Introduction Abbreviations used in this article: AIDS, acquired immunodeficiency syndrome, ALT, alanine aminotransferase, CMV, cytomegalovirus, CSF, cerebrospinal fluid, HAART, highly active antiretroviral therapy, HBV, hepatitis B virus, HCV, hepatitis C virus, HIV, human immunodeficiency virus, IRIS, immune reconstitution inflammatory syndrome, MAC, Mycobacterium avium complex, MTB, Mycobacterium tuberculosis, PML, progressive multifocal leukoencephalopathy The discovery of effective therapy for human immunodeficiency virus (HIV) infection has improved the outlook for patients with the acquired immunodeficiency syndrome (AIDS) (75,88,115,121,134). Since the introduction of highly active antiretroviral therapy (HAART), there has been a decrease in the incidence of opportunistic infections among HIVinfected patients along with a corresponding reduction in the mortality rate (7,30,45,102,117). The basis for these improvements appears to be a result of partial recovery of the host’s immune system. Suppression of viral replication by antiretroviral therapy allows for the reappearance of immune effector cells, that in turn, provide vital protection against opportunistic pathogens (15,32,92,95,132). However beneficial HAART has been, experience during the past several years has disclosed the emergence, in a small proportion of cases, of a unique set of complications. Soon after treatment is begun, some patients experience clinical deterioration due to restoration of their capacity to mount an inflammatory immune response against both infectious and noninfectious antigens. This phenomenon which carries such labels as the immune reconstitution syndrome (IRS) and immune restoration disease (IRD), has been described for a wide variety of infectious pathogens (26,36,46). The manifestations of this syndrome are diverse and depend on the particular infectious agent involved. Given that an increased inflammatory response underlies its presentation, we propose the name immune reconstitution inflammatory syndrome (IRIS). Autoimmune diseases that occur following institution of HAART may also be considered as part of the same process. For the purpose of this review, IRIS is defined as a paradoxical deterioration in clinical status attributable to the recovery of the immune system during HAART. Recognition of this entity is crucial, for successful treatment relies on alleviation of the patient’s symptoms without compromising antiretroviral or antimicrobial therapy. In this article, we review the present understanding of the basic science underlying IRIS, with illustrative examples from our case series, and review the existing clinical literature. Patients and Methods Patient identification and chart review; case definition After IRIS had been discussed at several teaching conferences in the Texas Medical Center, members of the full-time faculty, Department of Medicine (Infectious Disease Section), Baylor College of Medicine, were asked to identify patients with clinical scenarios compatible with this syndrome. The medical records of these patients were then reviewed by 1 of the investigators. Patients were included if they fulfilled the following 4 criteria: The patient had a diagnosis of AIDS; Treatment with anti-HIV medicines (usually, but not necessarily including a protease inhibitor) had led to an increase in CD4+ T lymphocytes and a decrease in HIV-1 viral load if measured. [Some cases of IRIS preceded the widespread use of HIV-1 viral loads. All cases where viral loads are not mentioned occurred during this era.]; Symptoms consistent with an infectious/inflammatory (autoimmune) condition appeared while on antiretroviral therapy, and; These symptoms could not be explained by a newly acquired infection, by the expected clinical course of a previously recognized infectious agent, or by side effects of therapy. Literature review We performed a computer-based search (MEDLINE, National Library of Medicine, Bethesda, MD; years 1996–2001, AIDSLINE, and AIDS conferences). Key words used in the search were immune restoration disease, immune reconstitution, immunoreconstitution, immune restitution, HAART, paradoxical reaction, HIV, and AIDS. The citations in all identified articles were evaluated, and all titles not previously found via the computerized search that contained the key words were reviewed. In addition, multiple Internet search engines were used to identify conferences related to AIDS, and papers presented at these conferences were reviewed. Articles published from 1996 until April 2001 that described various opportunistic infections and syndromes were also reviewed to elicit reports consistent with this syndrome. Pathophysiology of Immune Reconstitution with HAART Most studies evaluating HAART have utilized the combination of 1 protease inhibitor or nonnucleoside reverse transcriptase inhibitor plus 2 nucleoside analogue inhibitors. Following the initiation of such treatment, the levels of HIV RNA usually fall rapidly with a 90% decrease observed within 1–2 weeks (76,114). The viral load continues to decline for the first 8–12 weeks of therapy, often reaching levels ≤200 RNA copies/mL (112). An increase in immune effector cells appears coincident with the reduction in viral load. The initial expansion is seen in memory CD4+ T lymphocytes, as defined by CD45RO+. These cells have been activated previously by antigen exposure, and their increase can be detected within 1–2 weeks of starting therapy (7). Analysis of CD4+ cell turnover and lymphoid tissue suggests that redistribution rather than cell proliferation is responsible for the increase (19,75). Probable mechanisms include alterations in surface adhesion proteins as well as a decrease in apoptosis (5,87). The continuation of HAART leads to a proliferation in different subsets of CD4+ T lymphocytes. After 4–6 weeks, naive CD4+ cells, defined as CD45RA+, CD62L+, begin to increase (121). By definition, these cells have not been previously activated by antigen exposure. The numerical rise of naive CD4+ lymphocytes occurs in lymph nodes as well as in the blood, thus supporting the theory that the sustained increase in these cells reflects peripheral expansion as opposed to redistribution (57,105). The long-term rise in CD4+ lymphocytes is mainly accounted for by the persistent increase in these naive CD4+ cells (112). At the same time there is increased diversity of the T cell receptor repertoire along with a shift in cytokine production from a Th-2 to a Th-1 profile, with increases in interleukin (IL)-2 and interferon (IFN)-γ (64,77,81,99). The repopulation of these CD4+ cells is thought to depend on the amount of thymic tissue present, with patients who have higher baseline levels of thymic tissue having larger CD4+ cell increases following HAART (135). HIV infection appears to impair thymic function; studies using T-cell receptor rearrangement excision circles as markers of thymic output indicate that HAART generally brings about a rapid and sustained output of T cells from the thymus (40). HAART also affects CD8+ T lymphocytes, with increases in memory CD8+ cells seen in the first few weeks following the initiation of therapy (112). With prolonged treatment, these memory CD8+ cells decline and are gradually replaced by naive CD8+ T lymphocytes. CD8+ cells also show reduced activation markers along with broadened T-cell receptor profiles (58). The total CD8+ cell count remains steady during prolonged therapy, leading to a progressive increase in the CD4+/ CD8+ ratio (142). In addition to numerical increases in various arms of the immune system, HAART has been shown to result in functional improvements as well. Within 4 weeks of starting HAART, increases in delayed hypersensitivity and in vitro lymphocyte proliferative responses to common antigens such as Candida can be demonstrated (88). Responses continue to improve with increasing duration of therapy, as shown with assays using common antigens, as well as those from organisms that cause opportunistic infection (75,142). Komanduri et al (80) compared immune responses in patients with active cytomegalovirus (CMV) disease and those who had previously had CMV disease but had received HAART; the HAART-treated patients had significantly higher CMVspecific CD4+ cell responses than the non-HAART-treated CMV-infected patients. The enhancement in immune response appears to be especially marked toward widely prevalent organisms such as CMV or mycobacterium (87). Restoration of immune function occurs even when patients with advanced HIV disease are treated (100). The degree of HAARTinduced suppression of viral load and the increase in CD4+ cells, rather than their baseline values, best correlates with improvements in immune responses (90,138). Case Reports and Literature Review Mycobacterium avium complex Case 1: A 44-year-old with AIDS for 4 CD4+ cell count of on treatment with and for the past and Mycobacterium avium complex from and about a of then to antiretroviral and for therapy. to the with to and then and were for therapy without then due to of with and to therapy. weeks in 1 with and CD4+ cell count of the of the lymph nodes with all and A diagnosis of IRIS therapy and treatment for were the several weeks, symptoms Case A with AIDS, on treatment with seen in for and CD4+ cell count found to have of the and weeks this therapy and were to weeks of CD4+ cell count had and and of and lymph nodes were The diagnosis of IRIS HAART with and the several weeks symptoms and the to 1: Case of the and multiple lymph nodes in a with immune reconstitution inflammatory syndrome with Mycobacterium avium complex among the first infectious with the immune reconstitution inflammatory syndrome to its and infection is often a for a immune system In et al described patients who within weeks of on HAART. All of these patients had increases in memory CD4+ cells with a marked and of the nodes lymph with of and to an and response to HAART IRIS from the of infection in patients with AIDS The of which usually are not seen in AIDS, suggests that the clinical is due to a inflammatory In our Case is that the inflammatory response within the in of which in the patient’s 1: Immune reconstitution syndrome following highly active antiretroviral therapy, and present 1: Immune reconstitution syndrome following highly active antiretroviral therapy, and present immune response can in small and have all been described of these an inflammatory response if this inflammatory response can cause also long-term protection against the as shown in a of patients with infection who of disease without therapy for a immune response against by et al who described 4 patients who infection an of 4 weeks after starting HAART. all of the patients had been to antigens therapy, of the 4 a marked increase in the response to antigens at the time they presented et al that lymphocyte proliferative responses to antigens were in patients and patients with treated on HAART, but significantly in patients not HAART. patients thus with IRIS related to infection symptoms of IRIS within 1 of on HAART. In cases, there have been reports of IRIS as as Patients who infection in the of immune reconstitution to have a long-term even with of therapy Mycobacterium Case A not previously to have HIV infection, for and found to have to viral load HIV RNA and CD4+ cell count that contained Mycobacterium 4 rapidly this therapy, and were increased and infectious of the lymph of which and were Within weeks of initiation of HAART, CD4+ cell count had to and had an viral load. A diagnosis of IRIS and at with of persistent and therapy and HAART were a lymph with and with a of which with and Case A had from had a CD4+ cell count of a viral load of HIV RNA and on and presented with and A a inflammatory of the and A with Review of the with All were CD4+ cell count with a viral load HIV RNA treated with therapy with Case of the and in a with immune reconstitution syndrome with The that clinical deterioration may treatment for an infectious is not to HIV In the of HIV infection, the institution of therapy may cause increasing and that of the disease et al found that of patients for were to After 2 weeks of therapy of these patients a response to antigens. infection with leads to some degree of immune suppression that is with therapy. This underlies the use of as therapy for if a inflammatory response vital such as the system A inflammatory response be with the use of HAART and therapy in patients who are with HIV and The shift a Th-1 cytokine with increased levels of be expected to the immune response to the In such have been et al paradoxical clinical deterioration in of patients with infections after initiation of HAART. included prolonged of increasing increasing of and A review of cases in of patients including increasing and Since in patients is often the inflammatory response by HAART can cause the of the system in the of immune reconstitution is et al described the paradoxical of an in a patient who while therapy and HAART. A review of patients with both HIV and treated with HAART found an of paradoxical system All but 1 of the patients were with found on and the use of for Given the that can IRIS in the of MTB, some have to the of HAART until therapy has the load of organisms The time from initiation of HAART to the of IRIS in patients with is than in those with MAC, within as few as to as as have been used in reports with at when vital especially the system. Case A with HIV-1 infection presented with 1 of and contained cells and antigen and CD4+ cell count with viral load of HIV RNA treated with B and with response and on on HAART of and after initiation of HAART to have and contained with and lymphocytes. in the had increased to and with a antigen of A enhancement and All were and for IRIS with rapid of were the several weeks, and the patient with and contained with lymphocytes. antigen and all were with to show CD4+ cell count with a viral load of HIV RNA were with clinical The patient on and a prolonged with of Case especially the in a patient with and immune reconstitution inflammatory syndrome. A with HIV infection and CD4+ cell count with a viral load of HIV RNA treated with B and well. After of B on and After of HAART to have of and increasing of A a with and of the underlying for increasing After an search for a infectious with IRIS and on symptoms and to be in CD4+ cell count with a viral load of RNA weeks with and after Case of the in a with in the of the due to a from the immune reconstitution inflammatory of the system by in the of advanced HIV may elicit a inflammatory as by in the is coincident with immune system recovery to HAART, the inflammatory response may be HAART has been shown to increase by alterations in and production A when is the of HIV there is response to therapy, but antigen can in the for a prolonged of on the cases seen at our is that the of antigen without organisms can a immune response in the HAART-treated by Case of our series, infection with in in the of immune reconstitution have been cases of both and as well as with infection that occurred after the institution of HAART of these patients had been treated with as after of the cases to therapy, while the 2 therapy. The experience with IRIS is compared with the experience with IRIS with of the IRIS patients seen with in our had symptoms within 2 weeks of starting HAART. This is consistent with the time described by et al In to the patients who the patients who presented with had been treated an of that a in the immune reconstitution may have their Case A with prolonged and and assays for to HIV-1 were with a CD4+ cell count of consistent with CMV treated with weeks of with of the on and 4 weeks with in the with CD4+ cell count HAART and with of CMV disease to with IRIS and has not had of CMV disease CMV is a common of AIDS. usually occurs in patients with CD4+ cell than and is by a with inflammatory after the introduction of protease to a of disease in the of CMV infection The of the inflammatory response than that seen in CMV and the syndrome recovery that the could also be the to recovery The inflammatory response in this can proliferative and leading to The incidence of recovery has from to of this syndrome a a course has been of the there have been reports of using The of CMV infection has been in cases of IRIS CMV, which have from to show that patients with IRIS are to a to IRIS among some patients The side of the increased immune response against CMV is that can a disease which allows for the of therapy patients not all patients CD4+ T-cell responses those patients at for CMV long-term therapy. Case A with AIDS cell count of multiple of HAART. then on and load HIV RNA copies/mL and CD4+ cell count improved until weeks when presented with of the of the load HIV RNA copies/mL while CD4+ cell count on with but then and of the Treatment with and to a of in the same opportunistic infections in at a consistent rate of the degree of have demonstrated a and increase in in patients treated with HAART non-HAART-treated patients The of cases have by of therapy with the starting HAART and weeks CD8+ lymphocyte proportion at baseline and response in CD8+ cells at 1 have been with of Case A with for 4 years and HIV infection for 1 presented with persistent previously CD4+ cell count with a viral load of HIV RNA and and of After of HAART, CD4+ cell count and viral load of at to and also had lymph with in but in for which cause than and increased of and institution of of the immune system with HAART has been to result in the of both and Given the of the CD4+ T lymphocyte in the of the of CD4+ cells by infection with HIV be expected to improve the clinical course of HAART there were reports of patients with both to or even improve as their HIV The introduction of HAART has the patient after the addition of to HAART patients who had years previously after HAART; both well to therapy Most of the cases have gradually after several of HAART and have not The patient described is which has shown some in the treatment of to In addition to the patient described had of coincident with immune recovery due to HAART. In cases, HAART is in the of et al a case where the initiation of HAART in a patient with by of the to of the by a The that an increased immune response to human in and a previously disease Case A with HIV therapy with and CD4+ cell count presented with the of and and at a of increased in the consistent with of the CD4+ cell count of the with of in addition to the 1 described have disease following the institution of HAART et al and et al were to receptor in these of demonstrated the of the institution of HAART and the that of the T-cell repertoire during HAART be for the proliferation of T These cells from the mechanisms of immune leading to Case A with AIDS, a CD4+ cell count of and a viral load of HIV RNA on and CD4+ cell count after starting HAART presented with and progressive CD4+ cell count with a viral load of HIV RNA with a an with infection to and have recognized the effects of an inflammatory response in the treatment of in advanced studies have shown the beneficial effects of in the course of therapy, by the immune response to organisms The of HAART has the incidence of and there is that patients CD4+ cell rise can against the have been few reports of the CD4+ cell count as occurred in our patient (100). of the case described the of The seen in cases of of a of organisms and in the with a cell inflammatory there have been cases of a response to in all but 1 of these patients were some of antiretroviral therapy, the that an increased immune response responsible in those cases C and B hepatitis C virus and HIV have of there is a patient who are with from HAART affects levels and the immune response to has not been may cause from of hepatitis is HAART a rise in RNA and alanine after 2 weeks of therapy, of an increase in CD8+ T lymphocytes In cases, RNA levels to baseline within patients who were HAART hepatitis and after of by et al described a patient with infection who had marked after HAART. marked and inflammatory with an increase in CD8+ T lymphocytes that the patient’s immune of such as an there for a such as In after of HAART in a patient with infection and after initiation of HAART in patients with HIV and hepatitis B virus In the of HAART, patients have higher levels of of and levels of compared with patients with This suggests that the immune suppression by HIV allows for increased replication and by the immune system. HAART the immune response to is with 1 an incidence of as defined by among treated patients. this due to or an on viral is not et al described an patient who had symptoms of hepatitis after initiation of HAART. At the time that HAART for of that had been and of and had In cases, in levels have occurred in with clinical hepatitis following initiation of HAART of therapy led to the of a variety of hepatitis B with of and of the The diagnosis of IRIS in patients with or is patients can be expected to have increases in in the first few weeks after starting HAART. this the and HIV or the immune system and is for these patients to be of this that HAART is not patients to be observed there is a for both and may be to the multifocal leukoencephalopathy The of progressive multifocal leukoencephalopathy in advanced HIV disease has been with a time in The use of HAART, while not the of in all has been shown to increase significantly in patients with of an increased immune response to the virus, the With HAART, levels of virus in the decrease and levels of to virus increase an inflammatory has in several patients treated with HAART, with of these patients a inflammatory of these has with of In marked to the course of PML, all the patients described who in the of immune reconstitution have had or at of their Treatment The of the reports of IRIS therapy. At this the is to IRIS as a for this can to and for the use of The experience with in the has been in the treatment of tuberculosis, and These organisms have a for the system, which has for In the case of CMV disease, have been used in both and with treatment to decrease CMV antigen has also been have been used in the treatment of IRIS infection, especially in the of with appears in IRIS, increased is a as is in the of have been the of treatment, and have been used when in the cases the addition of to these in the of disease has in clinical in a the effects of are a found with use in advanced HIV infection The use of than has been cases of to which could be used by or in with The use of such as is We clinical and in patients who paradoxical clinical deterioration while highly active antiretroviral therapy for the treatment of human immunodeficiency virus (HIV) The patients had to antiretroviral therapy as defined by increased CD4+ T cell lymphocyte and in HIV viral loads. In of the deterioration attributable to a response to an infectious agent to be present starting HAART. of the patients against that had not been recognized starting HAART, that these organisms were the institution of therapy. of these patients had disease of the 2 had symptoms to cytomegalovirus, 1 had in with infection, and 1 had an in response to infections with were responsible for symptoms in 2 1 patient to while had progressive a disease with human the 2 1 had of a disease in which CD4+ T lymphocytes a in while the an which may have been related to the production of T lymphocytes during immune We propose that a capacity of the to mount an inflammatory response against persistent antigens or led to the of symptoms in these we this of the immune reconstitution inflammatory syndrome (IRIS). We found reports of an cases of We the on the basic science of immune reconstitution with HAART, along with immune responses that occur following HAART. The of cases occurred in with Mycobacterium avium complex Mycobacterium cytomegalovirus or diseases included and progressive multifocal disease, and For some such as and the clinical manifestations were to the same disease in the of HAART. such as Mycobacterium avium complex cytomegalovirus and inflammatory PML, were unique to patients with immune reports that there may be some from treatment with if the inflammatory response vital or has The of HAART has improved the of with in the of these patients to be of the for this therapy to cause a paradoxical decline in clinical the search for infectious be and the of to be evaluated, is to that improved immune can be the In IRIS, the to the and symptoms of immune reconstitution has to be with the to the patient on effective anti-HIV therapy. With increasing of patients with IRIS, may be to clinical to the to