Outline the features of the Immune Reconstitution Inflammatory Syndrome (IRIS) in patients with Human Immunodeficiency Virus (HIV) infection with regards to:

  1. Definition
  2. Pathogenesis 
  3. Risk factors
  4. Differential diagnosis 
  5. Clinical features 
  6. Management

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College answer

Definition

A collection of inflammatory disorders associated with paradoxical worsening of pre-existing infectious process following initiation of antiretroviral therapy primarily in HIV-infected patients.  It has also been described in patients receiving therapy for TB.

Pathogenesis

HIV infection produces CD4+ T cell immune suppression.

HIV half-life is generally between 1-4 days

With commencement of antiretroviral therapy there is greater than 90% reduction of HIV viral burden within 1-2 weeks.

CD4+ T lymphocyte count rapidly increases over the first 3-6 weeks

Increased lymphocyte activity then leads to systemic or local inflammatory reactions at the site or sites of pre-existing infection (known or unknown)

Risk Factors

Lower CD4 counts at time of initiation of therapy

High viral load at time of initiation of therapy

More significant response to antiretroviral therapy

Differential diagnoses 

Progression of initial opportunistic infection

New opportunistic infection

Drug toxicity

Clinical features 

Most patients develop symptoms within 1 week to a few months after the initiation of antiretroviral therapy.  Symptoms can be localised or systemic.  Features are similar to the primary infection.

Depend on the site and organism involved.  Commonly:

Pneumocystis jerovicii: fever, cough, dyspnoea, hypoxia and progressive radiographic pulmonary opacification.  BAL: large numbers of inflammatory cells

Cryptococcus: CNS: fever, headache, neck stiffness, photophobia. Pulmonary: lung lesions, hypoxia, respiratory failure and ARDS

TB: clinical or radiological pulmonary deterioration, lymphadenopathy, enlarging intracranial lesions

Others (any reasonable description OK): TB, MAC, CMV (uveitis), JC virus, Hepatitis B&C – worsened LFT’s. with fevers, seats anorexia; Kaposi sarcoma, toxoplasmosis (CNS)

Management 

Supportive

Continue antiretroviral therapy

Treat the underlying opportunistic infection

Severe symptoms = steroid therapy

Discussion

The college definition seems to be paraphrased from the opening paragraphs of Sharma & Soneja (2011), where it is described as a "paradoxical worsening of an existing infection or disease process".  Suggested definitions (French et al, 2004; Robertson et al, 2006) generally require some combination of the following features:

  • Temporal relationship with antiretroviral treatment
  • Worsening of inflammation
  • Symptoms not explained by new infection or worsening of a previous infection
  • Increase in CD4 count or decrease in HIV RNA copies

Obviously such HIV-centric definitions do not take into account the fact that IRIS can occur in several other conditions (eg. with tuberculosis).

Pathogenesis of IRIS is well-described in the IRIS article from UpToDate, from which the college answer appears to draw most of its inspirations.  For the purposes of regurgitating a point-form summary of what happens, the causes of IRS can be summarised thus:

  • The loss of CD-4 TH cells results  in a diminished immune response against a variety of antigens
  • As a consequence, with a very low CD4 cell count there may be infections with opportunistic pathogens which are sub-clinical and unrecognised
  • As HAART is started, HIV viral load rapidly decreases by as much as 90%  (as HIV has a short 1-4 day half life) and CD4 counts increase (over 3-6 weeks)
  • As CD4 counts increase, antigen-specific immune response pathways are restored
  • Thus, clinically silent opportunistic infections suddenly become clinically apparent as the immune response to them returns to normal
  • This typically manifests as inflammation of the locally affected tissues, or potentially as systemic inflammatory response resembling septic shock.

Risk factors for IRS  (according to Shellburn et al, 2005include:

  • Low CD4 counts at baseline
  • High HIV viral load at baseline
  • Highly active antiretroviral therapy (HAART)
  • Rapid drop of HIV RNA counts (i.e. vigorous response to HAART)
  • Infection with characteristic agents:
    • M. tuberculosis
    • M. avium complex
    • C. neoformans
    • P. jirovecii
    • VZV
    • HSV
    • CMV
    • Hepatitis viruses

Differential diagnosis (From Beshuizen et al, 2009):

  • Treatment failure of ART
  • Failure of treatment of an opportunistic infection
  • An alternative opportunistic infection.
  • Drug interactions
  • Drug toxicity

Clinical manifestations may include:

  • ARDS
  • Worsening of Pneumocystis pneumonia
  • Vasodilated shock
  • Fevers and rigors
  • Worsening of progressive multifocal leukoencephalopathy
  • Worsening of CNS tuberculosis infection (or pulmonary, for that matter)
  • Worsening of CMV retinitis and uveitis
  • Exacerbation (or de novo emergence) of VZV encephalitis
  • Worsening of cryptococcal meningitis (rising ICP)
  • Enlargement of CNS lesions due to M.tuberculosis
  • Worsening liver function due to IRIS reaction against Hep B or Hep C
  • Typically, features develop rapidly (within 90 days) of commencing HAART.

Management of IRIS (from Konishi et al, 2010)

  • Major management principles
    • Continue HAART 
    • Aggressively treat the opportunistic infection against which the reconstitution response has developed
    • Wait: most of the time, IRIS resolves over days or weeks
  • Specific therapy
    • NSAIDs
    • Corticosteroids (0.5-1.0mg/kg/day of prednisolone)
    • Infliximab, anti-TNF-α monoclonal antibody (Richaud et al, 2015)
    • Adalimumab, another kind of anti-TNF-α monoclonal antibody (Lwin et al, 2018)
  • Supportive therapy
    • Vasopressors, lung-protective ventilation, ICP management, FASTHUG
  • Worst case scenario
    • Interrupt HAART therapy

References

Mayer, Kenneth H., and Martyn A. French. "Immune reconstitution inflammatory syndrome: a reappraisal." Clinical Infectious Diseases 48.1 (2009): 101-107.

Sharma, Surendra K., and Manish Soneja. "HIV & immune reconstitution inflammatory syndrome (IRIS)." The Indian journal of medical research 134.6 (2011): 866.

French, Martyn A., Patricia Price, and Shelley F. Stone. "Immune restoration disease after antiretroviral therapy." Aids18.12 (2004): 1615-1627.

Robertson, Jaime, et al. "Immune reconstitution syndrome in HIV: validating a case definition and identifying clinical predictors in persons initiating antiretroviral therapy.Clinical infectious diseases 42.11 (2006): 1639-1646.

Shelburne, Samuel A., et al. "Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy." AIDS 19.4 (2005): 399-406.

Beishuizen, S. J., and S. E. Geerlings. "Immune reconstitution inflammatory syndrome: immunopathogenesis, risk factors, diagnosis, treatment and prevention." Neth J Med 67.10 (2009): 327-331.

Konishi, M., K. Uno, and E. Yoshimoto. "Management of immune reconstitution inflammatory syndrome." Nihon rinsho. Japanese journal of clinical medicine 68.3 (2010): 508-511.

Richaud, Clémence, et al. "Anti-tumor necrosis factor monoclonal antibody for steroid-dependent TB-IRIS in AIDS." Aids 29.9 (2015): 1117-1119.

Lwin, Nilar, Michael Boyle, and Joshua S. Davis. "Adalimumab for corticosteroid and infliximab-resistant immune reconstitution inflammatory syndrome in the setting of TB/HIV coinfection." Open forum infectious diseases. Vol. 5. No. 2. US: Oxford University Press, 2018.