What is immune reconstitution inflammatory syndrome?
Immune reconstitution inflammatory syndrome (IRIS) is an immune-mediated form of inflammation directed against antigens including various microorganisms and drugs, developing after recovery from a state immunosuppression [1]. It is most commonly seen as a paradoxical worsening of pre-existing infectious processes after the initiation of antiretroviral therapy in patients with advanced human immunodeficiency virus (HIV) infection. Although it can also be caused by non-infectious disorders, IRIS is usually described in association with mycobacterial, fungal, and viral opportunistic infections.
It can be classified into two types [2]:
- Paradoxical IRIS: the worsening of a previously diagnosed opportunistic infection after initiating antiretroviral therapy
- Unmasking IRIS: the presentation of a previously undiagnosed opportunistic infection with exaggerated inflammatory features after initiating antiretroviral therapy.
There are multiple synonyms for IRIS: immune reconstitution syndrome, immune recovery disease, immune reconstitution disease, immune restoration disease, immune rebound illness, and immune response reactions.
Who gets immune reconstitution inflammatory syndrome?
In 10–20% of HIV-infected patients starting on antiretroviral therapy, rapid improvement of immune function is followed by its dysregulation. This results in an aberrant inflammation that is usually directed against an opportunistic infection.
Similar paradoxical reactions have also been described in patients who are not infected with HIV. This is thought to be due to sudden change in the T helper responses to inflammation with inadequate anti-inflammatory responses in the following cases [1,3].
- After initiating treatment for tuberculosis (TB), lepromatous leprosy, or Whipple disease
- In some patients with severe cutaneous adverse drug reactions, autoimmune diseases, pregnancy, organ transplant recipients, and internal malignancies
- After discontinuing immunosuppressive drugs, such as systemic corticosteroids, tumour necrosis factor-alpha (TNF-α) inhibitors, immune checkpoint antagonists (see targeted cancer therapies), or chemotherapy.
What causes immune reconstitution inflammatory syndrome?
The underlying mechanisms that cause IRIS are not yet fully understood [4].
HIV infection causes multiple deleterious effects on the immune system. It is characterised by a gradual drop in CD4+ lymphocytes, leading to opportunistic infections and specific neoplasms.
The viral load declines in the first 8 to 12 weeks after starting treatment with antiretroviral therapy before it stabilises. At the same time, there is an inverse proportional increase in the CD4+ lymphocyte count. IRIS usually occurs during the early, most rapid phase of immune recovery.
What are the risk factors for immune reconstitution inflammatory syndrome?
The likelihood and severity of IRIS in HIV mainly depend on the following risk factors [4,5]:
- Severe CD4 lymphopenia (< 100 cells/µl)
- The extent and severity of the opportunistic infection or infections
- The HIV viral load before starting antiretroviral therapy
- The timing of the antiretroviral therapy and the initial response to treatment.
What are the clinical features of immune reconstitution inflammatory syndrome?
IRIS can occur a few weeks to several months after starting antiretroviral therapy for HIV. The clinical features closely relate to the type and location of pre-existing opportunistic infection, which can be previously diagnosed or unmasked after starting treatment [2]. In most cases, the patient has systemic symptoms. The main opportunistic infections associated with IRIS are listed in the table below.
| Opportunistic infection | Onset of symptoms | Clinical manifestations |
| Mycobacterium tuberculosis | < 2 months |
|
| Mycobacterium avium complex | 1–8 weeks |
|
| Cryptococcus neoformans | < 2 months |
|
| Pneumocystis jirovecii | 1–3 weeks |
|
| Cytomegalovirus | 4 weeks to 4 years |
|
| JC virus | 3–4 weeks |
|
| Herpes zoster | 1–4 months |
|
| Hepatitis B and C viruses (see viral hepatitis) | 2–8 weeks |
|
| Kaposi sarcoma | < 12 weeks |
|
How is immune reconstitution inflammatory syndrome diagnosed?
There is no confirmatory diagnostic test for IRIS, thus the diagnosis is based on clinical criteria.
- In paradoxical IRIS, the patient experiences clinical worsening despite being on effective treatment for the opportunistic infection [4].
- The diagnosis of unmasking IRIS is based on the specific test for the underlying opportunistic infection.
It is generally accepted that most or all of the following criteria for IRIS in HIV should be present [6]:
- Acquired immune deficiency syndrome (AIDS) with low CD4+ cell count before starting the treatment; the lower the CD4+ count, the higher the risk of IRIS
- A positive virological and immunological response to antiretroviral therapy
- Absence of any other cause of compatible illness, such as drug-resistant infection, bacterial superinfection, adverse drug reaction, drug interaction, or patient nonadherence to the treatment regime
- Clinical manifestations of an inflammatory condition
- Temporal association between the start of antiretroviral therapy and the onset of symptoms.
What is the differential diagnosis for immune reconstitution inflammatory syndrome?
IRIS has a broad differential diagnosis and requires a careful clinical evaluation to exclude:
- Progression of opportunistic infections
- Adverse effects of the treatment
- Non-adherence to the treatment
- Anti-microbial drug resistance.
What is the treatment for immune reconstitution inflammatory syndrome?
Most patients will require diagnostic tests and hospitalisation to minimise short-term morbidity and mortality. Antiretroviral therapy should not be stopped if IRIS is diagnosed. The treatment varies according to the severity of IRIS [7,8]:
- Mild cases can be treated with supportive care, non-steroidal anti-inflammatory drugs, and specific treatment for the opportunistic infection
- In severe cases or if there are neurological symptoms, corticosteroids can be considered (prednisone 1–2 mg/kg for 1–2 weeks), with close monitoring; corticosteroids should be avoided in viral infections.
What is the outcome for immune reconstitution inflammatory syndrome?
In many cases, IRIS is a self-limited condition that only requires supportive treatment and specific treatment for the opportunistic infection.
The mortality rate associated with IRIS varies according to the underlying opportunistic infection and is high in patients with central nervous system symptoms.