
33.3% Manifestation Pts %
Abdominal TB 14 33.3
TB Cervical LN 7 16.7
Disseminated Pulmonary TB 6 14.3
TB
Pleural Effusion 5 11.9
TBM 3 7.1

Pulmonary TB Disseminated TB 5 11.9

Others 2 4.8
TB Cervical LN
IRIS-TB Observed: 42 Total 42 100

Source: Bhrushundi M Mishra P, Nagpur, India, International AIDS Conference 2006

Project Prashiksha - Online Training of ART Medical Officer 2023

 Quiz-2

Question: Typically, IRIS occurs within _____weeks of ART initiation, though it may
present later, between ______ months after starting ART.
Select the correct option to fill in the blanks.

A. 2 weeks to 12 weeks; 8 weeks to 6 months

B. 2 weeks to 12 weeks; 2months to 6 months
C. 6 weeks to 12 weeks; 12 weeks to 6 months
D. 2 weeks to 12 weeks; 6 weeks to 6 months

Answer: D

Project Prashiksha - Online Training of ART Medical Officer 2023

 Categories of IRIS
Categories Antigen Target

Infection-unmasking Viable replicating infective antigen

Infection-paradoxical Dead or dying organisms

Auto immune Host

Malignancies Possible tumor or associated pathogen

Source : Devesh J. Dhasmana, Keertan Dheda, Pernille Ravn, Robert J. Wilkinson and Graeme Meintjes. IRIS in HIV-Infected
Patients Receiving Antiretroviral Therapy Pathogenesis, Clinical Manifestations & Management. Drugs, 2008; 68(2):191-208

Project Prashiksha - Online Training of ART Medical Officer 2023

 IRIS: Tuberculosis (Unmasking Form)
• TB is the most common OI, manifesting as “IRIS” after
ART initiation
• Associated with restoration of tuberculosis reactivity

• Common symptoms include-

o Fever,

o Cervical lymphadenopathy,

o Intra-thoracic lymphadenopathy

• Mean onset of symptoms is 2 weeks

Image courtesy:
CoE, GHTM, Tambaram
• Mean duration of symptoms is 3 weeks
Project Prashiksha - Online Training of ART Medical Officer 2023
 Paradoxical TB-IRIS
• A known HIV-TB patient was initiated on ART after taking ATT for two weeks
• 4 weeks after starting ART, patient developed fever, loss of appetite and dyspnoea
• CXR on the right reveals increased cardio-thoracic ratio with the blunting of cardio phrenic
angles. The picture is suggestive of the diagnosis of Pericardial Effusion
• Paradoxical TB IRIS: Worsening of symptoms of TB in a patient on ART and ATT due to IRIS
• Occurrence of TB Pericardial or Pleural Effusion as a manifestation of IRIS is common in India

Images Courtesy:
GHTM-ITECH
Fellowship,
Tambaram, Chennai

Prior to ART 4 Weeks after starting ART

Project Prashiksha - Online Training of ART Medical Officer 2023

 Unmasking TB- IRIS

Images
Courtesy
GHTM,
Tambaram,
Chennai

Prior to ART 11 weeks after ART

Pre- ART Chest X-ray- WNL

Post ART CXR- right cavitary lesion in the left lower lung field.
Sputum AFB + ve
Diagnosis: Pulmonary TB
Since it happened post ART, it is Unmasking IRIS-TB
Project Prashiksha - Online Training of ART Medical Officer 2023
 IRIS- PCP
A 22 years old male HIV positive since February 2000, on Cotrimoxazole preventive
therapy (CPT), found to be eligible for ART in March 2006
o ART was started on 8th March, 2006 (CD4: 58 cells)

o Presented with cough, grade 4 dyspnoea and tachypnoea on 16th May, 2006
(CD4: 162 cells)
o Diagnosis: IRIS-PCP

o Dramatic improvement of PCP therapeutic dose along with steroids in 2 weeks

time

Please see serial X-rays in the next slide

Project Prashiksha - Online Training of ART Medical Officer 2023

 IRIS-PCP

Prior to ART After initiating ART After the Therapeutic

March 8, 2006 May 16, 2006 dose of Cotrimoxazole
CD4 count: 58 CD4 count : 162

Case and Image Source: GHTM – I-TECH Fellowship Program, Tambaram, Chennai

Project Prashiksha - Online Training of ART Medical Officer 2023

 IRIS-Leprosy
• A 30 year old man, who was initiated on ART (TLE)
• Multiple papulonodular lesions were found
erupting all over the back 3 months after ART
initiation
• Biopsy from the Erythema Nodosum lesion was
suggestive of lepromatous leprosy
• It needs to be treated with MDT (Multi drug
therapy), which includes Rifampicin
• Management Plan:
• MDT
Case and Image Courtesy:
GHTM-ITECH Fellowship programme
• Continue ART

Project Prashiksha - Online Training of ART Medical Officer 2023

 IRIS: CMV Retinitis / Uveitis

Image Source: Graeme Meintjes, HIV service, GF Jooste Hospital, Department of Medicine,
UCT

Project Prashiksha - Online Training of ART Medical Officer 2023

 IRIS: Differential Diagnosis

• Active Opportunistic Infection

• Treatment Failure

• Adverse reactions to ARVs

• Failure to Anti-microbial therapy

Project Prashiksha - Online Training of ART Medical Officer 2023

 Management
• Mild form (with ongoing ART)

o Observation

• Localised IRIS (with ongoing ART)

o Local therapy such as minor surgical procedures for lymph node abscesses

• As per system involvement e.g., neurological, respiratory

Project Prashiksha - Online Training of ART Medical Officer 2023

 Management

Most of the situations (with ongoing ART)

• Unmasking &/or Recognition of ongoing infections
o Antimicrobial therapy is required to reduce and to eliminate the triggering
pathogen (antigenic load)
• Reconstituting immune reaction to non-replicating antigens
o No antimicrobial therapy is required
o Short term therapy with corticosteroids or non-steroidal anti -
inflammatory drugs to reduce the inflammation

Project Prashiksha - Online Training of ART Medical Officer 2023

 Management
• Short Course of Steroids maybe given to reduce Inflammation
o Dose of steroids: Prednisolone in dose of 1.5mg/kg orally for 2 weeks followed by
0.75mg/kg for 2 weeks orally and then tapered off
• Temporary cessation of ART has to be considered, only when Life-threatening/ Sight
threatening forms of IRIS develop
o IRIS-Cryptococcal meningitis
o IRIS-CMV retinitis
• Treat the OI with complete course of treatment before restarting ART

Project Prashiksha - Online Training of ART Medical Officer 2023

 Quiz-3

Question: One of the following cannot be a predisposing factor to develop IRIS.

Choose the incorrect option.
A. Young male PLHIV,
B. PLHIV with baseline CD4 count of 300 cells
C. PLHIV with a high viral load at baseline
D. A rapid fall in viral load after ART initiation

Answer: B
Lower CD4 counts (below 100 cells/mm3) at ART initiation

Project Prashiksha - Online Training of ART Medical Officer 2023

Important steps to reduce the development of IRIS

• Earlier HIV diagnosis and initiation of ART before decline of CD4 below 200 cells/mm3;

• Improved screening for OIs before ART, especially TB, Cryptococcus, CMV and

• Optimal management of OIs before initiating ART

• Timing of ART in people with OIs requires balancing a greater risk of IRIS after early
initiation against continuing high mortality if ART is delayed

Project Prashiksha - Online Training of ART Medical Officer 2023

 Key Messages

• IRIS is a wide variety of clinical syndrome in HIV-infected patients following

immune restoration, as a result of ART initiation

• HIV infected persons who come late in their disease course, with low CD4 counts
(advanced stage of immunodeficiency) are at the greater risk of IRIS

• IRIS is less likely to occur when ART is initiated early (when patient has high CD4
count)

• Clinicians need to consider IRIS as one of the diagnostic options, whenever PLHIV
develop various clinical manifestations after ART initiation

Project Prashiksha - Online Training of ART Medical Officer 2023

 Thank You

Project Prashiksha - Online Training of ART Medical Officer 2023