Immune Restitution Disease (IRD) or Immune Restoration Inflammatory Syndrome (IRIS)

“IRIS is defined as a paradoxical [for doctors who cannot believe the drugs they believe have side effects] clinical worsening due to a subclinical opportunistic pathogen (‘unmasking’ IRIS) or previously known treated (completed or ongoing) opportunistic pathogen (‘paradoxical’ IRIS) in the setting of an adequate response to ART [anti-retroviral therapy]. For the ‘unmasking’ form of IRIS, a new localized infection was required [to be detected]…in a patient who, prior to ART, exhibited no signs or symptoms of disease and in whom adequate OI [opportunistic infection] screening and clinical assessment had been performed…For the ‘paradoxical’ form of IRIS, a patient required the diagnosis and treatment initiation of an OI prior to ART initiation with a positive clinical response. Following ART, the patient experienced a new inflammatory process [return or worsening of disease]…Between 6 January 2006 and 7 July 2007, 546 patients initiated ART at the Johannesburg Hospital adult HIV clinic…423 patients [were deemed] eligible for the [study, and] contributed 180.8 person-years of follow-up during the study period, with a median of 182 days…Among the 423 cohort patients initiated on ART, there were 44 cases of IRIS…22 were confirmed cases, 21 were probable and one was a suspect IRIS case…Of the 44 cases, infectious etiologies included TB (18/44, 41%), cryptococcal meningitis (3/44, 6.8%), herpes simplex infection (4/44, 9.1%), varicella zoster infection (6/44, 13.6%), molluscum contagiosum (3/44, 6.8%), and Kaposi’s sarcoma (2/44, 4.5%). Dermatological manifestations including abscess formation and suppurative folliculitis [pus-filled hair follicles] were common, accounting for eight (18.2%) cases. Of the 44 cases, 35 (79.5%) were new presentations, and nine (20.5%) were due to exacerbations or recurrent episodes of previously documented infections.”

“The combination of a very low CD4 cell count and undiagnosed infection at the start of HAART are ideal conditions for immune reconstitution disease (IRD) to occur. This can partly explain the very high mortality rate during the first year of HAART observed in numerous trials conducted in Africa.”

“The immune recovery associated with ART results in dramatic clinical benefits, but this restoration of immunity may result in immunopathological reactions and clinical deterioration when ART is initiated in patients with TB. These reactions are termed “immune reconstitution inflammatory syndrome” (IRIS), also known as “immune restoration disease.”…Typically, paradoxical IRIS occurs within 6 weeks of the initiation of HAART [in TB patients], but it has been reported to occur many months after patients commence HAART. The reported incidence of paradoxical TB-associated IRIS is 8%–43%. In one series, worsening conditions were observed on chest radiographs in 45% of patients with TB who were treated with HAART, versus 20% of patients in the control group, which consisted of HIV-seronegative patients and HIV-infected patients not receiving HAART”

“The cohort included all adult HIV patients who started HAART at Seoul National University Hospital between 1998 and 2005…a quarter of all HIV patients in South Korea are seen at this hospital…We included tuberculosis events that were newly manifested after the start of HAART. In patients who already had tuberculosis…only tuberculosis that developed at sites distinct from those of the initial infections were included…27 tuberculosis events developed during the follow-up period [average 2.6 years]. Of 16 cases diagnosed as definite tuberculosis, 4 were classified as IRIS…and 12 as non-IRIS. Of the other 11 cases, diagnosed as probable tuberculosis, 5 were classified as IRIS tuberculosis and 6 as non-IRIS…Of the 11 tuberculosis events that developed within a year after starting HAART, nine were classified as IRIS tuberculosis…56% of IRIS tuberculosis cases did not have overt tuberculosis at the start of HAART.”

“Some HAART-treated patients (10–25%)…exhibit paradoxical deterioration in their clinical status, despite controlled viral replication and improvements in CD4 cell counts…Few cases of acute renal failure have been observed in a Mycobacterium tuberculosis-infected HIV-positive patient. We report such a case of acute granulomatous interstitial nephritis associated with IRIS [Immune Reconstitution Inflammatory Syndrome]…In our patient, acute renal failure occurred within the first 8 weeks, concurrently with skin signs, lymphadenopathy, cholestasis liver dysfunction, and increasing C-reactive protein…IRIS should be considered as a cause of acute renal failure and acute granulomatous interstitial nephritis after the initiation of HAART or antituberculous drugs in HIVinfected patients.”

“Some people infected with HIV who have started such treatment in countries where leprosy is endemic have developed florid leprosy lesions in the initial months of treatment…The manifestations described, however, are a well recognised complication of antiretroviral treatment known as immune reconstitution disease or immune reconstitution inflammatory syndrome (IRIS). This presents with the manifestation (or “unmasking”) of a previously subclinical coinfection or the deterioration of an opportunistic infection that had been responding to treatment…The first published case of leprosy associated immune reconstitution disease occurred in 2003 in a Ugandan living in London…Antiretroviral treatment has been available since 1996 in countries with high average incomes. Immune reconstitution disease has been well characterised in this setting and is associated with a predictable range of opportunistic infections…Immune reconstitution disease has, for example, recently been described in association with the parasitic infections leishmaniasis, strongyloidiasis, and schistosomiasis…From the patient’s perspective, HIV infection and leprosy are both highly stigmatising diseases, and having both is understandably distressing. This distress may be heightened by the patient’s perception that the leprosy was caused by the antiretroviral drugs. Frequent cases of this disease could make patients less enthusiastic about antiretroviral treatment programmes. Importantly, some lesions seen in leprosy associated with immune reconstitution disease are unusually florid, and severe neuropathy triggered during antiretroviral treatment might lead to permanent disability”

“We report the succession of an unusual acute presentation of tuberculous meningitis unmasked by antiretroviral treatment, corresponding to the first such case of IRIS, immediately followed by the onset of a severe ‘paradoxical reaction’ consisting of cerebral tuberculomas…A 26-year-old HIV-1-seropositive woman from Guinea with a CD4 cell count of 101 cells/ml and a viral load of 138 100 copies/ml began antiretroviral treatment. One month later, she had a 3-day history of acute headache and vomiting revealing a meningeal syndrome…Our patient had an unmasking form of IRIS as suggested by: (i) the close temporal relationship between the introduction of HAART and the onset of meningitis; (ii) the rapid and significant immune recovery; and (iii) the unusual acute onset of tuberculous meningitis.”

“Following HAART initiation, 496 (28.6%) patients experienced either incident pulmonary tuberculosis, or a WHO stage IV condition (OI/IRIS). Extra-pulmonary tuberculosis was reported in 145 patients, pulmonary tuberculosis in 108, wasting syndrome in 63, atypical disseminated mycobacteriosis in 25, extra-pulmonary Cryptococcus in 18, and other WHO stage IV conditions in 50 (some patients presented more than one clinical manifestation). The delay from HAART initiation to the diagnostic of OI/IRIS was in median 4 weeks.”

“A total of 756 ART-naive patients who enrolled during the study period initiated ART. Their median age was 33 years…Among patients with prevalent TB, a total of 19 (12%) were diagnosed as having TB-IRD. Symptoms developed a median of 2 weeks after initiation of ART and systemic as well as organ-specific symptoms were present in all. IRD presented as an exacerbation of existing disease manifestations alone in 10 patients with pulmonary disease among the majority (n=Ú9). Seven further patients with initial diagnoses of pulmonary TB developed new disease manifestations at another anatomic site as well as a concurrent exacerbation of respiratory disease in five. Two other patients with disseminated disease developed IRD that culminated in death; both had pulmonary, intra-abdominal and bone marrow involvement. These two cases occurred early in the history of the ART programme; since diagnoses were not established ante-mortem, neither was managed as IRD.”

“With affordable AIDS drugs arriving in many poor countries, experts say a startling and worrisome side effect has emerged: in some patients, the treatment uncovers a hidden leprosy infection…AIDS specialists in Brazil, India, Africa, the Caribbean and elsewhere are reporting that some patients on life-saving antiretroviral drugs are developing painful facial ulcers or losing feeling in their fingers and toes…Doctors have long known that dormant diseases can surge as a weak immune system recovers. The threat is sometimes called “Haart attacks” — a grim pun on the medical acronym for “highly active antiretroviral therapy.” The recovering immune system regains its ability to create fevers, flood infected tissue with white blood cells, break bacteria down into toxic waste products and build nodules around bacteria it cannot kill. But in a weakened patient, that inflammatory response itself can be dangerous. For example, when doctors know that an AIDS patient has tuberculosis, they often try to give TB drugs for two months to suppress the bacteria before starting antiretrovirals, because the patient’s own immune attack on the tuberculosis bacteria in the lungs can be fatal. [At least, that's their story, and they seem to be sticking to it]”

“Immune reconstitution disease, an adverse consequence of restoration of pathogen-specific immune responses, might also be a problem, particularly in those infected with tuberculosis.”

“A total of 3151 HIV-positive individuals who initiated HAART between December 2001 and December 2003 were included in the analysis…Pulmonary TB [tuberculosis in the lungs] was reported within the first 3 months after HAART initiation for 29/38 (76.3%), 21/40 (52.5%), 27/52 (51.9%), 46/69 (66.7%) and 8/10 (80.0%) patients with notified pulmonary TB in Cambodia, Thailand, Kenya, Malawi and Cameroon programmes, respectively [i.e. 6.6% of patients came down with TB within the 3.7-11.1 month followup]…Extra-pulmonary TB was reported within the first 3 months after HAART initiation in 34/62 (54.8%), 9/17 (52.9%), 14/21 (66.7%), 4/11 (36.4%) and 0 patients with notified extra-pulmonary TB in the same programmes, respectively”

“In 1993, a 32-year-old woman was diagnosed [with] HIV infection in our unit…The moment that primoinfection occurred in the past was unknown because it was asymptomatic. Since she declined to receive antiretroviral therapy, a progressive CD4+ T cell count decrease [took place] during the following 9 years [although no actual illness is noted]. In July 2002, she began HAART with zidovudine, lamivudine, and abacavir…In the next 3 months after the initiation of HAART, the patient developed several infectious events such as P. carinii pneumonia after 10 days, which was successfully treated with cotrimoxazole. Seven days later, the patient showed low level of conscience [consciousness?], convulsions…[A] biopsy of the colon…allowed the diagnosis of CMV colitis, which was treated with ganciclovir and foscarnet, while HAART was interrupted 6 weeks after its initiation due to an apparent IRD…Despite this new treatment, symptoms [of] fever, cough, and dyspnea [difficulty breathing] turned up…empiric CMV pneumonia was diagnosed. Ten days later, the patient [reported] loss of vision…Since the patient progressed with adverse clinical events, IRD was ruled out [because symptoms kept worsening even after HAART was ended, although ganciclovir is a drug closely related to some AIDS drugs] and a new HAART regimen including zidovudine, lamivudine, and lopinavir/ritonavir was prescribed…the patient developed fatal meningoencephalitis after 12 weeks of initiation of HAART [translation: the treatment was successful but the patient died]”

“[Ever more] conditions are reported as IRIS events. These most frequently occur with mycobacterial (tuberculosis or Mycobacterium avium complex infection) or cryptococcal disease (each in approximately 30% of cases)”

“It is now also evident that the development of HAART-associated immunity can lead to a variety of new clinical manifestations. These have been collectively termed as immune reconstitution inflammatory syndrome (IRIS), immune restoration or immune restitution disease and immune reconstitution phenomena…Paradoxical hypercalcaemia and acute renal failure following initiation of anti-tuberculosis therapy and HAART add to the more commonly described fever, worsening of lung infiltrates, new lymphadenopathy and swelling of tuberculomata…In a retrospective series based in London, we demonstrated the occurrence of active tuberculosis as an IRIS-like phenomenon in a group of individuals who had recently commenced HAART. This occurred at a median of 37 days, and affected 3% of such patients starting antiretrovirals…The number of clinical conditions associated with credible IRIS phenomena continues to grow. A full description of these is beyond the scope of this review.”

“Zygomycosis is caused by the rapidly growing molds of the orders Mucorales and Entomophthorales. Zygomycosis is often associated with conditions such as diabetic ketoacidosis, lymphoproliferative disorders, immunosuppression after organ transplantation, severe burns, chronic steroid use, chemotherapy, and deferoxamine administration. HIV infection by itself does not seem to be an important risk factor for this mycosis; however, several cases of zygomycosis in HIV-infected patients have been reported. Moreover, as the widespread use of protease inhibitors (PI) can predispose HIV patients to diabetes, zygomycosis may become more common in this population. We describe here a case of rhino-orbital zygomycosis occurring in an HIV-infected patient with PI[protease inhibitor]-induced decompensated [uncontrolled] diabetes mellitus.”

“Four HIV-1-infected patients presented with unusual clinical manifestations in the course of disseminated histoplasmosis, including liver abscesses, compressive lymphadenitis, intestinal obstruction, uveitis and arthritis within a median of 45 days after initiation of highly active antiretroviral therapy (HAART)”

“Antiretroviral therapy (ART) in immunodeficient HIV patients may be complicated by mycobacterial immune restoration disease (IRD) resulting from an immunopathological response to subclinical infections by nontuberculous mycobacteria [i.e. you don't get sick until you start taking AIDS drugs]…A 48-year-old man with past Pneumocystis jiroveci pneumonia and disseminated cytomegalovirus infection was commenced on lopinavir/ritonavir, zidovudine and lamivudine when the CD4 T-cell count was 48 cells/ml (6%) and the plasma HIV-1-RNA level was greater than 100 000 copies/ml. He was receiving prophylactic azithromycin and maintenance valganciclovir. On day 11 of ART he developed fever, and chest radiography (previously normal) showed patchy consolidation in both lungs…Anaemia and leukopenia had been present since starting ART and were not improved by the cessation of valganciclovir or the substitution of tenofovir for zidovudine”

“We run a community-based ART [antiretroviral therapy] programme in Gugulethu, Cape Town, South Africa. Between September 2002 and November 2004, 434 treatment-naive patients started triple-drug ART according to WHO 2002 treatment guidelines…During a total of 460 person-years of observation (PYO), 9 patients developed either recurrent (6) or new (3) symptomatic cryptococcal disease of the central nervous system. The median duration of ART at the onset of symptoms was 4 weeks. 6 of the 9 patients died and cryptococcal disease accounted for 6 out of 22 total deaths (27%) during the first 3 months of ART.”

“We agree with…that the start of antiretroviral therapy (ART) in Africa and other tuberculosis endemic regions is likely to unmask large numbers of cases of undiagnosed active tuberculosis [except they weren't active until AIDS drugs were started]. It is very important that healthcare providers in these settings are aware of this phenomenon and understand the issues involved in management. In a recent retrospective notes review of 131 consecutive patients treated for tuberculosis at our clinic in Kampala, 29 (22%) were patients not known to have tuberculosis, who presented within weeks of starting ART (median of 8 weeks). A good example of such a case is that of a 32-year-old man who had become increasingly unwell over a long period, with weight loss, low-grade fevers and an intermittent cough. Examination revealed a wasted patient, oral candidiasis but no specific features suggestive of active tuberculosis such as chest signs or significant lymphadenopathy…Thirteen days after starting the generic combination of nevirapine, stavudine and lamivudine the patient presented to our clinic acutely unwell with high-grade fever and a persistent dry cough. Examination revealed a temperature of 40.8C but no localizing signs. A chest radiograph revealed obvious milary infiltrations involving all lung zones. A blood slide for malaria and routine blood cultures were negative. The patient was started on standard quadruple antituberculous therapy (ATT),”

“The objective of this case series and literature review is to characterize the clinical course and prognosis of HIV-infected patients with Kaposi's sarcoma (KS) flare during immune reconstitution inflammatory syndrome (IRIS), a heterogeneous and sometimes fatal disorder of immune perturbation after initiation of highly active antiretroviral therapy (HAART). Medical records of 9 HIV-infected patients with KS flare after virologic and immunologic response to HAART were reviewed from a single institution. An additional 10 cases were abstracted by computerized search of the medical literature. In our single institution series, mean time to onset of KS flare was 5 weeks. Pretreatment mean CD4+ count was 190 cells/mm(3) and mean HIV viral load was 153,934 copies per milliliter. During flare, mean CD4+ count was 256 cells/mm(3) and mean HIV viral load was 1156 copies per milliliter. Similar aggregate results are represented in the literature. Six fatalities are reported, 4 from pulmonary KS and 2 from unrelated causes. Systemic chemotherapy universally led to tumor regression, but was administered in only 10 of 19 cases. In no instance was HAART discontinued. Onset of IRIS-associated KS flare is observed as early as 3 weeks, with most cases diagnosed within 2 months after immunologic and virologic response to HAART. Such a flare does not necessarily portend a poor prognosis. Even for those patients with rapidly symptomatic KS, early systemic chemotherapy is effective in suppressing IRIS-associated flare. Close clinical supervision is warranted for the KS patient initiating, changing, or resuming HAART. Particular vigilance is recommended for pulmonary involvement.”

“Results: Ten patients developed IRIS during the study period, giving an incidence of 10/239, or 4.2/100 person-years [95% confidence interval (CI), 2.2–7.8]. IRIS consisted of acute symptoms consistent with inflammation occurring within a median of 8 months (range, 2–37) after the diagnosis of cryptococcosis in the context of negative cultures and immunological and/or virological response to HAART. Radiology and histopathology detected features compatible with inflammation. Symptom severity required transfer into intensive care units for three patients and use of anti-inflammatory drugs for four. Three patients with evolutive IRIS died. Compared with patients without IRIS for whom complete clinical and microbiological informationwere available at baseline, previously unknown HIV infection [odds ratio (OR), 4.8; 95% CI, 1.0–21.7], CD4 cell count < 7 106 cells/l (OR, 4.0; 95% CI, 0.9–17.2), fungaemia (OR, 6.1; 95% CI, 1.1–35.2) and HAART initiation within 2 months of cryptococcosis diagnosis (OR, 5.50; 95%CI, 1.0–29.6) were independently associated with the risk of subsequent IRIS”

“Investigators have reported paradoxical effects when some patients begin HAART soon after initiation of therapy in patients with a concurrent opportunistic infection. These disorders are called reconstitution or reactivation syndromes”

“In the mid-1990s, clinicians noticed that certain patients deteriorated after starting HAART despite having decreasing HIV-1 RNA levels and rising CD4 cell counts. In these patients, receipt of HAART results in a pathological inflammatory response to either previously treated infections or subclinical infections. This inflammation could result in deleterious clinical outcomes, such as culture-negative meningitis or necrotizing lymphadenitis; it has been labeled as immune reconstitution disease (IRD) or immune reconstitution inflammatory syndrome (IRIS)…In the largest study of IRIS to-date, 31.6% of HIV-infected patients who were coinfected with M. tuberculosis, M. avium complex, or C. neoformans developed IRIS while on HAART, with an incidence of 15.1/100 patient-years of HAART in this high-risk cohort. These numbers are consistent with published data from smaller case series in which IRIS was seen in approximately 25-35% of HIV-infected patients responding to HAART. The majority of cases of IRIS occurred within the first 60 days of initiating HAART, which is in accord with prior individual reports and case series. As described previously, the onset of IRIS continues for up to 2 years following the initiation of HAART…As we hypothesized, having a more pronounced decrease in HIV-1 RNA levels within 90 days of starting HAART was associated with development of IRIS. The independent association of being antiretroviral drug naive and development of IRIS is likely related to having a more robust virological and immunological response to therapy in these group of subjects compared with those who were on prior therapy. A significant association between CD4 cell count increase and the diagnosis of IRIS was not seen until later in therapy…These [IRD/IRIS] patients often require significant interventions to minimize short-term morbidity [sickness] but their long-term outcome appears relatively good. Further studies looking at how to decrease the rate of IRIS in high-risk patients appear warranted by its prevalent nature and the association of IRIS with increased hospitalizations and invasive procedures.”

“Primary cerebellar degeneration is still rare in HIV disease. HIV cerebellar syndromes are commonly caused by opportunistic infection, neoplasm, or encephalitis, and may be accompanied by cognitive impairment…We report a case of cerebellopontine atrophy in the setting of immune reconstitution.A 33-year-old HIV-positive man with a previously low absolute CD4 cell count and a high plasma viral burden achieved undetectable plasma virus levels on indinavir, lamivudine and stavudine. After 9 months, when his CD4 cell count had improved…he developed acute progressive ataxia [lack of coordination]. Within 4 months he was wheelchair bound. Concomitant nystagmus [involuntary oscillation of the eyeball], dysarthria [difficulty speaking], and dysdiadochokinesis [inability to execute rapidly alternating movements] suggested a cerebellar syndrome…Magnetic resonance imaging scans…indicated cerebellar atrophy 4 months later. Serology and cultures revealed no signs of opportunistic pathogens…The CD4 cell count continued to rise and the viral load remained undetectable until compassionate discontinuation of HAART. After discontinuing antiretroviral agents he died of an unrelated infection, with no change in the neurological findings.”

“Suppression of HIV viraemia by antiretroviral therapy is accompanied by atypical ‘opportunistic infections’ or other inflammatory diseases in some patients. When these conditions were first reported, there was uncertainty about whether they were a consequence of the restoration of an immune response against opportunistic pathogens, or opportunistic infections resulting from residual defects of cell-mediated immunity. Subsequently, there has been acceptance that they are a consequence of immune reconstitution in patients who experience a virological response to HAART…Here, we argue that atypical ‘opportunistic infections’ after commencing HAART are the consequence of restoring an immune response against the antigens of opportunistic pathogens that is immunopathological rather than protective. These conditions are therefore considered to be immune restoration disease (IRD) rather than immunodeficiency disease. [i.e. it's the immune system that's the problem, not the solution! Although why is it that when your immune system is suppressed you get opportunistic infections yet when drugs 'restore' your immune system you also get opportunistic infections?]…The observation of atypical presentations of Mycobacterium avium complex (MAC) disease in patients treated with zidovudine [AZT] monotherapy was the first indication that restoring pathogen-specific immune responses can cause immunopathology…Soon after the introduction of HAART, it was observed that some patients presented with an initial or recurrent episode of cryptococcal meningitis during the first few weeks of therapy…Pneumocystis carinii pneumonitis [PCP] that has improved on anti-Pneumocystis therapy may relapse following the introduction of HAART…Hepatotoxicity [liver damage] is an adverse effect of HAART in up to 18% of patients. This is a direct effect of antiretroviral drugs, particularly nevirapine and high-dose ritonavir, in some patients but hepatotoxicity occurs most often in patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) co-infection…Eye disease is the most common presentation of CMV IRD. It presents as retinitis [acute inflammation of the retina] in the first 3 months of HAART or as uveitis [damage to the back of the iris], usually much later than retinitis…Rates of varicella zoster virus (VZV) disease are increased in patients responding to HAART [i.e. with a lower viral load or higher CD4 cell counts]…HAART is the only effective therapy for progressive multifocal leukoencephalopathy (PML) in HIV patients, probably because it augments CD4 T-cell responses to JC virus (JCV) antigens. However, in some patients who commence HAART, PML may become worse or present for the first time…Granulomatous inflammation of the lungs, which has the characteristics of sarcoidosis [formation of nodules in the lungs], has been described in patients responding to HAART…Autoimmune diseases presenting for the first time, or as an exacerbation of established disease, have also been reported in HIV patients responding to HAART.”

“To our knowledge . . . cases of lymphoma that appear during the first weeks of therapy have not been published, although this possibility has been mentioned mainly in meetings. We report here three patients who developed rapidly growing lymphomas of different cell lineages within the first 2 months of the initiation of HAART”

“Fever was the initial manifestation of the illness [now known as 'immune reconstitution disorder'] in all [108] patients. It occurred within 2 weeks of starting ZDV therapy and was often profound, with temperatures of >40C occurring in some patients. Patient 4 was hospitalized for 5 weeks because of severe and protracted fevers. No cause for the fevers was demonstrated despite extensive investigations [of course, it couldn't have been the AZT!]…It was notable that the MAI [Mycobacterium avium intracellulare] infection associated with the use of ZDV therapy was localized to tissues without evidence of mycobacteraemia in any patient, despite multiple blood cultures for mycobacterial infection. However, three patients developed mycobaceraemia 8-25 months after commencement”