Immune Reconstitution Inflammatory Syndrome In Patients Research Articles

Changes in the balance of Th17/Treg cells and oxidative stress markers in patients with HIV‑associated pulmonary tuberculosis who develop IRIS.

Tuberculosis (TB) is the most common opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus (HIV) infection and is one of the primary causes of death from AIDS. The increased accessibility to highly active antiretroviral therapy (HAART) has significantly improved the clinical outcome of patients with HIV infection. However, following ART, rapid restoration of the immune system leads to immune reconstitution inflammatory syndrome (IRIS). Oxidative stress and innate immunity play a role in TB-associated IRIS (TB-IRIS). The present study investigated the changes that occur in oxidative stress markers and T helper (Th)17/regulatory T (Treg) cell balance and their significance in IRIS patients with HIV-associated pulmonary TB. A total of 316 patients with HIV-associated pulmonary TB were treated with HAART and followed up regularly for 12 weeks. Those who developed IRIS were included in the IRIS group (n=60), while the remaining patients were included in the non-IRIS group (n=256). The changes in plasma oxidative stress markers superoxide dismutase (SOD) and malondialdehyde (MDA) were detected with the ELISA, and the ratio of Th17 to Treg cells in whole blood were analyzed before and after treatment through the flow cytometric assay. Following treatment, MDA and Th17 cells levels were significantly increased while SOD and Treg cells levels were decreased in the IRIS group (P<0.05) compared with before treatment. In the non-IRIS group, a non-significant decrease was observed in SOD levels (P>0.05), while the MDA levels significantly decreased compared with before treatment (P<0.05) and the Th17 and Treg cells levels were both significantly increased (P<0.05). After treatment, compared with the non-IRIS group, the IRIS group showed a significant increase in MDA and Th17 cells and decrease in SOD and Treg cells levels (P<0.05). In addition, Th17 cells levels were positively correlated with MDA but negatively correlated with SOD levels. Treg levels were negatively correlated with MDA and positively correlated with SOD levels (P<0.05). The area under the curve values of serum MDA and SOD, Th17 and Treg levels predicting the occurrence of IRIS were 0.738, 0.883, 0.722 and 0.719, respectively (P<0.05). These results indicated that the above parameters have certain diagnostic value for the occurrence of IRIS. The occurrence of IRIS in patients with HIV-associated pulmonary TB may be associated with oxidative stress and Th17/Treg cell imbalance.

Prognostic factors for immune reconstitution inflammatory syndrome in patients with HIV and tuberculosis during antiretroviral therapy

Antiretroviral therapy (ARVT) promotes the growth of a CD4 lymphocyte subpopulation, which leads to the development of immune reconstitution inflammatory syndrome (IRIS) in a number of patients with late-stage HIV and tuberculosis (TB) coinfection. Early prognostic factors for IRIS should be identified to timely initiate pathogenetic therapy aimed at its relief and ARVT continuation. Objective. To develop a method for the early diagnosis of IRIS in patients with HIV/TB coinfection during ARVT and to identify criteria for initiating pathogenetic therapy. Subjects and methods. The investigation enrolled 200 patients with HIV/TB coinfection who were divided into 2 groups: 1) 100 patients who received antituberculosis therapy (ATBT) without ARVT; 2) 100 patients who had combination (ARVT + ATBT) treatment. A control group included 50 healthy volunteers. To determine the prognostic factors for IRIS, all the patients underwent studies of viral load, CD4 lymphocyte levels, plasma lipid profile, and a complete blood count with a differential blood count before and after 1 month of treatment. Results. In Group 2, the signs of IRIS were detected in 30 (30%) patients; those were absent in 70 (70%) patients at 10-14 days after the start of combination (ARVT + ATBT) therapy. The level of stab neutrophils was significantly higher in patients with the signs of IRIS than in those without IRIS, despite the absence of a difference in viral load and CD4 lymphocyte levels (p&gt;0.05). All the patients with HIV/TB coinfection showed changes in the indicators of the lipid spectrum. However, there were significant differences between the patients with and without IRIS only in the level of triglycerides (TG) (1.4±0.2 and 0.9±0.2 mmol/l, respectively; p&lt;0.001). Timely detoxification therapy for patients with the signs of IRIS (manifestations of intoxication syndrome and elevated TG levels) resulted in the relief of this syndrome, which made it possible to continue ARVT. Conclusion. The significant increase in the level of TG in patients with the signs of IRIS during ARVT + ATBT allows this indicator to be used as an early laboratory marker of the risk for IRIS to timely prescribe pathogenetic therapy and to continue ARVT, which is important in predicting the disease.

Too much of a good thing: Immune reconstitution inflammatory syndrome in a patient with Still's disease

Immune Reconstitution Inflammatory Syndrome (IRIS) is a potential complication when treating non HIV immunosuppressed patients with opportunistic infections. We present a case of a 49-year-old female with Adult-onset Still's disease on prednisone 40 mg daily who came to ED with right leg weakness and intractable headache for one week. She was diagnosed with Cryptococcus meningitis. Patient completed the induction phase of antifungal therapy and the steroids were tapered over four weeks. One month after discharge, a patient was brought in to ED, minimally responsive to verbal stimuli and had new left hemiparesis with persistent right leg weakness was noted on exam. An MRI of the brain was consistent with diffuse leptomeningeal enhancement compatible with meningoencephalitis. LP was notable for elevated opening pressure of 36cmH2O and CSF studies were negative for recurrence of cryptococcal infection. Given the timeline of patients presentation one month after discontinuation of steroids, and workup consistent with sterile meningitis, immune reconstitution inflammatory syndrome was identified as the likely diagnosis. The patient was started on 50 mg of Prednisone daily. Six weeks after presentation, the patient's mental status returned to baseline, left hemiparesis resolved, and right lower extremity strength significantly improved. Clinicians should have a high index of suspicion for CNS IRIS in patients presenting with new neurologic findings in the setting of rapid discontinuation of steroids due to infection. IRIS in HIV patients with cryptococcal meningitis is a well-established entity; the purpose of this case report is to bring attention to similar inflammatory syndrome in non-HIV patients with cryptococcal meningitis.

Prednisone for the Prevention of Paradoxical Tuberculosis-Associated IRIS

BackgroundEarly initiation of antiretroviral therapy (ART) in human immunodeficiency virus (HIV)–infected patients who have tuberculosis reduces mortality among patients with low CD4 counts, but it increases the risk of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS).MethodsWe conducted this randomized, double-blind, placebo-controlled trial to assess whether prophylactic prednisone can safely reduce the incidence of paradoxical tuberculosis-associated IRIS in patients at high risk for the syndrome. We enrolled HIV-infected patients who were initiating ART (and had not previously received ART), had started tuberculosis treatment within 30 days before initiating ART, and had a CD4 count of 100 cells or fewer per microliter. Patients received either prednisone (at a dose of 40 mg per day for 14 days, then 20 mg per day for 14 days) or placebo. The primary end point was the development of tuberculosis-associated IRIS within 12 weeks after initiating ART, as adjudicated by an independent committee.ResultsAmong the 240 patients who were enrolled, the median age was 36 (interquartile range, 30 to 42), 60% were men, and 73% had microbiologically confirmed tuberculosis; the median CD4 count was 49 cells per microliter (interquartile range, 24 to 86), and the median HIV type 1 RNA viral load was 5.5 log10 copies per milliliter (interquartile range, 5.2 to 5.9). A total of 120 patients were assigned to each group, and 18 patients were lost to follow-up or withdrew. Tuberculosis-associated IRIS was diagnosed in 39 patients (32.5%) in the prednisone group and in 56 (46.7%) in the placebo group (relative risk, 0.70; 95% confidence interval [CI], 0.51 to 0.96; P=0.03). Open-label glucocorticoids were prescribed to treat tuberculosis-associated IRIS in 16 patients (13.3%) in the prednisone group and in 34 (28.3%) in the placebo group (relative risk, 0.47; 95% CI, 0.27 to 0.81). There were five deaths in the prednisone group and four in the placebo group (P=1.00). Severe infections (acquired immunodeficiency syndrome–defining illnesses or invasive bacterial infections) occurred in 11 patients in the prednisone group and in 18 patients in the placebo group (P=0.23). One case of Kaposi’s sarcoma occurred in the placebo group.ConclusionsPrednisone treatment during the first 4 weeks after the initiation of ART for HIV infection resulted in a lower incidence of tuberculosis-associated IRIS than placebo, without evidence of an increased risk of severe infections or cancers. (Funded by the European and Developing Countries Clinical Trials Partnership and others; PredART ClinicalTrials.gov number, NCT01924286.)

Immune Reconstitution Inflammatory Syndrome and Rebound Syndrome on Withdrawal of Immunomodulatory Drugs for Multiple Sclerosis: Current Understanding and a Case Report

Recent years have seen significant increases in the numbers of patients with multiple sclerosis (MS) receiving treatment with new immunomodulatory drugs. The number of cases in which these drugs are withdrawn because of side effects, intolerance, inadequate efficacy or planned pregnancy also increases. We present here a review of the problem of severe complications associated with the termination of treatment with natalizumab and fingolimod, in the form of immune reconstitution inflammatory syndrome (IRIS) and ricochet syndrome (withdrawal syndrome or rebound syndrome). The history of the term IRIS is considered, along with the diagnostic criteria for this syndrome in patients infected with human immunodeficiency virus. Variants of IRIS in patients interrupting natalizumab treatment are described. The clinical and radiological signs are assessed, as are the possible mechanisms of development of rebound syndrome on withdrawal of natalizumab and fingolimod treatment. The need for developing diagnostic criteria and studying risk factors for the development of IRIS and rebound syndrome in MS patients terminating therapy with new immunomodulatory drugs is emphasized.

Risk Factors and Frequency of Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome among HIV/Tuberculosis Co-infected Patients in Southern India

Immune reconstitution inflammatory syndrome (IRIS) continues to be a complication in HIV/tuberculosis (TB) co-infected patients initiating highly active antiretroviral therapy (HAART). The aim of this study was to evaluate the risk factors associated with developing IRIS to identify a possible biomarker to predict or diagnose IRIS in patients initiating HAART. A total of 175 HIV/TB co-infected patients initiating HAART were followed up longitudinally during September 2010 to May 2013 attending a HIV care clinic in Chennai. Patients were followed up longitudinally after HAART initiation and baseline demographic, laboratory parameters and treatment characteristics between patients with IRIS events and those without IRIS events were compared. Chi-square or Fisher’s exact test for categorical variables and a Wilcoxon rank-sum test for continuous variables were performed using SPSS, version 12.0 software. Patients with IRIS had a significantly lower median baseline CD4+ T-cell count (P = 0.0039). There were no differences in terms of sex, CD4 T-cell %, plasma viral load, time interval between initiating ATT and HAART between the IRIS and non-IRIS patients. Low CD4+ T-cell count (<100 cells/μL) could be used as a marker to screen and monitor patients initiating HAART.

P4. Contrast-enhancing lesions within the spinal chord help to identify IRIS in patients with natalizumab-PML

Most, if not all patients with natalizumab-associated progressive multifocal leukoencephalopathy (PML) who are treated by plasma exchange (PLEX) develop an immune reconstitution inflammatory syndrome (IRIS), which often leads to severe tissue destruction within the brain. While steroids can efficiently treat IRIS, they worsen PML and a reliable and prompt diagnosis of IRIS in natalizumab-PML patients is thus critical. We report on a patient with supratentorial manifestations of natalizumab-PML who developed difficulties urination three weeks after PLEX and corresponding new gadolinium-enhancing lesions within the spinal chord. Cerebral MRI confirmed the diagnosis of IRIS. Therefore, detection of contrast-enhancing lesions within the spinal chord may help to identify IRIS in patients with natalizumab-PML.

Contrast-Enhancing Lesions within the Spinal Chord Suggests Immune Reconstitution Inflammatory Syndrome (IRIS) in a Patient with Natalizumab Associated Progressive Multifocal Leukencephalopathy (Natalizumab-PML)

Background: Many patients with natalizumab-associated progressive multifocal leukoencephalopathy (PML) who are treated by plasma exchange (PLEX) develop an immune reconstitution inflammatory syndrome (IRIS), which often leads to severe tissue destruction within the brain. While steroids can efficiently treat IRIS, they worsen PML and a reliable and prompt diagnosis of IRIS in natalizumab-PML patients is thus critical. Clinical presentation: We report on a patient with supratentorial manifestations of natalizumab-PML after PLEX and corresponding new gadolinium-enhancing lesions within the spinal cord, which were clinically corresponding to difficulties to urinate. Conclusion: Cerebral MRI supported the diagnosis of IRIS. Therefore, detection of contrast-enhancing lesions within the spinal cord may indicate IRIS in patients with natalizumab-PML.

Use of Maraviroc in the prevention and Treatment of Immune Reconstitution Inflammatory Syndrome in Natalizumab-Associated Progressive Multifocal Leukoencephalopathy

We discuss the case of a patient with Progressive Multifocal Leukoencephalopathy (PML), developed after treatment with Natalizumab for 42 months for relapsing remitting multiple sclerosis (RRMS). Imaging was consistent with wide-spread PML with features that portended a high risk of development of Immune Reconstitution Inflammatory Syndrome (IRIS). After completion of plasmapheresis, she was started on oral maraviroc, chemokine receptor 5 antagonists. Our patient did not develop radiological signs or symptoms of clinical IRIS and tolerated maraviroc without adverse side-effects. We propose that maraviroc merits further examination as an agent that may prevent IRIS in patients with natalizumab-associated PML.

Return of meningeal symptoms in a patient treated for cryptococcal meningitis

Sirs: A 28-year-old Guinese man was admitted to our hospital with a 3-week history of severe headache, vomiting and fever. Ten months earlier he was diagnosed with AIDS. The presenting AIDS-defining illness then, was disseminated cryptococcosis: Cryptococcus neoformans had been recovered from CSF, bronchoalveolar washings, and blood. Standard treatment of CM with amphotericin B and flucytosine followed by fluconazole [1] resulted in clinical and microbiological cure. The patient had been taking fluconazole 200 mg QD PO as secondary prophylaxis since. After successful treatment of CM, HAART was initiated. This preceded admission by 320 days. The CD4 cell count rose from 0 to 120 cells/µl and HIV1-RNA to undetectable levels (<50 copies/ ml). There was no reason to doubt compliance to fluconazole prophylaxis. On examination an ill-looking man was seen, with low-grade pyrexia and stable haemodynamics. He was alert and cooperative, with no signs of meningism or mental confusion. Neurological examination and further physical examination revealed no abnormalities. Laboratory results were unremarkable. Brain CT-scan without contrast did not show any mass lesions, or hydrocephalus. Clear CSF was obtained, opening pressure was >50 cm H2O. CSF contained 0.59 g/l protein, 3.0 mmol/l glucose (at a serum glucose concentration of 5.1 mmol/l) and 272 × 106/l leukocytes, mainly monocytic. It tested positive for cryptococcal antigen. Considering relapse CM, treatment appropriate to this diagnosis was initiated (amphotericin B 1 mg/kg intravenously per day and flucytosine 100 mg/ kg/d PO). After 1 week his headache and malaise had not improved. Both stain and culture were negative for Cryptococcus neoformans. Cryptococcal antigen titers were found to be low: 1:16 in serum and 1:4 in CSF. Therefore the diagnosis was revised to Cryptococcus neoformans-related immune reconstitution inflammatory syndrome (IRIS). Antifungal treatment was discontinued and prednisone was prescribed (1 mg/kg/day IV). One more lumbar puncture was needed for temporary relief of symptoms due to raised CSF pressure. Our patient made a dramatic recovery and was discharged from hospital 3 days later, symptom-free. Prednisone was tapered in 4 months. IRIS can manifest itself as a latent infection unmasked by immune reconstitution, or as sterile inflammation in response to persisting antigens of an infection already treated. Therefore, latent infection should be ruled out in patients commencing antiretroviral therapy. Key to the diagnosis of cryptococcal-related IRIS in patients treated with HAART is the absence of fungal cells in all cultures. Cryptococcal antigen in blood or CSF of HIV-infected patients previously treated for CM, is a poor marker of infection [2]. Shelburne et al. found low cryptococcal antigen titres of value in discriminating cryptococcal-related IRIS from CM in a retrospective cohort study [3]. Other factors predictive of cryptococcal-related IRIS are a higher white blood cell count in CSF, higher CSF glucose and a higher CD4 cell count. . Lumbar puncture opening pressure was significantly higher in the IRIS group. These findings reflect the inflammatory nature of the syndrome due to immune restoration. The presence of the following risk factors for IRIS support the diagnosis in this case: a rise in CD4 cell count, a decrease in viral load, and compliance with a secondary prophylactic treatment regime of fluconazole. For treatment of the aseptic meningitis, anti-inflammatory drugs are a logical choice. Short-term corticosteroid administration was shown to be safe and well tolerated in patients who are receiving antiretroviral treatment [4]. It proved beneficial to prevent paradoxical reactions in tuberculous meningitis [5] and in other described cases of cryptococcal meningitis associated IRIS [6]. At a dose of 60 mg prednisone IV, our patient responded well. However, studies defining the role of corticosteroids in IRIS are urgently needed. The use of corticosteroids was demonstrated to be harmful in CM or cryptococcoma [7]. Therefore, exclusion of active cryptococcal disease remains the most important step in managing Cryptococcus neoformans—related IRIS. Guidelines for the treatment of CM recommend daily lumbar punctures in all patients with initially elevated opening pressures (>25 cm H2O) until the pressure is adequately controlled [1, 7]. Since the mechanism for increased intracranial pressure is thought to be the same in CM and cryptococcal IRIS, adherence to these guidelines seems prudent. Concluding, the HIV-positive patient treated with highly active antiretroviral therapy and returning meningeal symptoms after treatment for cryptococcal meningitis is diagnostically challenging. Distinguishing between Cryptococcus neoformans-related IRIS and active cryptococcal disease as two different clinical entities is crucial.