Immune Reconstitution Inflammatory Syndrome (IRIS)

Epidemiology

Definition

Immune Reconstitution Inflammatory Syndrome (IRIS) is an Inflammatory Response with Either Paradoxical Worsening of a Preexisting Infection (“Paradoxical IRIS”) or Worsening of an Unrecognized Preexisting Infection (“Unmasking IRIS”)
- Treatment of HIV/AIDS with Antiretroviral Therapy (ART) is the Best Described Precipitant of IRIS

Physiology

Immune Reconstitution Due to Human Immunodeficiency Virus (HIV) Treatment (see Human Immunodeficiency Virus)

AIDS-Defining Illnesses Associated with Immune Reconstitution Inflammatory Syndrome (IRIS)

Infectious Illnesses
- Bacillus Calmette-Guerin (BCG) (see Bacillus Calmette-Guerin)
- Bartonellosis (see Bartonellosis)
- Cryptococcosis (see Cryptococcosis)
- Cytomegalovirus (CMV) (see Cytomegalovirus)
- Dermatophytosis
- Hepatitis B Virus (see Hepatitis B Virus)
- Hepatitis C Virus (see Hepatitis C Virus)
- Herpes Simplex Virus (HSV) (see Herpes Simplex Virus)
- Histoplasmosis (see Histoplasmosis)
- Human Herpesvirus 8 (Kaposi’s Sarcoma-Associated Herpesvirus) (see Human Herpesvirus 8, [[Human Herpesvirus 8]] and Kaposi Sarcoma)
- JC Virus (see JC Virus)
- Leishmaniasis (see Leishmaniasis)
- Leprosy (see Leprosy)
- Molluscum Contagiosum (see Molluscum Contagiosum)
- Mycobacterium Avium Complex (MAC) (see Mycobacterium Avium Complex)
- Parvovirus B19 (see Parvovirus B19)
- Penicillium Marneffei (see Penicillium Marneffei)
- Pneumocystis Jirovecii (see Pneumocystis Jirovecii)
- Schistosomiasis (see Schistosomiasis)
- Tuberculosis (see Tuberculosis)
- Varicella-Zoster Virus (VZV) (see Varicella-Zoster Virus)
Other Illnesses
- Grave’s Thyrotoxicosis (see Grave’s Disease)
- Sarcoidosis (see Sarcoidosis)

Clinical Data

Systematic Review and Meta-Analysis of IRIS (Lancet Infect Dis, 2010) [MEDLINE]
- Incidence of IRIS is Variable Across Different AIDS-Defining Illnesses
  - Illnesses Associated with the Highest Incidence of IRIS
    - CMV Retinitis (see Cytomegalovirus)
    - Cryptococcal Meningitis (see Cryptococcosis)
    - Tuberculosis (see Tuberculosis)
  - Illnesses Associated with the Lowest Incidence of IRIS
    - Herpes Zoster (see Varicella-Zoster Virus)
    - Kaposi Sarcoma (see Kaposi Sarcoma)
- Incidence of IRIS is Inversely Correlated with the CD4 Count at Baseline
  - Higher Incidence of IRIS is Observed in Patients with CD4 <50 cells/μL: particularly in patients with tuberculosis, CMV-associated immune recovery uveitis, and cryptococcal meningitis
  - Higher Incidence of IRIS at Lower CD4 Counts is Not Surprising, Since CMV Retinitis is Typically an Infection Which Occurs at CD4 <50 cells/μL, Cryptococcal Meningitis Typically Occurs at Low CD4 Counts (While Tuberculosis and Kaposi Sarcoma Tend to Occur at Higher CD4 Counts)
- Mortality Rate Associated with IRIS: 4%
  - Mortality Rate from IRIS is Much Higher with Cryptococcal Meningitis

Immune Reconstitution in Other Clinical Scenarios

Treatment of Lepromatous Leprosy (see Leprosy)
- Epidemiology: cases of IRIS have been described in non-HIV patients treated for leprosy (Rev Infect Dis, 1981) [MEDLINE]
Treatment of Tuberculosis (see Tuberculosis)
- Epidemiology: cases of IRIS have been described in non-HIV patients treated for tuberculosis (Lancet, 1984) [MEDLINE]
Engraftment of Hematopoietic Stem Cell Transplant (HSCT) (see Hematopoietic Stem Cell Transplant)
Recovery of Neutropenia After Chemotherapy
Withdrawal of Anti-Tumor Necrosis Factor-α (TNFα) Therapy (see Anti-Tumor Necrosis Factor-α Therapy)
- Epidemiology: cases have been described in non-HIV patients with withdrawal of anti-TNFα therapy (Diagn Microbiol Infect Dis, 2009) [MEDLINE]
Withdrawal of Corticosteroids (see Corticosteroids)
- Epidemiology: cases have been described in non-HIV patients with corticosteroid withdrawal
Withdrawal of Immunosuppression in Transplant Patients with Cryptococcosis
- Epidemiology: cases have been reported (Clin Infect Dis, 2005) [MEDLINE]

Clinical Manifestations

General Comments

Timing of IRIS
- Most Cases of IRIS Manifest 1 wk-Months After Initiation of ART Therapy for HIV
Clinical Manifestations are Variable, Depending on the Infection and Organ System Involved

IRIS Associated with Preexisting Cryptococcal Infection

General Comments
- Onset of Symptoms
  - Symptoms Usually Occur within 2 mo of Initiation of Therapy (But May Be Delayed for >6 mo in Some Cases)
- Localization of Symptoms
  - May Be Either Neurologic or Pulmonary
Neurologic Manifestations
- Diagnosis
  - Lumbar Puncture (see Lumbar Puncture)
  - Paucity of Cerebrospinal Fluid Leukocytes at Initial Cryptococcal Meningioencephalitis Diagnosis (<25 Cell/μL) is Associated with an Increased Risk of IRIS
    - Repeat Cerebrospinal Fluid Analysis After the Onset of IRIS Frequently Reveals Increased Leukocytes, as Compared to the Initial Analysis: however, cultures usually remain sterile
- Clinical
  - Eye Pain (see Eye Pain)
  - Fever (see Fever)
  - Increased Headache (see Headache)
  - Nausea (see Nausea and Vomiting)
  - Nuchal Rigidity (see Nuchal Rigidity)
  - Photophobia (see Photophobia)
Pulmonary Manifestations
- Acute Respiratory Distress Syndrome (ARDS) (see Acute Respiratory Distress Syndrome, [[Acute Respiratory Distress Syndrome]])
- Cavitary Lung Lesions (see Cystic-Cavitary Lung Lesions)
- Hypoxemia (see Hypoxemia)
- Respiratory Failure (see Respiratory Failure)
Other Manifestations
- General Comments: while rare, these manifestations may occur in patients with disseminated cryptococcosis
- Cutaneous Abscesses
- Hypercalcemia
- Mediastinal Lymphadenitis

IRIS Associated with Cytomegalovirus (CMV)

Other Manifestations
- Fever (see Fever)

IRIS Associated with Mycobacterial Infection

General Comments
- For Tuberculosis, the Immune Reconstitution May Follow Either the Initiation of Antituberculous Therapy Alone (in Non-HIV or HIV Patients) or the Initiation of Antiretroviral Therapy (ART) (in HIV Patients)
Immune Reconstitution Due to Antituberculous Therapy
- Mechanism: immune-mediated
- Diagnosis:
- Clinical Features
  - Fever (see Fever)
  - Malaise
  - Pulmonary Symptoms
    - Acute Respiratory Distress Syndrome (ARDS) (see Acute Respiratory Distress Syndrome, [[Acute Respiratory Distress Syndrome]]): can occur in rare cases
    - New/Worsening Pulmonary Infiltrates
    - New Pleural Effusions (see Pleural Effusion-Exudate)
    - Worsening Hilar/Mediastinal Lymphadenopathy (see Mediastinal Mass)
  - Weight Loss (see Weight Loss)
  - Worsening Intracranial Tuberculomas
  - Worsening Lymphadenitis
- Prognosis: self-limited in most cases
Immune Reconstitution Due to Antituberculous Therapy and Antiretroviral Therapy
- Incidence: the incidence of IRIS with pulmonary TB and HIV coinfection after anitiretroviral therapy than in non-HIV pulmonary TB cases alone
- Timing of Onset: IRIS tends to occur within the first 60 days after starting antiretroviral therapy
- Clinical Features
  - Bowel Perforation
  - Cutaneous Lesions
  - Epididymitis (see xxxx)
  - Granulomatous Nephritis
  - Peritonitis (see xxxx)
  - Worsening Lymphadenitis

IRIS Associated with Hepatitis B/C

xxx

IRIS Associated with JC Virus

xxx

IRIS Associated with Leishmaniasis

xxx

IRIS Associated with Pneumocystis Jirovecii

xxx

IRIS Associated with Varicella-Zoster Virus (VZV)

xxx

IRIS Associated with Sarcoidosis

xxx

Prevention

Delayed Initiation of HIV Therapy

COAT Trial Examining the Timing of ART Therapy in HIV Patients with Cryptococcal Meningitis (NEJM, 2014) [MEDLINE]
- Delaying Initiation of ART for 5 wks After the Diagnosis of Cryptococcal Meningitis was Associated with Improved Survival, as Compared to Initiating Therapy at 1-2 wks (Especially in Patients with a Paucity of WBC in the CSF)

Treatment

xxx

References

General

The immunology of leprosy: speculations on the leprosy spectrum. Rev Infect Dis. 1981;3(3):422 [MEDLINE]
Paradoxical expansion of intracranial tuberculomas during chemotherapy. Lancet. 1984;2(8396):181 [MEDLINE]
Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med. 1998 Jul;158(1):157-61 [MEDLINE]
Immunorestitution disease involving the innate and adaptive response. Clin Infect Dis. 2000;30(6):882 [MEDLINE]
Acute respiratory failure following HAART introduction in patients treated for Pneumocystis carinii pneumonia. Am J Respir Crit Care Med. 2001 Sep 1;164(5):847-51 [MEDLINE]
An immune reconstitution syndrome-like illness associated with Cryptococcus neoformans infection in organ transplant recipients. Clin Infect Dis. 2005;40(12):1756. Epub 2005 Apr 29 [MEDLINE]
Central nervous system immune reconstitution disease in acquired immunodeficiency syndrome patients receiving highly active antiretroviral treatment. J Neurovirol. 2005;11 Suppl 3:16-22 [MEDLINE]
Immune reconstitution inflammatory syndrome after cessation of the tumor necrosis factor alpha blocker adalimumab in cryptococcal pneumonia. Diagn Microbiol Infect Dis. 2009;64(3):327 [MEDLINE]
Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis. 2010 Apr;10(4):251-61. doi: 10.1016/S1473-3099(10)70026-8 [MEDLINE]
Immune Reconstitution Inflammatory Syndrome (IRIS): What pathologists should know. Semin Diagn Pathol. 2017;34(4):340. Epub 2017 Apr 26 [MEDLINE]

Prevention

Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med. 2014 Jun 26;370(26):2487-98. doi: 10.1056/NEJMoa1312884 [MEDLINE]