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Immune Reconstitution Inflammatory Syndrome: Emergence of a Unique Syndrome During Highly Active Antiretroviral Therapy

SHELBURNE, SAMUEL A. III; HAMILL, RICHARD J.; RODRIGUEZ-BARRADAS, MARIA C.; GREENBERG, STEPHEN B.; ATMAR, ROBERT L.; MUSHER, DANIEL M.; GATHE, JOSEPH C. JR.; VISNEGARWALA, FEHMIDA; TRAUTNER, BARBARA W.

Article

From Departments of Medicine (SAS, RJH, MCR-B, SBG, RLA, DMM, JCG, FV, BWT) and Molecular Virology & Microbiology (RJH, SBG, RLA, DMM), Baylor College of Medicine; Veterans Affairs Medical Center (RJH, MCR-B, DMM); Ben Taub General Hospital/Thomas Street Clinic (SBG, RLA, FV); and Park Plaza Hospital (JCG), Houston, Texas.

Support for this study was provided in part by the Department of Veterans Affairs. This work was presented at the 39th Annual Meeting of the Infectious Diseases Society of America, October 27, 2001, in San Francisco, CA (Abstract #660).

The contributions of RJ Hamill, MC Rodriguez-Barradas, and DM Musher are in the public domain.

Address reprint requests to: Richard J. Hamill, MD, Section of Infectious Diseases (111G), Veterans Affairs Medical Center, 2002 Holcombe Boulevard, Houston TX 77030-4211. Fax: 713-794-7045; e-mail: richard.hamill@med.va.gov.

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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.

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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:

  1. The patient had a diagnosis of AIDS;
  2. 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.];
  3. Symptoms consistent with an infectious/inflammatory (autoimmune) condition appeared while on antiretroviral therapy, and;
  4. 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.
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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.

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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).

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Case Reports and Literature Review

Mycobacterium avium complex

Case 1: A 44-year-old man with AIDS for 4 years, CD4+ cell count of 30/μL, on combined treatment with zidovudine and lamivudine for the past 7 months, developed fever and malaise. Mycobacterium avium complex (MAC) was cultured from his blood and clarithromycin brought about a resolution of his symptoms. Saquinavir was then added to his antiretroviral regimen and ethambutol was added for additional anti-MAC therapy. Ten days later he returned to the hospital with fever up to 106 °F, malaise, and headaches. First amikacin, then rifabutin, and finally clofazimine were added for additional anti-MAC therapy because he remained persistently febrile without any new positive cultures. Saquinavir was then withdrawn due to concern of drug interaction with rifabutin. He defervesced and was discharged to complete anti-MAC therapy. Several weeks later saquinavir was restarted. He returned in 1 week with fever and abdominal pain. His CD4+ cell count was 140/μL. Ultrasound of the abdomen showed extensive retroperitoneal lymphadenopathy. Biopsy of the affected lymph nodes revealed granulomatous inflammation with all stains and cultures negative. A diagnosis of IRIS was made. Antiretroviral therapy and treatment for MAC were continued and, over the next several weeks, his symptoms resolved.

Case 2: A 45-year-old man with AIDS, on treatment with zidovudine, was seen in clinic for fever, nausea, and vomiting; his CD4+ cell count was 30/μL. He was found to have MAC infiltration of the liver. On ethambutol, clofazimine, ciprofloxacin, and amikacin he slowly defervesced. Six weeks into this therapy indinavir and lamivudine were added to zidovudine. Three weeks later he returned because of abdominal pain. His CD4+ cell count was 170/μL. He had massive hepatosplenomegaly and lymphadenopathy (Figure 1). His calcium level was 13 mg/dL and his (1,25) vitamin D3 level was increased. Biopsies of liver and lymph nodes showed granulomatous inflammation; cultures were negative. The diagnosis of IRIS was made. HAART was continued together with clarithromycin, ethambutol, and rifabutin. Over the next several weeks his abdominal symptoms resolved and the calcium level returned to normal.

Fig. 1

Fig. 1

Comment: MAC was among the first infectious agents associated with the immune reconstitution inflammatory syndrome (47,71,119). Due to its ubiquitous nature and low pathogenicity, MAC infection is often subclinical, providing a target for a restored immune system (115). In 1998, Race et al (125) described 5 patients (Table 1) who developed lymphadenitis within 1–3 weeks of being started on HAART. All of these patients had significant increases in memory CD4+ cells with a marked leukocytosis, and biopsies of the affected nodes showed granulomatous inflammation. Localized lymph node enlargement with caseous necrosis, negative blood cultures, absence of wasting, and close temporal relationship to an excellent virologic and immunologic response to HAART distinguishes MAC-induced IRIS from the usual pattern of MAC infection in patients with AIDS (20,38,41,118). The presence of granulomas, which usually are not seen in AIDS, suggests that the clinical presentation is due to a restored inflammatory response. In our Case 2, it is likely that the inflammatory response within the granulomas resulted in extrarenal 1-α- hydroxylationalpha;-hydroxylation of 25-OH-vitamin D which in turn caused the patient’s hypercalcemia.

TABLE 1

TABLE 1

TABLE 1

TABLE 1

The vigorous HAART-induced immune response can bring out MAC-related lesions in unusual locations (see Table 1). Necrotic subcutaneous nodules, endobronchial tumors, small bowel involvement and paravertebral abscesses have all been described (8,17,28,32,34). Histologic examination of these lesions shows an intense inflammatory response surrounding few, if any, organisms. While this inflammatory response can cause acute morbidity, it also provides long-term protection against the organism, as shown in a prospective study of patients with localized MAC infection who remained free of disease without specific anti-MAC therapy (117).

Immunologic evidence for a HAART-mediated enhanced immune response against MAC was provided by Foudraine et al (45) who described 4 patients who developed symptomatic MAC infection an average of 4 weeks after starting HAART. While all of the patients had been anergic to MAC antigens before therapy, 3 of the 4 showed a marked increase in the lymphoproliferative response to mycobacterial specific antigens at the time they presented clinically. Havlir et al (61) showed that lymphocyte proliferative responses to MAC antigens were similar in non-HIV-infected patients and HIV-infected patients with treated disseminated MAC on HAART, but significantly lower in HIV-infected patients not receiving HAART.

Of 32 patients thus far reported with IRIS related to MAC infection (see Table 1), 25 (78%) developed symptoms of IRIS within 1 month of being started on HAART. In individual cases, there have been reports of IRIS presenting as long as 25 months later (28,32). Patients who develop localized MAC infection in the setting of HAART-induced immune reconstitution appear to have a good long-term prognosis even with cessation of specific anti-MAC therapy (117).

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Mycobacterium tuberculosis

Case 3: A 45-year-old man, not previously known to have HIV infection, was hospitalized for fever and pulmonary infiltrates. He was found to have antibody to HIV-1. His viral load was 468,907 HIV RNA copies/mL, and his CD4+ cell count was 30/μL. Transbronchial biopsy revealed caseating granulomas that contained mycobacteria; cultures yielded Mycobacterium tuberculosis (MTB). On 4 anti-MTB drugs, he rapidly defervesced. One week into this therapy, zidovudine, lamivudine, and nelfinavir were begun. Five days later, his cough increased and fever recurred. No new infectious source was found. Computerized tomography (CT) of the abdomen revealed enlarging intraabdominal lymph nodes, biopsy of which showed granulomatous inflammation; special stains and cultures were negative. Within 3 weeks of initiation of HAART, his CD4+ cell count had risen to 90/μL, and he had an undetectable viral load. A diagnosis of IRIS was made, and prednisone was begun at 60 mg per day with resolution of his persistent fever and pulmonary complaints. Anti-MTB therapy and HAART were continued. Six months later he developed a large supraclavicular lymph node; excisional biopsy revealed chronic inflammation with stains and cultures negative. He returned 9 months later with a left-sided neck mass, biopsy of which again revealed only granulomatous inflammation with negative stains and cultures.

Case 4: A 28-year-old HIV-infected woman had recently emigrated from Africa. She had a CD4+ cell count of 177/μL, a viral load of 17,700 HIV RNA copies/mL, and was started on zidovudine, stavudine, and efavirenz. Six months later she presented with fever, weight loss, and right lower-quadrant abdominal pain. A purified protein derivative (PPD) skin test elicited a severe inflammatory reaction. CT scan of the abdomen showed cecal inflammation and lymphadenopathy (Figure 2). A laparotomy with cecectomy was performed. Review of the specimen showed granulomatous inflammation with caseous necrosis. All stains were negative; cultures yielded MTB. CD4+ cell count was now 234/μL with a viral load ≤400 HIV RNA copies/mL. She was treated with 4-drug anti-MTB therapy with good results.

Fig. 2

Fig. 2

Comment: The concept that clinical deterioration may follow treatment for an infectious process is not new to HIV infection. In the absence of HIV infection, the institution of anti-MTB therapy may cause hectic fevers, increasing lymphadenopathy, and other features that suggest worsening of the disease (2,23). Rooney et al (128) found that 23% of patients admitted for MTB were anergic to PPD. After 2 weeks of anti-MTB therapy 74% of these patients showed a restored response to MTB antigens. Thus, infection with tuberculosis itself leads to some degree of immune suppression that is reversible with anti-MTB therapy. This concept underlies the use of corticosteroids as adjuvant therapy for MTB if a vigorous inflammatory response might compromise vital structures, such as the central nervous system (39).

A brisk inflammatory response might be anticipated with the concomitant use of HAART and anti-MTB therapy in patients who are co-infected with HIV and MTB. The shift towards a Th-1 cytokine profile with increased levels of IFN-γ might be expected to alter the immune response to the mycobacterium. In fact, many such instances have been reported (27,31,48,63,67,83,98,110,113). Narita et al (110) noted transient paradoxical clinical deterioration in 36% of patients with combined HIV-MTB infections after initiation of HAART. Clinical worsening included prolonged fever of >101.5 °F, increasing respiratory symptoms, increasing lymphadenopathy, development of cutaneous lesions, and ascites. A retrospective radiologic review of cases revealed worsening radiographs in 45% of patients including increasing lymphadenopathy, lobar consolidations, and pleural effusions (43).

Since MTB in HIV-infected patients is often disseminated, the inflammatory response induced by HAART can cause significant morbidity outside the lung (48). Involvement of the central nervous system in the setting of immune reconstitution is particularly problematic. McCormack et al (98) described the paradoxical growth of an intracranial tuberculoma in a patient who developed seizures while receiving antituberculous therapy and HAART. A retrospective review of patients with both HIV and MTB treated with HAART found an 8.7% prevalence of paradoxical central nervous system lesions (63). All but 1 of the patients were symptomatic, with vasogenic edema found on neuroimaging, and required the use of glucocorticoids for resolution. Given the high morbidity that can accompany IRIS in the setting of MTB, some physicians have opted to delay the onset of HAART until anti-MTB therapy has decreased the load of organisms (24).

The time from initiation of HAART to the presentation of IRIS in patients infected with MTB is more variable than in those infected with MAC, occurring within as few as 10 days to as long as 180 days later (see Table 1). Corticosteroids have been used in anecdotal reports with good success at preventing further damage when HAART-mediated inflammation threatens vital structures, especially the central nervous system.

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Cryptococcus neoformans

Case 5: A 39-year-old man recently diagnosed with HIV-1 infection presented with 1 week of fever, nausea, vomiting, and headache. Cerebrospinal fluid (CSF) contained 14 white blood cells (WBC)/μL, protein was 196 mg/dL, and glucose was 36 mg/dL. CSF cryptococcal antigen titer was 1:4096, and cultures grew Cryptococcus neoformans. CD4+ cell count was 76/μL with viral load of 238,000 HIV RNA copies/mL. He was treated with amphotericin B and flucytosine with good response and discharged on oral fluconazole. He was started on HAART consisting of nelfinavir, lamivudine, and stavudine. Eleven days after initiation of HAART he began to have fever, headache, and blurry vision. CSF contained 71 WBC/μL with 15% neutrophils and 75% lymphocytes. Total protein in the CSF had increased to 255 mg/dL and glucose was 18 mg/dL with a CSF cryptococcal antigen titer of 1:2048. A magnetic resonance imaging (MRI) scan showed diffuse meningeal enhancement (Figures 3A and 3B). All CSF cultures were negative, and dexamethasone was started for IRIS with rapid resolution of symptoms. Steroids were tapered over the next several weeks, and the patient returned with headache and fever. CSF contained 24 WBC/μL with 93% lymphocytes. Cryptococcal antigen titer was 1:1024, and all cultures were negative. CT scan with contrast continued to show diffuse meningeal enhancement. CD4+ cell count was 138/μL with a viral load of 11,000 HIV RNA copies/mL. Steroids were restarted, again with clinical improvement. The patient was discharged on oral fluconazole and a prolonged steroid taper, with resolution of his symptoms.

Fig. 3

Fig. 3

Case 6: A 62-year-old man was diagnosed with HIV infection and cryptococcemia. CD4+ cell count was 26/μL with a viral load of 571,240 HIV RNA copies/mL. He was treated with amphotericin B and responded well. After 11 days of amphotericin B he was started on ritonavir, saquinavir, stavudine, and lamivudine. After 8 days of HAART he began to have cough productive of purulent sputum and increasing shortness of breath. A chest CT showed a new pleural effusion with consolidation and cavitation of the underlying lung parenchyma (Figure 4). He was intubated for increasing respiratory distress. After an extensive search for a new infectious process was unrevealing, he was diagnosed with IRIS and started on prednisone. His pulmonary symptoms improved, and he was able to be extubated in 3 days. CD4+ cell count was 55/μL with a viral load of 1,035 RNA copies/mL. Six weeks later he suffered cardiorespiratory arrest with pronounced anoxic brain injury and died after 6 days.

Fig. 4

Fig. 4

Comment: Infection of the central nervous system by C. neoformans in the setting of advanced HIV may elicit only a mild inflammatory reaction as evidenced by low leukocyte counts in the CSF. When cryptococcal meningitis is coincident with immune system recovery secondary to HAART, however, the inflammatory response may be quite brisk (144). HAART has been shown to increase anticryptococcal activity by polymorphonuclear leukocytes, perhaps through alterations in IL-12 and superoxide production (106). A particularly vexing problem arises when cryptococcal meningitis is the presenting manifestation of HIV infection. Often there is good response to antifungal therapy, but cryptococcal antigen can persist in the CSF for a prolonged period of time. Based on the cases seen at our institution, it is clear that the presence of antigen without viable organisms can incite a significant immune response in the HAART-treated patient.

As evidenced by Case 6 of our series, infection with C. neoformans presents in unusual fashions in the setting of immune reconstitution (see Table 1). There have been cases of both mediastinal and cervical lymphadenitis as well as cutaneous abscesses associated with cryptococcal infection that occurred months after the institution of HAART (10,85,93). Four of these 5 patients had been treated with fluconazole as secondary prevention after previous cryptococcal meningitis. Three of the cases responded to continued antifungal therapy, while the other 2 required antiinflammatory therapy.

The experience with C. neoformans-induced IRIS is limited compared with the experience with IRIS with mycobacterial diseases. Two of the 3 IRIS patients seen with C. neoformans meningitis in our series had symptoms within 2 weeks of starting HAART. This is consistent with the time period described by Woods et al (144). In contrast to the patients who developed meningeal inflammation, the patients who presented with lymphadenopathy had been treated an average of 9 months, suggesting that a later phase in the immune reconstitution process may have mediated their presentations.

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Cytomegalovirus

Case 7: A 47-year-old man was admitted with prolonged weight loss and malaise. Enzyme-linked immunosorbent assay (ELISA) and Western blot assays for antibodies to HIV-1 were positive with a CD4+ cell count of 20/μL. Endoscopy revealed severe ulcerative esophagitis consistent with CMV infection. He was treated with 3 weeks of intravenous ganciclovir with confirmed healing of the esophageal lesion. He was discharged on indinavir, stavudine, lamivudine, and oral ganciclovir. He returned 4 weeks later with decreased vision in the right eye. Ophthalmologic exam showed vitreitis with retinal detachment. CD4+ cell count was 100/μL. He continued HAART and oral ganciclovir with no further loss of visual acuity, nor did his CMV disease progress to involve his other eye. He was diagnosed with IRIS and has not had further progression of CMV disease despite stopping ganciclovir.

Comment: CMV retinitis is a common complication of very late-stage AIDS. It usually occurs in patients with CD4+ cell counts less than 50/μL and is characterized by a necrotizing retinitis with minimal inflammatory response. Shortly after the introduction of protease inhibitors, physicians began to recognize a new type of ocular disease in the setting of CMV infection (65,73). The intensity of the inflammatory response was far greater than that seen in standard CMV retinitis, and the syndrome was termed “immune recovery vitreitis.” When it was noted that the anterior eye chamber could also be involved, the term was expanded to “immune recovery uveitis” (51,62,127). The inflammatory response in this situation can induce proliferative vitreoretinopathy and posterior subcapsular cataracts leading to severe visual compromise (120,131). The estimated incidence of “immune recovery uveitis” has ranged from 0.109 to 0.830/person-year (6,68,73). While early descriptions of this syndrome reported a transient nature, a more protracted course has been noted of late (74,145). When the inflammation threatens vision there have been anecdotal reports of efficacy using local corticosteroids (25). The systemic nature of CMV infection has been noted in cases of IRIS involving CMV, which have ranged from pneumonitis to colitis (see Table 1) (52,103). Recent data show that patients with CMV-associated IRIS are more likely to carry HLA-B44, suggesting a genetic predisposition to IRIS among some patients (122).

The positive side of the increased immune response against CMV is that it can induce a longlasting disease remission, which allows for the discontinuation of anti-CMV therapy (68,92,133). While most patients do quite well, not all patients reconstitute CMV-specific CD4+ T-cell responses (79); those patients remain at risk for recurrent CMV retinitis requiring long-term specific anti-CMV therapy.

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Herpes zoster

Case 8: A 57-year-old man with AIDS (CD4+ cell count of 20/μL) failed multiple combinations of HAART. He was then started on lamivudine, zidovudine, efavirenz, and lopinavir/ ritonavir. Viral load was 547,566 HIV RNA copies/mL and CD4+ cell count was 131/μL. He felt clinically much improved until 10 weeks later when he presented with herpes zoster of the ophthalmic division of the left cranial nerve V. Viral load was 70,812 HIV RNA copies/mL while CD4+ cell count was now 173/μL. He was started on valacyclovir with initially encouraging results but then developed superficial keratitis and iritis of the left eye. Treatment with topical steroids was commenced and his visual acuity returned nearly to baseline. Two months later he suffered a second episode of zoster in the same location.

Comment: Unlike other opportunistic infections in HIV-infected patients, herpes zoster develops at a relatively consistent rate regardless of the degree of immunosuppression (18). Studies have demonstrated between a twofold and fivefold increase in herpes zoster in HIV-infected patients treated with HAART versus non-HAART-treated HIV-infected patients (5,95). The majority of cases have developed by week 16 of therapy with the longest interval between starting HAART and developing herpes zoster being 103 weeks (5). CD8+ lymphocyte proportion at baseline and peak response in CD8+ cells at 1 month have been associated with development of herpes zoster (95).

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Sarcoidosis/Kaposi sarcoma

Case 9: A 33-year-old man with sarcoidosis for 4 years and HIV infection for 1 year presented with persistent fever. One year previously his CD4+ cell count was 200/μL with a viral load of >750,000 HIV RNA copies/mL. He started zidovudine, lamivudine, and nelfinavir and continued his usual prednisone dose of 30 mg/day. After 5 months of HAART, CD4+ cell count was 355/μL and viral load was undetectable. He developed lesions of Kaposi sarcoma at numerous sites. Five months later he developed daily fever to >101 °F, and additional Kaposi lesions appeared. He also had enlarging retroperitoneal lymph nodes. Liposomal doxorubicin was prescribed with significant improvement in his skin lesions but no change in his fever pattern, for which no cause other than sarcoidosis was found. His fever and retroperitoneal lymphadenopathy persisted despite increased doses of prednisone and institution of thalidomide.

Comment: Recovery of the immune system with HAART has been noted to result in the worsening of both sarcoidosis and Kaposi sarcoma (12,104,109,141). Given the pivotal role of the CD4+ T lymphocyte in the pathogenesis of sarcoidosis, the depletion of CD4+ cells caused by infection with HIV might be expected to improve the clinical course of sarcoidosis. Before HAART there were reports of patients with both disorders whose sarcoidosis did seem to stabilize or even improve as their HIV progressed (91). The introduction of HAART has produced the opposite effect (12,56,60,104,109). One patient developed sarcoid only after the addition of IL-2 to preexisting HAART (11,107). Two patients who had asymptomatic sarcoidosis diagnosed many years previously developed symptomatic pulmonary sarcoidosis after HAART; both responded well to steroid therapy (89). Most of the cases have developed gradually after several months of HAART and have not required any specific treatment. The patient described above is taking thalidomide, which has shown some efficacy in the treatment of sarcoidosis resistant to corticosteroids (21).

In addition to sarcoidosis, the patient described above had worsening of cutaneous Kaposi sarcoma coincident with immune recovery due to HAART. In most cases, HAART is helpful in controlling the lesions of Kaposi sarcoma (15). However, Weir et al (141) reported a case where the initiation of HAART in a patient with known Kaposi sarcoma was followed by worsening of the Kaposi sarcoma to near-obstruction of the larynx by a large sarcoma. The authors hypothesized that an increased immune response to human herpes virus-8 resulted in inflammation and edema around a previously unsuspected Kaposi sarcoma lesion.

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Graves disease

Case 10: A 46-year-old man with HIV began therapy with stavudine, lamivudine, and nelfinavir. CD4+ cell count was 120/μL. He presented 10 months later with the gradual onset of diarrhea, symptomatic tachycardia, and fever. Triiodothyronine (T3) level was 168 ng/mL (normal, 0.45–1.37 ng/mL), thyroxine (T4) was normal, and thyroid stimulating horomone (TSH) was <0.1 μU/mL. Antithyroglobulin antibody was positive at a dilution of 1:10. Radioactive iodine scan showed diffusely increased uptake in the thyroid gland consistent with Graves disease. Repeat analysis of the CD4+ cell count was 170/μL. Radioactive iodine ablation of the gland was accomplished successfully with resolution of symptoms.

Comment: Eight patients, in addition to the 1 described above, have developed Graves disease following the institution of HAART (see Table 1) (51,69,70). Gilquin et al (53) and Jubault et al (70) were able to detect thyrotropin receptor antibodies in these patients; retrospective analysis of stored serum demonstrated the absence of autoantibodies before the institution of HAART (70). Gilquin and colleagues raise the concern that thymic-mediated redevelopment of the T-cell repertoire during HAART might be abnormal, thereby allowing for the proliferation of autoreactive T cells. These cells might escape from the usual mechanisms of immune regulation leading to autoreactivity.

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Pneumocystis carinii

Case 11: A 47-year-old man with AIDS, a CD4+ cell count of 90/μL, and a viral load of 99,000 HIV RNA copies/mL, was started on lopinavir/ritonavir, didanosine, lamivudine, and efavirenz. When his CD4+ cell count reached 300/μL he stopped trimethoprim-sulfamethoxazole prophylaxis. Four months after starting HAART he presented with fever, malaise, and progressive dyspnea. His CD4+ cell count was now 525/μL with a viral load of 235 HIV RNA copies/mL. Chest X-ray showed bilateral infiltrates with a left lower lobe consolidation. Bronchoscopy revealed an intense interstitial pneumonitis with granulomas formed around Pneumocystis carinii organisms. His infection responded to trimethoprim-sulfamethoxazole and corticosteroids.

Comment: Physicians have long recognized the deleterious effects of an inflammatory response in the treatment of Pneumocystis carinii pneumonia (PCP) in advanced HIV. Multiple studies have shown the beneficial effects of corticosteroids early in the course of therapy, presumably by modifying the immune response to dying organisms (16,49,108). The advent of HAART has dramatically lowered the incidence of PCP, and there is convincing evidence that patients whose CD4+ cell counts rise above 200/μL can safely stop taking prophylaxis against the organism (1,9,86). There have been very few reports of PCP occurring once the CD4+ cell count rises above 200/μL, as occurred in our patient (100). Another atypical feature of the case described above was the presence of granulomas. The usual microscopic pathology seen in cases of PCP consists of a mixture of P. carinii organisms and cellular debris in the alveolar space with a sparse interstitial mononuclear cell inflammatory infiltrate (50). While there have been cases of a granulomatous response to P. carinii occurring in HIV-infected patients, all but 1 of these patients were receiving some type of antiretroviral therapy, raising the possibility that an increased immune response was responsible in those cases (13,14,44,78).

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Hepatitis C and B viruses

Because hepatitis C virus (HCV) and HIV have similar routes of acquisition, there is a large patient population who are co-infected, with estimates ranging from 30%-50% (37). How HAART affects HCV levels and the immune response to HCV has not been definitively answered (126,147). Because antiretrovirals may cause hepatotoxicity, differentiating direct drug toxicity from immune-induced exacerbations of hepatitis is difficult. HAART induces a transient rise in HCV RNA and alanine aminotransferase (ALT) after 2 weeks of therapy, perhaps because of an increase in cytotoxic CD8+ T lymphocytes causing immune-mediated hepatocyte destruction (140). In most cases, HCV RNA levels return to baseline within 3 months (124,129).

Two patients who were anti-HCV negative before beginning HAART developed hepatitis and became anti-HCV positive after treatment; retrospective analysis of pretherapy serum by PCR revealed HCV (66). Zylberberg et al (147) described a patient with HCV infection who had marked hepatic decompensation approximately 7 months after beginning HAART. Liver biopsy revealed marked hepatic necrosis and inflammatory activity, with an increase in hepatic CD8+ T lymphocytes that mirrored the patient’s overall immune reconstitution. There was no evidence of drug-induced hepatotoxicity, such as an eosinophilic infiltrate, nor was there evidence for a direct HCV effect, such as fibrosing cholestasis. In another case, symptomatic cryoglobulinemia developed after 3 months of HAART in a patient with HCV infection (107).

Similar diagnostic and therapeutic dilemmas appear after initiation of HAART in patients co-infected with HIV and hepatitis B virus (HBV). In the absence of HAART, co-infected patients have higher levels of HBV DNA polymerase, less spontaneous clearance of HBeAg, and lower levels of ALT compared with patients infected with HBV alone (54). This suggests that the immune suppression mediated by HIV allows for increased HBV replication and decreased clearance by the immune system. How HAART influences the immune response to HBV is still being investigated, with 1 study (132) showing an 8.5% incidence of severe hepatic cytolysis, as defined by ALT >200 IU/L, among treated co-infected patients. Whether this was due to drug toxicity or an immune-mediated attack on viral infected hepatocytes is not clear. Carr et al (22) described an HBV-infected patient who had symptoms of acute hepatitis after initiation of HAART. At the time that HAART was stopped for fear of drug-induced hepatitis, serologic evaluation revealed that HBeAg had been cleared and titers of anti-HBc and anti-HBe had increased. In numerous other cases, transient rises in HBV DNA levels have occurred in conjunction with clinical hepatitis following initiation of HAART (94,96,123,139). Continuation of therapy led to the appearance of a variety of hepatitis B antibodies with clearance of HBsAg and resolution of the hepatitis.

The diagnosis of IRIS in patients with HCV or HBV is problematic. Many patients can be expected to have transient increases in liver enzymes in the first few weeks after starting HAART. Whether this represents interactions between the hepatotropic viruses and HIV or between the immune system and virusinfected hepatocytes is still under investigation. Physicians caring for these patients need to be aware of this interaction so that HAART is not stopped unnecessarily. Such patients need to be observed closely since there is a significant potential for both immune-mediated and drug-induced hepatotoxicity. Only liver biopsy may be able to clarify the pathogenesis.

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Progressive multifocal leukoencephalopathy

The development of progressive multifocal leukoencephalopathy (PML) in advanced HIV disease has been associated with a mean survival time measured in months. The use of HAART, while not preventing the development of PML in all patients, has been shown to increase survival significantly in patients with PML (3,137), presumably because of an increased immune response to the JC virus, the causative organism. With HAART, levels of JC virus in the CSF decrease and levels of antibody to JC virus increase (35,55). Nevertheless, an inflammatory PML variant has developed in several patients treated with HAART, with MRIs of these patients showing contrast enhancement, suggesting a strong inflammatory component (29,82). Biopsy of these lesions has revealed extensive demyelination with surrounding inflammation consisting of lymphoplasmoid cells. In marked contrast to the usual course of PML, all the patients described who developed PML in the setting of immune reconstitution have had either improvement or at least stability of their neurologic deficits.

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Treatment

The anecdotal nature of the reports of IRIS precludes firm recommendations regarding therapy. At this stage, the most important step is probably to recognize IRIS as a possible explanation for new symptoms; this can help to minimize invasive diagnostic procedures and allow for the early use of therapeutic agents. The most extensive experience with antiinflammatory agents in the literature has been in the treatment of M. tuberculosis, C. neoformans, and CMV. These organisms have a predilection for the central nervous system, which has little tolerance for inflammation. In the case of CMV ocular disease, corticosteroids have been used in both local and systemic fashions with encouraging results (72,74,131). Long-term, aggressive anti-CMV treatment to decrease CMV antigen has also been advocated (84). Systemic corticosteroids have been used in the treatment of IRIS involving M. tuberculosis infection, especially in the setting of intracranial tuberculomas with surrounding edema (27,48,63,67,98,110).

When C. neoformans meningitis appears in IRIS, increased intracranial pressure is a significant problem, as it is in primary cryptococcal meningitis. Recent guidelines emphasize the importance of treating intracranial hypertension (59,130). While large volume lumbar punctures have been the mainstay of treatment, lumbar and lumbar-peritoneal drains have been used successfully when necessary (42). As outlined in the cases above, the addition of corticosteroids to these regimens in the setting of IRIS-associated cryptococcal disease has resulted in dramatic clinical improvement in a short time. While the immunosuppressant effects of corticosteroids are a concern, recent investigators found no significant adverse outcomes associated with short-term use in advanced HIV infection (97).

The use of pharmaceutical interventions other than steroids has been limited. Mild cases of inflammation might respond to nonsteroidal antiinflammatory drugs (NSAIDs), which could be used by themselves or in conjunction with corticosteroids. The use of other antiinflammatory therapies, such as thalidomide, is currently being investigated.

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Summary

We describe clinical features and essential laboratory data in 24 patients who underwent paradoxical clinical deterioration while receiving highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus (HIV) infection. The patients had responded to antiretroviral therapy as defined by increased CD4+ T cell lymphocyte counts and reductions in HIV viral loads. In 14 of 24 patients, the deterioration was attributable to a response to an infectious agent proven to be present before starting HAART. While 8 of the remaining 10 patients developed inflammation against microbes that had not been clinically recognized before starting HAART, it seems likely that these organisms were already established before the institution of therapy. Two of these patients had mycobacterial disease of the colon, 2 had symptoms secondary to disseminated cytomegalovirus, 1 had lymphadenitis in association with Bartonella infection, and 1 had an atypical pneumonia in response to Pneumocystis carinii. Presumably latent infections with herpes viruses were responsible for symptoms in 2 cases; 1 patient developed severe periproctitis secondary to herpes simplex while another had progressive Kaposi sarcoma, a disease associated with human herpes virus-8. Of the final 2 patients, 1 had worsening of sarcoidosis, a disease in which CD4+ T lymphocytes play a central role in pathogenesis, while the other developed an autoimmune disorder (Graves disease), which may have been related to the production of autoreactive T lymphocytes occurring during immune reconstitution. We propose that a restored capacity of the host to mount an inflammatory response against persistent microbial antigens or self-antigens led to the development of symptoms in these patients; we call this constellation of events the immune reconstitution inflammatory syndrome (IRIS).

We found reports of an additional 158 cases of IRIS. We discuss here the literature on the basic science of immune reconstitution engendered with HAART, along with microbial-specific immune responses that occur following HAART. The preponderance of cases occurred in association with Mycobacterium avium complex (28 cases), Mycobacterium tuberculosis (34 cases), cytomegalovirus (19 cases), or herpes zoster (38 cases). Other associated diseases included Cryptococcus neoformans meningitis and lymphadenitis, Kaposi sarcoma, Hepatitis B, Hepatitis C, progressive multifocal leukoencephalopathy, Graves disease, and sarcoidosis. For some presentations, such as sarcoidosis, cryptococcal meningitis, and herpes zoster, the clinical manifestations were quite similar to the same disease occurring in the absence of HAART. Other presentations, such as localized Mycobacterium avium complex lymphadenitis, cytomegalovirus vitreitis, and inflammatory PML, were unique to patients with immune reconstitution. Anecdotal reports suggest that there may be some benefit from treatment with antiinflammatory drugs if the inflammatory response compromises vital structures or has caused substantial systemic symptoms.

The advent of HAART has improved the prognosis of persons infected with HIV. Clinicians involved in the care of these patients need to be aware of the potential, however, for this therapy to cause a paradoxical decline in clinical status. While the search for new infectious processes must be diligent and the possibility of drug toxicity needs to be evaluated, it is important to recognize that improved immune function, itself, can be the source. In IRIS, the need to ameliorate the signs and symptoms of immune reconstitution has to be balanced with the desire to maintain the patient on long-term, effective anti-HIV therapy. With increasing recognition of patients with IRIS, it may now be possible to initiate clinical trials to determine the most appropriate approach to treatment.

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