Immune Restoration Inflammatory Syndrome IRIS

1
Immune Restoration Inflammatory Syndrome (IRIS)

• Woraphot Tantisiriwat, MD,MPH
• Faculty of Medicine,
• Srinakharinwirot University,
• Bangkok, Thailand

2
Overview

• Immune reconstitution with potent antiretroviral
  therapy
• Unusual manifestations of OIs after potent
  antiretroviral therapy
• Immune Restoration Syndrome
• Case Discussion

3
Effects of potent antiretroviral therapy

• Decrease HIV plasma RNA to levels
• Increase CD4 cell count

4
T-Cell Changes During HIV Infection
Healthy
HIV
Late disease
Naive cells
Memory cell clones
Effector cell clones
Source Goodnow. In Ciba Foundation Symposium
204 The Molecular Basis of Cellular Defense
Mechanisms. John Wiley Sons 1997190-207.
5
Effect of Therapy?
Post treatment
Late disease
Post treatment
Naive cells Memory cell clones Effector cell
clones
6
CD4 T-Cell Dynamics With HAART
Total
Memory cells
CD4 T Cells
Naive cells
HIV-1specific T cells
Time
8-12 Weeks
7
Changes in OIs Manifestations with HAART
(Tantisiriwat W et al AIDS Reader 122-30,1999)

• MAC
• M Kansasi
• CMV
• Viral hepatitis (B,C)
• TBc
• VZV
• Cryptococcus

• Localized lymphadinitis
• Mediastinal adinitis, osteomyelitis, arthritis
• Vitritis, retinits with ? CD4
• Worsening hepatitis
• Paradoxical reaction
• Acute retinal necrosis, ? shingles
• Recurrent of meningitis, Pulmonary and cutaneous
  cryptococcosis

8
Immune recovery inflammatory syndrome

• Retrospective study of 133 patients responding to
  potent ART
• 33 with history of prior OIs developed
  inflammatory reaction 1-2 mo after starting
• recrudescence of HSV zoster
• CMV retinitis MAC
• Acute HCV hepatitis MTB adenitis
• Low baseline CD4 count strong predictor
• French et al, HIV Med,107-15,2000

9
Immune Restoration Syndrome

• Immune reconstitution syndrome
• Immune recovery inflammatory syndrome
• Immune reconstitution inflammatory syndrome

10
Immune Restoration Syndrome

• Improve CMI with restoration of CD4 cells both
  memory and naive cells
• Increased CD4/CD8 cells detect hidden pathogens
  which were ignore with deficiency of immunity
  previously
• Result in inflammatory process of the area of
  occult infections
• Usually improved with control of inflammation and
  specific treatment

11
Potential Impact of Factors Influencing
Development of IRISStoll M et al Curr Infect
Report 266-76, 2003
12
Immune Restoration Syndrome

• Risk factors
• Low CD4 cell count
• High burden of pathogen or pathologic antigen
• Dysregulation of immune process
• Shift towards Th-1 cytokine profile with ?
  IFN-?
• MHC gene haplotypes (HLA-B44)
• Cytokine gene polymorphisms (IL6,12, TNF, etc)
• Price P, et al Hum Immunol 157-64, 2001
• French M, et al HIV Med 107-15, 2000
• French M, et al WEST PAC Conference, Perth, 2002
• Shelburne SA, et al Medicine 213-27,2002
• Chien J, et al Chest 933-6, 1998

13
MAC IRS

• Lymphadinitis (within 3 months after HAART)
• Significant ? in memory CD4 cells with ? WC
• Bx granulomatous inflammation
• Localized lymph node enlargement with caseation
• Negative blood culture
• Race et al Lancet 351 252-5,1998

14
MAC IRS (cont)

• Necrotizing subcutaneous nodules
• Endobronchial tumors
• Small bowel involvement
• Paravertebral abscesses
• Brown M, et al Sex Transm Infect 149-50, 2001
• Bartley PB, et al Int J Tubec Lung Dis 1132-6,
  1999
• Currier JS, et al Ann Intern Med 493-503, 2000
• del Giudice, et al Arch Dermatol 1129-30, 1999
• Cinti SK, et al CID 511-4, 2000

15
MTB IRS

• 36 of patients with combined MTB HIV
  infections after initiation of HAART developed
  paradoxical clinical deterioration
• Prolong fever (101.5F)
• Increasing respiratory symptoms
• Increasing lymphadenopathy
• Cutaneous lesions
• Ascites
• CXR worsening (?lymph node, consolidation,
  effusion)
• Tuberculoma Narita M, et al Am J Respir
  Crit Care Med 157-61, 1998 McCormack JG, et al
  CID 1008-9, 1998

16
CMV IRS

• Eye
• Intensity of inflammatory response ??? compared
  to standard CMV retinitis
• Immune recovery vitreitis
• Immune recovery uveitis
• Inflammatory reaction can lead to proliferative
  vitreoretinopathy and posterior chamber cataracts
  resolved in severe visual compromise
• Local steroid treatment may be helpful
• Jacobson M, et al Lancet 1443-5, 1997
• Holland GN. Ocular Immunol Inflamm 215-21, 1999
• Postelmans L, et al Ocular Immunol Inflamm
  237-40, 1999
• Cassoux N, et al Ocular Immunol Inflamm
  231-5,1999

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CMV IRS (cont)

• Systemic
• Pneumonitis
• colitis
• Possible HLA-B44 related
• Gilquin J, et al AIDS 1659-60, 1997
• Miller RF, et al Sex Transm Infect 60, 2000
• Price P, et al Hum Immunol 157-64, 2001

18
Cryptococcal IRS

• Presence of cryptococcal Ag without viable
  organisms can incite significant immune response
  in HAART-treated patient
• Recurrent meningitis
• Pulmonary cryptococcosis
• Cutaneous cryptococcosis
• Mediastinal and cervical lymphadinitis
• Shelburne SA, et al Medicine 213-27,2002
• Blanche P, et al Scand J Infect 615-6, 1998
• Lanzafame M, et al Chest 848-9, 1999
• Manfredi R, et al Mycopathologia 73-8, 1999

19
Herpes Zoster IRS

• 2X 5X increased in incidence of zoster in
  patients treated with HAART compared to non
  treated patients
• Mean occurrence week 16
• Longest interval reported week 103
• Peak CD8 response in 1 month has been
  associated with development of zoster
• Acute retinal necrosis
• Andersson J, et al AIDS F123-29, 1998
• Martinez E, et al CID 1510-3, 1998
• Estrada V, et al AIDS S90, 1998

20
Hepatitis C IRS

• Worsening of hepatitis
• Possible related with increase in cytotoxic CD8
  T lymphocytes causing in immune-mediated
  hepatocyte destruction
• Increased in HCV RNA levels, mostly return to
  baseline within 3 months
• ? Drug side effect related
• Pouti M, et al J Infect Dis 2033-6, 2000
• Rutchmann OT, et al J Infect Dis 783-5, 1998
• Vento S, et al AIDS 116-7, 1998

21
Hepatitis B IRS

• Worsening of hepatitis
• Transient ? HBV DNA clinical hepatitis
• Continuation of HAART may lead to clearing of
  HBsAg and resolution of hepatitis
• ? Drug side effect related
• Mangold C, et al CID 144-8, 2001
• Mastroianni CM, et al AIDS 1939-40, 1998
• Proia LA, et al Am J Med 249-51, 2000
• Velasco M, et al 1765-66, 1999

22
JC IRS

• With HAART, JC virus in CSF ? and also levels of
  antibody to JC virus
• Inflammatory PML variant MRI enhancement of
  lesion extensive demyelination with surrounding
  inflammation consisting with lymphoplasmoid cells
• Collazos J, et al AIDS 1426-8, 1999
• Kotecha N, et al Am J Med 541-3, 1998

23
PCP IRS

• Reports of granulomatous response in stead of
  usual interstitial mononuclear cell inflammatory
  cell debris
• Bleiweiss IJ, et al Chest 580-3, 1988
• Blumenfeld W, et al Ann Intern Med 505-7, 1988
• Flannary MT, et al South Med J 409-10, 1996
• Klein JS, et al AJR 753-4, 1989

24
Sarcoidosis Kaposi Sarcoma IRS

• Worsening of sarcoidosis IL-2 and ? CD4 T
  cells Response to steroid, thalidomide
• Lenner R, et al Chest 978-81, 2001
• Usually KS resolved with HAART
• Report of worsening KS lesion with inflammation
  edema
• Weir A, et al AIDS 116-7, 1998

25
Non-infectious IRS

• Graves Disease
• Graves disease after institution of HAART
• thyrotropin receptor antibodies which were
  negative before HAART
• HAART associated thymic-mediated redevelopment of
  T-cell repertoire abnormality results in
  proliferation of auto-reactive T cells causing
  autoreactivity
• Gilquin J, et al Lancet 1907-8, 1998
• Jubault V, et al J Clin Endocrinol Metab 4254-7,
  2000

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Non-infectious IRS (cont)

• SLE
• Vasculitis
• Reiter Syndrome
• Rheumatoid arthritis
• Polymyositis
• Alopecia universalis
• Hyperergic reaction (against tatoos, foreign
  bodies)
• Behrens G, et al. Lancet 3511057-8, 1998
• Ward HA, et al. J Am Acad Dermatol 46284-93,
  2002
• Bell C et al. Int J STD AIDS 13580-1, 2002
• Sellier P et al. Am J Med 109510-2, 2000
• Sereti I et al. AIDS 15138-40, 2001
• Silvestre JF et al. Arch Dermatol 137669-70, 2001

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Practical concept

• Immune Reconstitution Syndrome is common
  especially in the setting of very low CD4 cell
  count (HAART
• Screening for hidden OIs before starting HAART
  would be helpful to avoid unpleasant situation
• Unusual/ usual presentations of OIs within 3
  months of starting HAART, think of immune
  reconstitution syndrome and may be beyond
• Steroid specific treatment should be helpful

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Stoll M et al Curr Infect Report 266-76, 2003
29
Clinical Scenario

• 33 yr old female Dx HIV infection 6 yr ago,
  husband died from cryptococcal infection
• No antiretroviral treatment
• On Bactrim 2 yr
• Come to see you today for persistent low grade
  fever x 2 wks
• No symptoms except some blurred vision of Rt. eye

30
Clinical Scenario

• Fundoscopy CMV retinitis both eyes, Rt. side is
  close to macular
• CD4 cell count 10
• HIV viral load 478,000
• CBC Hb 10, WC 1.6 N28 L35 M33 E1 B3, plt 310
• LFT WNL
• CXR no pulmonary infiltrate
• Cryptococcal Ag positive 132
• Blood culture for MAC done

31
Clinical Scenario

• LP CSF WC 8 all mononuclear cell
• CSF cryptococcal Ag negative
• Pt underwent ampho B Rx x 2wks follow by
  fluconazole 400 mg/d
• Pt received ganciclovir intraocular Rx
• Also received dapsone for PCP prophylaxis and
  Azithromycin for MAC prophylaxis
• Blood culture for MAC negative

32
Clinical Scenario

• Antiretroviral therapy was started (D4T 3TC
  Effavirenz)
• Pt complaint for dizziness, confusion after 1
  week of antiretroviral therapy
• Neurologic symptoms was increased during the next
  2-3 weeks ? more confusion, behavior change with
  visual hallucination and weakness of lower limbs

33
Clinical Scenario

• MRI brain Temporal lobe encephalitis
• LP CSF WC 51 mono29 PMN22, protein 650, glucose
  59, cryptococcal Ag negative
• CSF herpes PCR negative
• CSF CMV PCR positive
• Systemic ganciclovir IV was started
• Clinical improvement with resolution of
  behavioral change and weakness

34
Clinical Tip Problems After Initiation of
Antiretroviral therapy

• Screen for OIs and aware of IRS or hidden OIs
  especially during the first 3 months of ARV
  (especially for low CD4 cell count patients)
• Understand and aware of short term and long term
  side effect of use ARV
• Aware of interaction of present medication and
  ARV
• Aware of treatment failure

35
Special thank to

• William G Powderly, MD Washington University,
  USA
• Carl J Fichtenbaum, MD University of
  Cincinnati, USA