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Immune Reconstitution Inflammatory Syndrome - 12/14/2012

posted Dec 14, 2012, 11:14 AM by Rohit Das   [ updated Dec 27, 2012, 6:37 AM by Purnema Madahar ]

Today, I wanted to talk about an interesting topic that came up recently – Immune Reconstitution Inflammatory Syndrome (IRIS). Let me put this into context; we have a young woman on the floors with advanced AIDS (CD4 count found to be 31 during the admission) and a history of pulmonary MAC, inconsistently being treated for both, who initially presented with diffuse abdominal pain and constitutional symptoms. She was ultimately diagnosed with disseminated MAC. She had been worked up at an outside hospital prior to her presentation, and was simultaneously started on ARVs and combination MAC therapy for about 1-2 weeks, which was continued upon admission to our hospital. Three to four days into the hospitalization, she developed worsening abdominal pain, distention and nausea/vomiting. On imaging, she was noted to have a small bowel obstruction, likely due to worsening intra-abdominal lymphadenopathy, impinging and obstructing the small bowel. So…

·         What is IRIS? Which patients are at risk for it?

·   What are the guidelines for starting ARVs in AIDS patients with opportunistic infections, and what is the data behind those recommendations?

·         What are the management options for IRIS?

What is IRIS? Which patients are at risk for it?

·         IRIS is thought of as a worsening of a pre-existing infection or occult infection (“unmasking") in the context of improving immunologic function due to ARV therapy. Generally, the diagnosis requires AIDS with a low pre-treatment CD4 count (<100, though IRIS can occur with TB even at CD4 counts above 200), a virologic response to ARVs and obviously a temporal association between onset of ARVs and clinical symptoms (studies have shown a median onset timing of 30-40 days, but can be as short as one week, or as long as 3 months…). The incidence varies among studies, and varies with different pathogens, but overall is approximately 16-30%.

·         The clinical manifestations of IRIS are dependent on the organism, as well as the extent of infection by the organism, as symptoms can be localized or systemic.  There is a ton of literature on TB associated IRIS, as this is a very big deal in prevalent areas where TB is a major contributor to overall mortality. Nevertheless, IRIS is associated with multiple organisms, including MAC, Pneumocystis, CMV, Cryptococcus…basically everything you can think of has at least case reports in the literature…

·         Focusing on MAC-associated IRIS in the context of our patient, in one prospective study (attached) of 51 patients, about an equal number of patients presented with peripheral lymphadenitis, pulmonary disease or abdominal disease. The mean CD4 count prior to ARV treatment was 20, and 120 at the time of IRIS diagnosis. The mean interval to the onset of symptoms was 3 weeks. Nearly 70% of cases of intra-abdominal disease were preceded by disseminated infection.

·         As alluded to, the main risk factors for IRIS are a low pre-treatment CD4 count/high viral load and degree of immunologic improvement on ARVs. There is also controversial data as to whether protease inhibits are associated with IRIS, thought to be via HIV-independent effects on T-lymphocyte proliferation and enhancement of macrophage-produced cytokines.

What are the guidelines for starting ARVs in AIDS patients with opportunistic infections, and what is the data behind those recommendations?

·        In the attached RCT, stratified by opportunistic infection and CD4 count at entry, patients were randomized to getting ARVs 14 days after acute OI treatment (“early ART” cohort) versus after completion of therapy (“deferred ART” cohort). TB patients were excluded (we’ll get to TB and IRIS studies a bit later…).

o   The OI’s included in this study were largely PCP (63%), Cryptococcus (12%), among others. In a 3 level composite primary outcome including death/AIDS progression, there was no difference between the two groups. In secondary outcome analyses, the early cohort did have significantly fewer AIDS progression/death events, and also needed a significantly shorter time to achieve a CD4 count above 50 (not surprising). Based on this and additional studies, the guidelines for most opportunistic infections is to start ARV therapy within 2 weeks of acute OI treatment. 

·         The timing of ARV therapy in the context of TB has been studied extensively, particularly in the SAPiT trial (attached), which examined integrated ARV therapy (ARVs at <4 weeks or at 8-12 weeks after starting TB therapy) versus sequential therapy (ARVs after TB treatment), and demonstrated a clear mortality benefit with integrated therapy, which led to the trial being terminated early. Subsequent sub-analyses have yielded these basic guidelines:

o   For patients with a CD4 count <50, the risk of AIDS-related death outweighs the consequences of IRIS related events, and ARVs are recommended within 2 weeks of starting TB treatment

o   For patients with a CD4 count >50, timing depends on the severity of HIV disease. For severe HIV disease (which correlates to markers of chronic disease – low BMI, albumin, hemoglobin, etc.), ARVs should be started with 2-4 weeks, for reasons similar to above.

o   For not so severe HIV disease and a CD4 count >50, initiation at 8-12 weeks is recommended, as the consequences of IRIS outweigh AIDS related outcomes.

What are the management options for IRIS?

·         This is a difficult question to answer, unfortunately. The large majority of IRIS cases are self-limited, not life threatening, and it is therefore reasonable to continue ARV therapy and treat supportively.

·         Sometimes the decision is pathogen dependent. For example, for PML, ARV therapy is the only effective therapy. On the other side of things, cryptococcal IRIS carries a very bad prognosis (21% mortality), so continuation of ARVs is a very risky venture. Though there are not any controlled trials, there is some observational evidence supporting the use of glucocorticoids and/or NSAIDs, especially in the context of obstructing mass lesions...though very important to consider the adverse effects of steroids carefully…

Quite an interesting topic…

In other news…I figured out how to view the website’s traffic!!!!!1 Apparently I’m getting 30-35 viewers on days when I post the daily…decent numbers, but certainly hope for more…spread the word!!