Episode 120: Immune Reconstitution Inflammatory Syndrome (IRIS)
Abeda Faharti and Dr. Schlaerth present the definition, diagnosis, and treatment of IRIS. Moderated by Dr. Arreaza.
Written by Abeda Farhati, MS4, Ross University School of Medicine. Editing and comments by Katherine Schlaerth, MD, and Hector Arreaza, MD.
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Definition.
Have you heard of IRIS? No, not the color portion of our eyes. IRIS is short for Immune Reconstitution Inflammatory Syndrome. This condition occurs in immunocompromised patients with HIV/AIDS due to an overactive inflammatory response. In most cases, it occurs after initiating antiretroviral therapy (ART). To understand IRIS in HIV patients, we must first understand HIV.
HIV.
The Human Immunodeficiency Virus (HIV) infection was first reported in 1981. The virus attacks the immune system, destroying white blood cells called CD4+ T lymphocytes, which are part of our body's defense mechanism. These cells are also known as "helper T cells" and are responsible for destroying viruses, bacteria, and other germs that make us sick.
When your CD4+ count is low, you are more likely to get serious infections from viruses, bacteria, and fungi, which usually do not cause problems in otherwise healthy individuals. These infections are called Opportunistic infections, and they can be deadly. To restore CD4+ T lymphocytes, HIV patients are started on ART to normalize their immune response to pathogens. As a result of these treatments, HIV patients' lives have been significantly improved and prolonged.
[Comment by Dr. Arreaza: It is paradoxical, but some HIV patients are among the healthiest patients I have seen.]
Despite this, no treatment is guaranteed to be without side effects. Increases in CD4+ T lymphocytes trigger the immune system to respond to any persisting antigen, regardless of whether it is fragments or intact organisms. As a result, a hyperinflammatory response may occur.
Diagnosis.
There are no established criteria for diagnosing IRIS. It is generally accepted that IRIS requires the worsening of an existing infection or an unrecognized, preexisting infection in the context of improved immune function.
For a diagnosis to be made, most, if not all of the following features must be present:
- The presence of a low CD4 count (less than 100 cells) before initiating treatment with ART (Except IRIS secondary to preexisting TB infection can occur with CD4 counts >200 cells).
- The presence of an inflammatory condition, especially after ART is initiated.
- The absence of drug-resistant infection, bacterial superinfection, drug allergy, or other adverse drug reactions.
- The absence of patient noncompliance or reduced drug levels due to drug-drug interactions or malabsorption.
Clinical Manifestations.
IRIS can be presented in patients in 2 ways:
- Patient’s with a preexisting infectious disease that has NOT been treated, getting paradoxically worse after initiating treatment with ART ---this is known as “unmasking IRIS” OR
- Patient’s with a preexisting infectious disease that has been previously diagnosed and treated but regained capacity after treatment with ART, causing it to mount an inflammatory response – this is known as “paradoxical IRIS.”
In summary: Unmasking IRIS and paradoxical IRIS.
Patients with IRIS have clinical features that vary widely. The presentations are strongly dependent on the type of preexisting opportunistic infection. For example, about 75% of patients with a mycobacterial or cryptococcal-related infection will develop a fever. In contrast, fever is rarely seen in cytomegalovirus (CMV) infections.
Risk & Prevention.
Researchers have found that lower CD4 cell counts or high HIV RNA levels at the time of anti-retroviral treatment initiation increase the risk of developing IRIS. One way to prevent IRIS development is to treat opportunistic infections prior to starting ART. Although this reduces the risk of IRIS development, it does not guarantee it.
Treatment.
In “unmasking IRIS,” patients can be treated with antibiotics, antivirals, or antifungals against the underlying infectious organism. In severe cases, steroids can also be used to suppress inflammation until the infection has been eradicated. Unfortunately, there is no treatment for paradoxical IRIS. Most patients who experience “paradoxical IRIS” reactions will get better spontaneously without additional therapy.
Incidence of IRIS.
The overall incidence of IRIS is unknown; however, studies have shown that anywhere from 25 to 30% of HIV patients who start antiretroviral treatment develop IRIS in the first six months. You may ask, which preexisting infections can lead to patients developing IRIS?
Pathogens associated with IRIS.
Different pathogens have been associated with the development of IRIS. The leading pathogens include:
- Mycobacterium tuberculosis
- Mycobacterium avium complex
- Cytomegalovirus
- Cryptococcus neoformans
- Pneumocystis jirovecii
- Herpes simplex virus
- Hepatitis B virus
- Human herpes virus 8 (associated with Kaposi sarcoma)
Non-HIV etiologies.
IRIS can also be seen in other immunocompromised conditions, such as:
- Solid organ transplant recipients
- Postpartum period – 3 to 6 weeks after giving birth
- Neutropenic patients – with an absolute neutrophil count of less than 500
- Patients on Tumor Necrosis Factor Antagonists (TNF antagonists)- are used to treat chronic conditions such as ulcerative colitis, Crohn’s disease, or sarcoidosis.
In summary, Immune Reconstitution Inflammatory Syndrome (IRIS) is a hyper-inflammatory state seen after initiating ART in HIV patients whose improved immune system responds to previously acquired opportunistic infection, whether treated or not.
The treatment is directed to the unmasked specific opportunistic infection or support therapy if no active infection is found.
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Conclusion: Now we conclude episode number 121, “Immune Reconstitution Inflammatory Syndrome (IRIS).” This syndrome presents in about 30% of HIV patients when they start ART. A stronger immune system means a stronger immune reaction. So, keep in mind this diagnosis when your HIV patients get sicker when they are supposed to get better after starting ART.
This week we thank Hector Arreaza, Abeda Farhati, and Katherine Schlaerth. Audio edition by Adrianne Silva.
Even without trying, every night you go to bed a little wiser. Thanks for listening to Rio Bravo qWeek Podcast. We want to hear from you, send us an email at RioBravoqWeek@clinicasierravista.org, or visit our website riobravofmrp.org/qweek. See you next week!
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Links:
- “CD4 Lymphocyte Count: MedlinePlus Medical Test.” Medlineplus.gov, accessed on November 4, 2022.https://medlineplus.gov/lab-tests/cd4-lymphocyte-count/#:~:text=A%20CD4%20count%20is%20mostly,have%20trouble%20fighting%20off%20infections.
- Sun HY, Singh N. Immune reconstitution inflammatory syndrome in non-HIV immunocompromised patients. Curr Opin Infect Dis. 2009 Aug;22(4):394-402. doi: 10.1097/QCO.0b013e32832d7aff. PMID: 19483618. https://pubmed.ncbi.nlm.nih.gov/19483618/
- Thapa, Sushma, and Utsav Shrestha. “Immune Reconstitution Inflammatory Syndrome.” PubMed, StatPearls Publishing, 2022, www.ncbi.nlm.nih.gov/books/NBK567803/.
- Wolfe, Cameron. Immune reconstitution inflammatory syndrome, UpToDate. ww.uptodate.com, https://www.uptodate.com/contents/immune-reconstitution-inflammatory-syndrome. Accessed November 14, 2022.
- Royalty-free music used for this episode: “Keeping Watch,” New Age Landscapes. Downloaded on October 13, 2022, from https://www.videvo.net/royalty-free-music-albums/new-age-landscapes/.
