Skin and mucosal manifestations of immune reconstitution inflammatory syndrome in people living with HIV: a review.

Opportunistic infections have significantly decreased in individuals living with human immunodeficiency virus and receiving antiretroviral therapy. However, in approximately 10%-25% of patients, severe skin reactions during immune reconstruction are constantly increasing. This may manifest as either an exacerbation of a chronic disease or the development of a new disorder, referred to as immune reconstitution inflammatory syndrome. This review focuses on the current knowledge regarding the dermatological symptoms of immune reconstitution inflammatory syndrome observed in recent years. These symptoms encompass various pathogens, neoplasms, and certain autoimmune diseases. In addition to the most common skin reactions, attention is directed towards conditions not previously described in any review, such as psoriasis.

Complex Decisions in HIV-Related Cryptococcosis: Addressing Second Episodes of Cryptococcal Meningitis.

PURPOSE OF REVIEW: This review highlights the difficulties in diagnosing and treating persons with a prior history of cryptococcal meningitis who improve but suffer from a recurrence of symptoms. This scenario is well known to those who frequently care for patients with cryptococcal meningitis but is not well understood. We highlight major gaps in knowledge. RECENT FINDINGS: We recently summarized our experience with 28 persons with paradoxical immune reconstitution inflammatory syndrome (IRIS) and 81 persons with microbiological relapse. CD4 count and cerebrospinal fluid white blood cell count were higher in IRIS than relapse but neither was reliable enough to routinely differentiate these conditions. Second-episode cryptococcal meningitis remains a difficult clinical scenario as cryptococcal antigen, while excellent for initial diagnosis has no value in differentiating relapse of infection from other causes of recurrent symptoms. Updated research definitions are proposed and rapid, accurate diagnostic tests are urgently needed.

Caso probable de síndrome de reconstitución inmune por mpox en una persona con inmunosupresión avanzada por VIH / Probable case of mpox immune reconstitution inflammatory syndrome (IRIS) in a person with HIV disease

Se presenta el caso clínico de persona viviendo con VIH, con mala adherencia a tratamiento, sin vacunación previa para mpox, que evolucionó con un cuadro clínico probable de síndrome de reconstitución inmune posterior a reinicio de TAR, debido a la progresión de las lesiones cutáneas. Recibió tratamiento con tecovirimat por siete días, con evolución clínica favorable. Corresponde al primer caso reportado que recibió terapia con tecovirimat en Chile.

We report a clinical case of a person living with HIV with poor adherence to treatment, no previous mpox vaccination, who had a probable mpox syndrome immune reconstitution after restarting ART, due to worsening of skin lesions. He received treatment with tecovirimat for 7 days, clinically improved and was discharged in good condition. We reported this first clinical case that received tecovirimat in Chile.

Newly diagnosed type 1 diabetes mellitus in a human immunodeficiency virus-infected patient with antiretroviral therapy-induced immune reconstitution inflammatory syndrome: a case report.

BACKGROUND: Diabetes that develops in human immunodeficiency virus (HIV)-infected patients who receive antiretroviral therapy (ART) is usually type 2 diabetes mellitus (T2DM); however, autoimmune diabetes, such as type 1 diabetes mellitus (T1DM) can also develop in this population. After treatment with ART, patients might experience clinical deterioration following an increase in the CD4 cell count, which is termed immune reconstitution inflammatory syndrome (IRIS). Here, we describe an HIV-infected patient on ART who developed T1DMat due to IRIS, highlighting the clinical complexity in diagnosis and treatment. CASE PRESENTATION: A 36-year-old man infected with HIV had a nadir CD4 cell count of 15.53/µL before medication, which increased to 429.09/µL after 9 months of regular ART. The fasting serum glucose at 9 months was between 96 mg/dL and 117 mg/dL. After 11 months of ART, the patient was admitted to hospital for diabetic ketoacidosis (DKA) and Graves' disease (GD). Noninsulin antidiabetics (NIADs) were prescribed following the resolution of DKA. However, poor glycemic control was noted despite well-titrated NIADs. Further investigation demonstrated poor pancreatic beta cell function and elevated anti-glutamic acid decarboxylase (anti-GAD) and anti-tyrosine phosphatase-like insulinoma antigen 2 (anti-IA2) titers. According to the results, he was diagnosed with T1DM and received multiple daily injections(MDI) of insulin. The regimen of MDI was insulin degludec as basal insulin and insulin aspart as prandial insulin. After MDI therapy, his glycemic control was improved. CONCLUSION: In this case, T1DM was ascribed to IRIS. Although this phenomenon has been demonstrated in previous case reports, further study is necessary to realize the mechanism of this association. Therefore, we emphasize that when HIV-infected patients on ART experience an unstable blood glucose level and abnormal thyroid function, physicians should consider T1DM and GD associated with ART-induced IRIS to reduce the subsequent complications and more serious endocrine dysfunction.

Immune reconstitution inflammatory syndrome drives emergence of HIV drug resistance from multiple anatomic compartments in a person living with HIV.

Reservoirs of HIV maintained in anatomic compartments during antiretroviral therapy prevent HIV eradication. However, mechanisms driving their persistence and interventions to control them remain elusive. Here we report the presence of an inducible HIV reservoir within antigen-specific CD4+T cells in the central nervous system of a 59-year-old male with progressive multifocal leukoencephalopathy immune reconstitution inflammatory syndrome (PML-IRIS). HIV production during PML-IRIS was suppressed by modulating inflammation with corticosteroids; selection of HIV drug resistance caused subsequent breakthrough viremia. Therefore, inflammation can influence the composition, distribution and induction of HIV reservoirs, warranting it as a key consideration for developing effective HIV remission strategies.

Immune Reconstitution Inflammatory Syndrome After Hematopoietic Stem Cell Transplantation in a FOXN1 -deficient Patient.

The FOXN1 gene mutation is a unique disorder that causes the nude severe combined immunodeficiency phenotype. In patients with severe combined immunodeficiency, hematopoietic stem cell transplantation (HSCT) is life-saving if performed earlier. Thymic transplantation is the curative treatment for FOXN1 deficiency because the main pathology is thymic stromal changes. In this report, we describe the clinical features of a Turkish patient with a homozygous FOXN1 mutation treated with HSCT from his human leukocyte antigen-matched sibling. On follow-up, he showed Bacille Calmette Guerin adenitis and was evaluated as having immune reconstitution inflammatory syndrome. By presenting our patient, we aimed to draw attention to the development of HSCT and subsequent immune reconstitution inflammatory syndrome as a treatment option in patients with FOXN1 deficiency.

[Differential diagnosis of immune reconstitution inflammatory syndrome and progressive multifocal leukoencephalopathy after natalizumab withdrawal]. / Differentsial'naya diagnostika vospalitel'nogo sindroma vosstanovleniya immuniteta i progressiruyushchei mul'tifokal'noi entsefalopatii pri otmene natalizumaba.

The appearance of new foci on MRI, the increase in neurological deficits, including the appearance of cognitive disorders and disturbances in the level of consciousness in patients with multiple sclerosis during the «washing period¼ when transferring from natalizumab (NZ) to another drug, may be due to both progressive multifocal leukoencephalopathy (PML) and exacerbation of the disease in the absence of therapy. Discontinuation of NS is fraught not only with a resumption, but with an increase in disease activity, the development of an immune reconstitution inflammatory syndrome (IRIS) due to the opening of the blood-brain barrier. Often, the processes of differential diagnosis of IRIS and natalizumab-associated PML are complex and require the use of additional methods of examination and monitoring of the dynamics of the patient's condition. However, the severity of the condition and the severity of the consequences caused by incorrect therapeutic tactics significantly reduce the time for diagnosis and require an immediate decision. The difficulties of differential diagnosis of IRIS and PML are reflected in the clinical case.

Changes in Brain Volumes Are Relevant during Natalizumab-Associated Progressive Multifocal Leukoencephalopathy: Lessons from a Case Report.

This is a case report concerning a Natalizumab-associated Progressive Multifocal Leukoencephalopathy (PML) with cerebellar localization and wakefulness disturbances. Awakening and clinical improvement dramatically occurred as soon as the immune reconstitution inflammatory syndrome (IRIS) took place, being it mild in nature and colocalizing with the PML lesion. In these ideal experimental conditions, we applied brain magnetic resonance imaging post-analysis in order to know changes in brain volumes underlying the pathological process over the infection period. White matter volume increased with a decrease in grey matter during IRIS. Conversely, we found a constant increase in cerebrospinal fluid volume throughout the duration of PML, suggesting a widespread abiotrophic effect, far from the lesion. Furthermore, brain parenchymal fraction significantly decreased as expected while the total brain volume remained stable at all times. Neurodegeneration is the main contributor to the steady disability in Natalizumab-associated PML. This process is thought to be widespread and inflammatory in nature as well as sustained by IRIS and humoral factors derived from the PML lesion.

Case Report: Immune reconstitution inflammatory syndrome after hematopoietic stem cell transplantation for severe combined immunodeficiency.

We report a case of immune reconstitution inflammatory syndrome (IRIS) after hematopoietic stem cell transplantation (HSCT). The patient had sever bacillus Calmette-Guerin (BCG) vaccine-caused disseminated infection and had received allogeneic HSCT for X-linked severe combined immunodeficiency disease. After HSCT, complicated by treatment-responding veno-occlusive disease and acute graft-versus-host disease, at the time when immunosuppressants were withdrawn, the patient experienced recurrent fever accompanied by elevated inflammatory indicators. After receiving glucocorticoids and ibuprofen, the patient's condition improved, and a diagnosis with BCG-related IRIS was made.

Pneumocystis jirovecii-associated immune reconstitution inflammatory syndrome-like phenomenon in a child with leukaemia: a case report and literature review.

BACKGROUND: Immune reconstitution inflammatory syndrome (IRIS) refers to the phenomenon of intense immune responses against pathogens in patients with AIDS undergoing antiretroviral therapy to reconstitute immune function, resulting in functional impairment of multiple organs. Non-AIDS immunosuppressed hosts may also develop similar manifestations to IRIS during immune recovery. CASE PRESENTATION: An 8-year-old girl presented with acute lymphoblastic leukaemia was admitted for scheduled chemotherapy treatment. During chemotherapy, she experienced pancytopenia and Pneumocystis jirovecii pneumonia, which was diagnosed based on the abnormal shadows observed on chest computed tomography, the elevation of serum ß-D-glucan, and the positive mNGS results of Pneumocystis jirovecii in both sputum and blood. After treatment with Granulocyte Colony-Stimulating Factor, sulfamethoxazole, and caspofungin, aggravation of lung lesions was discovered and severe interstitial lung disease developed in a short period along with a rapidly increasing leukocyte count. Intravenous methylprednisolone pulse therapy was given, but lung function did not improve, and she finally died after the withdrawal of medical care. CONCLUSIONS: For patients with acute lymphocytic leukaemia infected with Pneumocystis jirovecii, the rapid aggravation of pulmonary lesions in the process of blood recovery and immune reconstitution should raise vigilance against the possibility of IRIS-like reactions. The use of granulocyte stimulating factors may aggravate the inflammatory response in the lungs. The timing, dosage, and duration of treatment of glucocorticoids and the impact of high-dose methylprednisolone pulse therapy on the prognosis of patients should be explored in further research.

Intestinal barrier dysfunction mediates Whipple's disease immune reconstitution inflammatory syndrome (IRIS).

BACKGROUND & AIMS: Classical Whipple's disease (CWD) affects the gastrointestinal tract and causes chronic diarrhea, malabsorption, and barrier dysfunction with microbial translocation (MT). Immune reconstitution inflammatory syndrome (IRIS) is a serious complication during antimicrobial treatment of CWD. The pathomechanisms of IRIS have not been identified and mucosal barrier integrity has not been studied in patients with IRIS CWD. METHODS: In 96 CWD patients (n = 23 IRIS, n = 73 non-IRIS) and 30 control subjects, we analysed duodenal morphology by histology, measured serum markers of MT, and proinflammatory cytokines in biopsy supernatants, and correlated microbial translocation with T cell reconstitution and activation. RESULTS: Before treatment, duodenal specimens from patients who later developed IRIS exhibited a more pronounced morphological transformation that suggested a disturbed barrier integrity when compared with the non-IRIS group. Villous atrophy was mediated by increased apoptosis of epithelial cells, which was insufficiently counterbalanced by regenerative proliferation of crypt cells. Pretreatment deficiencies in the mucosal secretion of proinflammatory cytokines and chemokines (e.g., IL-6, CCL2) in these patients markedly resolved after therapy induction. High serum levels of lipopolysaccharides (LPS), soluble CD14 (sCD14), and LPS-binding protein (LBP) combined with low endotoxin core antibody (EndoCAb) titres suggested systemic MT in CWD patients developing IRIS. CD4+ T cell count and activation in IRIS CWD patients correlated positively with sCD14 levels and negatively with EndoCAb titres. Furthermore, the degree of intestinal barrier dysfunction and MT was predictive for the onset of IRIS. CONCLUSION: Prolonged MT across a dysfunctional intestinal mucosal barrier due to severe tissue damage favors dysbalanced immune reconstitution and systemic immune activation in IRIS CWD. Therefore, the monitoring of inflammatory and MT markers in CWD patients might be helpful in identifying patients who are at risk of developing IRIS. Therapeutic strategies to reconstitute the mucosal barrier and control inflammation could assist in the prevention of IRIS.

Macrophages Are the Key Players in Promoting Hyper-Inflammatory Response in a Mouse Model of TB-IRIS.

TB-IRIS is an abnormal inflammatory response in a subset of HIV-TB co-infected patients shortly after initiation of anti-retroviral therapy (ART). Therapy in these patients could have greatly improved the life expectancy as ART reconstitutes the function and number of CD4+ T cells and many patients see improvement in symptoms but paradoxically up to 54% of co-infected patients develop TB-IRIS. Different studies have indicated that both innate and adaptive immunity are involved in the pathology of IRIS but the role of macrophages in abnormal activation of CD4+ T cells is poorly understood. Since macrophages are one of the major antigen-presenting cells and are infected by M.tb at a high frequency, they are very much likely to be involved in the development of TB-IRIS. In this study, we have developed a mouse model of experimental IRIS, in which M.tb-infected T-cell knockout mice undergo a fatal inflammatory disease after CD4+ T cell reconstitution. Lung macrophages and blood monocytes from M.tb-infected TCRß-/- mice showed upregulated expression of cell surface activation markers and also showed higher mRNA expression of inflammation-associated chemokines and matrix metalloproteases responsible for tissue damage. Furthermore, cytokine and TLR signaling feedback mechanism to control excessive inflammation was also found to be dysregulated in these macrophages under lymphopenic conditions. Previous studies have shown that hyperactive CD4+ T cells are responsible for disease induction and our study shows that somehow macrophages are in a higher activated state when infected with M.tb in an immune-deficient condition, which results in excessive activation of the adoptively transferred CD4+ T cells. Understanding of the mechanisms underlying the pathophysiology of TB-IRIS would facilitate identification of prospective biomarkers for disease development in HIV-TB co-infected patients before starting antiretroviral therapy.

Dynamics of T-Lymphocyte Activation Related to Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome in Persons With Advanced HIV.

Most persons living with HIV (PLWH) experience a significant restoration of their immunity associated with successful inhibition of viral replication after antiretroviral therapy (ART) initiation. Nevertheless, with the robust quantitative and qualitative restoration of CD4+ T-lymphocytes, a fraction of patients co-infected with tuberculosis develop immune reconstitution inflammatory syndrome (TB-IRIS), a dysregulated inflammatory response that can be associated with significant tissue damage. Several studies underscored the role of adaptive immune cells in IRIS pathogenesis, but to what degree T lymphocyte activation contributes to TB-IRIS development remains largely elusive. Here, we sought to dissect the phenotypic landscape of T lymphocyte activation in PLWH coinfected with TB inititating ART, focusing on characterization of the profiles linked to development of TB-IRIS. We confirmed previous observations demonstrating that TB-IRIS individuals display pronounced CD4+ lymphopenia prior to ART initiation. Additionally, we found an ART-induced increase in T lymphocyte activation, proliferation and cytotoxicity among TB-IRIS patients. Importantly, we demonstrate that TB-IRIS subjects display higher frequencies of cytotoxic CD8+ T lymphocytes which is not affected by ART. Moreover, These patients exhibit higher levels of activated (HLA-DR+) and profilerative (Ki-67+) CD4+ T cells after ART commencenment than their Non-IRIS counterparts. Our network analysis reveal significant negative correlations between Total CD4+ T cells counts and the frequencies of Cytotoxic CD8+ T cells in our study population which could suggest the existance of compensatory mechanisms for Mtb-infected cells elimination in the face of severe CD4+ T cell lymphopenia. We also investigated the correlation between T lymphocyte activation profiles and the abundance of several inflammatory molecules in plasma. We applied unsupervised machine learning techniques to predict and diagnose TB-IRIS before and during ART. Our analyses suggest that CD4+ T cell activation markers are good TB-IRIS predictors, whereas the combination of CD4+ and CD8+ T cells markers are better at diagnosing TB-IRIS patients during IRIS events Overall, our findings contribute to a more refined understanding of immunological mechanisms in TB-IRIS pathogenesis that may assist in new diagnostic tools and more targeted patient management.

Immune reconstitution inflammatory syndrome-associated Graves disease in HIV-infected patients: clinical characteristics and response to radioactive iodine therapy.

OBJECTIVES: We aimed to describe the clinical characteristics and the response to radioactive iodine (RAI) treatment of immune reconstitution inflammatory syndrome-associated Graves disease (IRIS-GD) in comparison to Graves disease (GD) seen in HIV-uninfected patients. METHODS: We retrospectively reviewed the medical records of patients treated with RAI for GD. We obtained clinical, biochemical and HIV-related information of patients from their medical records. We compared patient characteristics and response to RAI treatment between patients with IRIS-GD and GD seen in HIV-uninfected patients. RESULTS: A total of 253 GD patients, including 51 patients with IRIS-GD, were included. Among IRIS-GD patients, CD4 cell nadir was 66 cells/µL (range: 37-103) with a peak HIV viral load of 60 900 copies/mL (range: 36 542-64 500). At the time of diagnosis of IRIS-GD, all patients had a completely suppressed HIV viraemia with a CD4 cell count of 729 cells/µL (range: 350-1279). The median interval between the commencement of HIV treatment and the onset of GD was 63 months. At 3 months follow-up, the proportion of patients with IRIS-GD achieving a successful RAI treatment outcome (euthyroid/hypothyroid state) was lower than that of HIV-uninfected patients (35.3% vs. 63.4%, respectively; p < 0.001). The response rate remained lower (60.8%) among patients with IRIS GD than among HIV-uninfected GD patients (80.2%, p = 0.004) at 6 months follow-up. After correcting for differences in age, gender and pre-treatment thyroid-stimulating hormone level, there was no significant difference in RAI treatment response between the two groups. CONCLUSIONS: After correcting for possible confounders, the response to RAI treatment was not different between patients with IRIS-GD and GD in HIV-uninfected patients.

Orbital non-HIV immune reconstitution inflammatory syndrome after cytapheresis.

The immune reconstitution inflammatory syndrome is a phenomenon typically described in HIV patient during the restoration of CD4 count after highly active antiretroviral therapy. Non-HIV immune reconstitution inflammatory syndrome has also been described after organ transplantation or immune recovery in neutropenic patients. We report the case of a 50-year-old man who presented to our department with left painful proptosis and ophthalmoplegia 2 days after having performed cytapheresis for a mantel cell lymphoma. Systemic work up and biopsy were performed and symptoms were relieved with intravenous steroids therapy. To our knowledge, this is the first case of orbital non-HIV immune reconstitution inflammatory syndrome described in the literature.

Tumor necrosis factor antagonists for paradoxical inflammatory reactions in the central nervous system tuberculosis: Case report and review.

RATIONALE: Paradoxical reaction/immune reconstitution inflammatory syndrome is common in patients with central nervous system tuberculosis. Management relies on high-dose corticosteroids and surgery when feasible. PATIENT CONCERN: We describe 2 cases of HIV-negative patients with corticosteroid-refractory paradoxical reactions of central nervous system tuberculosis. DIAGNOSES: The 2 patients experienced clinical impairment shortly after starting therapy for TB, and magnetic resonance imaging showed the presence of tuberculomas, leading to the diagnosis of a paradoxical reaction. INTERVENTIONS: We added infliximab, an anti-tumor necrosis factor (TNF)-alpha monoclonal antibody, to the dexamethasone. OUTCOMES: Both patients had favorable outcomes, 1 achieving full recovery but 1 suffering neurologic sequelae. LESSONS: Clinicians should be aware of the risk of paradoxical reactions/immune reconstitution inflammatory syndrome when treating patients with tuberculosis of the central nervous system and should consider the prompt anti-TNF-α agents in cases not responding to corticosteroids.