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.

Emerging trends in COVID-19 treatment: learning from inflammatory conditions associated with cellular therapies.

Coronavirus disease 2019 (SARS-CoV2) is an active global health threat for which treatments are desperately being sought. Even though most people infected experience mild to moderate respiratory symptoms and recover with supportive care, certain vulnerable hosts develop severe clinical deterioration. While several drugs are currently being investigated in clinical trials, there are currently no approved treatments or vaccines for COVID-19 and hence there is an unmet need to explore additional therapeutic options. At least three inflammatory disorders or syndromes associated with immune dysfunction have been described in the context of cellular therapy. Specifically, Cytokine Release Syndrome (CRS), Immune Reconstitution Inflammatory Syndrome (IRIS), and Secondary Hemophagocytic Lymphohistiocytosis (sHLH) all have clinical and laboratory characteristics in common with COVID19 and associated therapies that could be worth testing in the context of clinical trials. Here we discuss these diseases, their management, and potential applications of these treatment in the context of COVID-19. We also discuss current cellular therapies that are being evaluated for the treatment of COVID-19 and/or its associated symptoms.

Acquired Holmes Tremor in a Human Immunodeficiency Virus Immune Reconstitution Inflammatory Syndrome Patient Treated with Deep Brain Stimulation.

BACKGROUND: The authors present a case of a 66-year-old male who was diagnosed with human immunodeficiency virus, and his medical course of highly active antiretroviral therapy was complicated with the development of immune reconstitution inflammatory syndrome, which led to development of movement disorder consisting of right-sided resting tremor, neck dystonia, and jaw clenching. CASE DESCRIPTION: The patient's symptoms resembled that of rubral tremor, and he underwent placement of a deep brain stimulation electrode into the left ventral intermediate nucleus of the thalamus with significant improvement of symptoms. CONCLUSIONS: This is the first reported case in the literature of a human immunodeficiency virus-positive patient's treatment course complicated with immune reconstitution inflammatory syndrome with neurologic manifestation, which was refractory to medical therapy and thus treated with deep brain stimulation.

A Kidney Transplant Recipient With Fulminant Progressive Multifocal Leukoencephalopathy-Immune Reconstitution Inflammatory Syndrome: A Rare Clinical Outcome and Review of the Literature.

Progressive multifocal leukoencephalopathy is a devastating disease affecting the central nervous system that may be seen in immunocompromised patients. We present a case of a kidney transplant recipient who received tacrolimus, mycophenolic acid, and prednisone and who developed motor deficits, altered cognition, and speech abnormalities, which culminated in a coma. The diagnosis was made by detecting John Cunningham polyomavirus DNA with polymerase chain reaction and observing characteristic findings on magnetic resonance imaging. Soon after immunosuppressive therapy was withdrawn, the patient's clinical status deteriorated due to immune reconstitution inflammatory syndrome, and prednisone was administered. Unfortunately, the patient died about 9 months after onset of symptoms. This case serves to illustrate the fulminant progression of progressive multifocal leukoencephalopathy and the possible complications that may arise when treating it.

Immune reconstitution inflammatory syndrome in the lung in non-human immunodeficiency virus patients.

BACKGROUND: We evaluated immune reconstitution inflammatory syndrome (IRIS) in the lung in non-human immunodeficiency virus (HIV) patients. METHODS: We reviewed articles related to IRIS occurrence in the lung in non-HIV patients using a PubMed search. The keywords used for the search were "immune reconstitution syndrome" and "non-HIV." Only patients with lung involvement were included. Those with suggested IRIS caused by white blood cell recovery were excluded. RESULTS: There were 37 cases of IRIS in the lung in non-HIV patients. Complicating infections included tuberculosis (n = 17), histoplasmosis (n = 9), aspergillosis (n = 5), cryptococcosis (n = 4), and Pneumocystis pneumonia (n = 2). We also evaluated the underlying diseases, IRIS pathogenesis, management, and prognosis. IRIS was most commonly encountered in patients treated with anti-tumor necrosis factor (TNF) antibody who developed disseminated or extrapulmonary tuberculosis, leading to treatment discontinuation. CONCLUSIONS: The diagnosis and management of IRIS in the lung in non-HIV patients should be investigated further, especially in the era of anti-TNF treatment.

TB-IRIS pathogenesis and new strategies for intervention: Insights from related inflammatory disorders.

In almost one in five HIV/tuberculosis (TB) co-infected patients, initiation of antiretroviral therapy (ART) is complicated by TB immune reconstitution inflammatory syndrome (TB-IRIS). Corticosteroids have been suggested for treatment of severe cases, however no therapy is currently licensed for TB-IRIS. Hence, there is a strong need for more specific therapeutics, and therefore, a better understanding of TB-IRIS pathogenesis. Immune reconstitution following ART is a precariously balanced functional restoration of adaptive immunity. In those patients predisposed to disease, an incomplete activation of the innate immune system leads to a hyper-inflammatory response that comprises partially overlapping innate, adaptive and effector arms, eventually leading to clinical symptoms. Interestingly, many of these pathological mechanisms are shared by related inflammatory disorders. We here describe therapeutic strategies that originate from these other disciplines and discuss their potential application in TB-IRIS. These new avenues of interventions range from final-phase treatment of symptoms to early-phase prevention of disease onset. In conclusion, we propose a novel approach for the discovery and development of therapeutics, based on an updated model of TB-IRIS pathogenesis. Further experimental studies validating the causal relationships in the proposed model could greatly contribute to providing a solid immunological basis for future clinical trials on TB-IRIS therapeutics.

Management of Advanced HIV Disease.

Great progress has been made in caring for persons with human immunodeficiency virus. However, a significant proportion of individuals still present to care with advanced disease and a low CD4 count. Careful considerations for selection of antiretroviral therapy as well as close monitoring for opportunistic infections and immune reconstitution inflammatory syndrome are vitally important in providing care for such individuals.

Severe Progressive Multifocal Leukoencephalopathy (PML) and Spontaneous Immune Reconstitution Inflammatory Syndrome (IRIS) in an Immunocompetent Patient.

Background: Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection with JC-virus (JCV), a papova-virus, affecting mostly oligodendrocytes and the white matter of the central nervous system. Progressive Multifocal Leukoencephalopathy (PML) almost exclusively occurs in immunocompromised patients based on different underlying conditions of severe cellular immunodeficiency such as HIV/AIDS, secondary to neoplastic and autoimmune diseases, or during immunosuppressive therapy. Case presentation: We present the case of an otherwise healthy and immunocompetent patient without immunosuppressive therapy who was admitted with hemianopsia to the right side, sensory aphasia and changes of behavior. Magnet resonance imaging (MRI) and laboratory testing confirmed the diagnosis of PML, although functional tests did not show any evidence for cellular immunodeficiency. Extensive immunological tests did not reveal an apparent immunodeficiency. During symptomatic therapy the patient developed seizures which were assumed to be caused by a spontaneous immune reconstitution inflammatory syndrome (IRIS) demonstrated by MRI. We added a high dose of intravenous corticosteroids to the antiepileptic treatment and seizures ended shortly thereafter. However, the impairments of vision, behavior and language persisted. Conclusions: Our case report highlights that an apparently immunocompetent patient can develop PML and IRIS spontaneously. Therefore, MRI should be applied immediately whenever a rapid progression of PML symptoms occurs as treatment of IRIS with corticosteroids can result in a marked clinical improvement.

CNS immune reconstitution inflammatory syndrome.

Immune reconstitution inflammatory syndrome (IRIS) describes a syndrome of aberrant reconstituted immunity, often in association with HIV infection, beginning with a normalization of CD4+ T-cell counts resulting in a dysregulated immune response against an infecting opportunistic pathogen and the host. In this chapter, we discuss the unique nature of IRIS when present in the central nervous system (CNS IRIS) and the changes experienced with each host pathogen and its unique influence on the immune system. Consensus on the mechanism of action of the immune system in IRIS pathology is less clear and multiple theories have been proposed. Here we explore the early history of the term IRIS, proposed mechanisms and animal models, as well as common CNS pathogens associated with IRIS, and management strategies.

To do or not to do? plasma exchange and timing of steroid administration in progressive multifocal leukoencephalopathy.

OBJECTIVE: To retrospectively analyze the effect of plasma exchange (PLEX; yes = PLEX+ , no = PLEX- ) and steroids administration timing (prophylactically [proST] or therapeutically [therST]) on the longitudinal clinical course of patients with natalizumab-related progressive multifocal leukoencephalopathy (PML) and full-blown immune reconstitution inflammatory syndrome (PML-IRIS). METHODS: Clinical and radiological data of 42 Italian patients with PML were analyzed. Patient's data are available until 12 months after PML diagnosis. PLEX and steroids treatment as time-dependent covariates were entered in: (1) a Cox model to investigate their impact on full-blown PML-IRIS latency; (2) an analysis of variance ANOVA to investigate their impact on IRIS duration; and (3) a linear mixed model to assess their impact on the longitudinal clinical course (measured by means of Expanded Disability Status Scale [EDSS]). RESULTS: Treatment with PLEX was not associated to PML-IRIS latency (hazard ratio [HR] = 1.05; p = 0.92), but once IRIS emerged, its duration was significantly longer in patients who underwent PLEX (101 vs 54 days in PLEX+ and PLEX- patients; p = 0.028). Receiving proST versus therST was not associated to IRIS latency (HR = 0.67; p = 0.39) or duration (p = 0.95). Patients who underwent proST had a significantly higher EDSS increase during PML (0.09 EDSS points per month; p = 0.04) as compared to those who had therST. INTERPRETATION: This study highlights that: (1) caution on the use of PLEX should be considered as the current data do not support a beneficial effect of PLEX and (2) caution on the early use of steroids is suggested because their prophylactic use to prevent full-blown PML-IRIS seems to negatively impact on the longitudinal disability course. Ann Neurol 2017;82:697-705.

Successful repeat ECMO in a patient with AIDS and ARDS.

Veno-venous extracorporeal membrane oxygenation (ECMO) is being more commonly used in patients with acute respiratory distress syndrome (ARDS) due to potentially reversible illnesses. Survival from ARDS using ECMO has been reported even in patients with AIDS. However, the indications for ECMO for ARDS due to immune reconstitution inflammatory syndrome (IRIS) in patients with AIDS are unknown. A 23-year-old man with AIDS and Pneumocystis jirovecii pneumonia was admitted to the intensive care unit with severe ARDS refractory to mechanical ventilator support requiring ECMO. Although ECMO was discontinued, a second treatment with ECMO was necessary due to IRIS-associated ARDS, resulting in an excellent patient outcome. This patient's clinical course suggests two important messages. First, ECMO is a reasonable option for the treatment of patients with ARDS even in a patient with AIDS. Second, ECMO may be effective for the treatment of patients with IRIS.

The cursed duet today: Tuberculosis and HIV-coinfection.

The tuberculosis (TB) and HIV syndemic continues to rage and are a major public health concern worldwide. This deadly association raises complexity and represent a significant barrier towards TB elimination. TB continues to be the leading cause of death amongst HIV-infected people. This paper reports the challenges that lay ahead and outlines some of the current and future strategies that may be able to address this co-epidemic efficiently. Improved diagnostics, cheaper and more effective drugs, shorter treatment regimens for both drug-sensitive and drug-resistant TB are discussed. Also, special topics on drug interactions, TB-IRIS and TB relapse are also described. Notwithstanding the defeats and meagre investments, diagnosis and management of the two diseases have seen significant and unexpected improvements of late. On the HIV side, expansion of ART coverage, development of new updated guidelines aimed at the universal treatment of those infected, and the increasing availability of newer, more efficacious and less toxic drugs are an essential element to controlling the two epidemics. On the TB side, diagnosis of MDR-TB is becoming easier and faster thanks to the new PCR-based technologies, new anti-TB drugs active against both sensitive and resistant strains (i.e. bedaquiline and delamanid) have been developed and a few more are in the pipeline, new regimens (cheaper, shorter and/or more effective) have been introduced (such as the "Bangladesh regimen") or are being tested for MDR-TB and drug-sensitive-TB. However, still more resources will be required to implement an integrated approach, install new diagnostic tests, and develop simpler and shorter treatment regimens.

HIV-1 tuberculosis-associated immune reconstitution inflammatory syndrome.

Patients co-infected with HIV-1 and tuberculosis (TB) are at risk of developing TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) following commencement of antiretroviral therapy (ART). TB-IRIS is characterized by transient but severe localized or systemic inflammatory reactions against Mycobacterium tuberculosis antigens. Here, we review the risk factors and clinical management of TB-IRIS, as well as the roles played by different aspects of the immune response in contributing to TB-IRIS pathogenesis.

Inflammatory indices in meconium aspiration syndrome.

INTRODUCTION: Meconium aspiration syndrome (MAS) is linked to inflammation, but data on the patterns of hematological indices and C-reactive protein (CRP) in MAS are lacking. The aim of the study was to evaluate CRP, white blood cell count (WBC), absolute neutrophil count (ANC), and immature-to-total neutrophil ratio (IT-ratio) in MAS and to assess their association with disease severity. METHODS: Retrospective cross-sectional study including 239 consecutively admitted neonates with MAS to a level III NICU. Neonates with early onset sepsis were excluded. Results Neonates with severe MAS (invasive mechanical ventilation for <7 days) and very severe MAS (invasive mechanical ventilation for ≥7 days or high frequency ventilation or ECMO) had higher CRP and IT-ratio compared to neonates with non-severe MAS (no invasive mechanical ventilation) during the first 2 days of life (CRP: 13.0 and 40.9 vs. 9.5 mg/L, P = 0.039 and <0.001, respectively) and neonates with very severe MAS had lower WBC and ANC. All four inflammatory indices correlated significantly with duration of invasive mechanical ventilation, duration of respiratory support and with length of hospital stay, arterial hypotension, and persistent pulmonary hypertension. Neonates with all four inflammatory indices beyond the normal range had a more than 20-fold increase in risk for very severe MAS. CONCLUSION: High CRP and IT-ratio and low WBC and ANC values were closely linked to a more severe course of MAS during the early phases of the disease. These findings reflect the role of inflammation in the pathogenesis of MAS. Pediatr Pulmonol. 2016;51:601-606. 2015 Wiley Periodicals, Inc.

Progressive multifocal leukoencephalopathy and immune reconstitution inflammatory syndrome (IRIS).

Progressive multifocal leukoencephalopathy is a viral encephalitis induced by the John Cunningham (JC) virus, an ubiquitous neurotropic papovavirus of the genus polyomavirus that in healthy people in latency resides in kidney and bone marrow cells. Activation and entry into the CNS were first seen in patients with malignancies of the hematopoietic system and an impaired immune system. During the 1980 and the 1990s with the appearance of human immunodeficiency virus infection in humans, PML was found to be the most important opportunistic infection of the central nervous system. As a result of highly efficient immunosuppressive and immunomodulatory treatments, in recent years, the number of PML cases again increased. PML is prevented by an intact cellular immune response and accordingly immune reconstitution can terminate established disease in the CNS. However, forced immune reconstitution can lead to massive destruction of virus-infected cells. This may result in clinical exacerbation associated with high morbidity and mortality and referred to as PML with immune reconstitution inflammatory syndrome (PML-IRIS). In the present review, we discuss virological properties and routes of infection in the CNS, but mostly focus on the pathology of PML and PML-IRIS and on the role of the immune system in these disorders. We show that PML and PML-IRIS result from predominant JC virus infection of oligodendrocytes and, to a lesser extent, of infected neurons. Inflammation in these encephalitides seems to be driven by a dominant cytotoxic T cell response which is massively exaggerated during IRIS.

Síndrome inflamatorio de reconstitución inmune (SIRI) en pacientes pediátricos que acuden a la consulta de VIH/SIDA del servicio de pediatría médica infecciosa del Hospital Universitario de Caracas / Immune reconstitution inflammatory syndrome (IRIS) in pediatric patients attending consultation HIV / AIDS medical service pediatric infectious Hospital Universitario de Caracas

La Organización Mundial de la Salud define al síndrome inflamatorio de reconstitución inmune (SIRI) como un grupo de signos y síntomas que resultan de la recuperación inmunológica del paciente VIH/SIDA después del inicio de la terapia retroviral de gran actividad (TARGA) cuya incidencia es del 10% al 25%. Estudiar los pacientes con diagnóstico de infección por VIH controlados en el Servicio de Pediatría Médica Infecciosa del Hospital Universitario de Caracas que desarrollaron SIRI. Se realizó estudio retrospectivo con revisión de datos de pacientes pediátricos con diagnóstico de VIH que presentaron SIRI. Los mismos fueron recabados de la base de datos de la consulta VIH/SIDA diseñada en Access 2010 y analizados con EPIINFO 3.5.4. El 15% de los pacientes con diagnóstico de VIH presentaron SIRI, siendo del sexo masculino 80%; 60% fueron clasificados inicialmente en estadio C3. La edad media fue de 5,26 años, (SD: ± 4,34). La carga viral de inicio de TARGA 320.318 copias/mL (SD: ± 260 727), contaje de linfocitos T CD4+: 127 células/mm³ (SD:±148) relación CD4/CD8: 0,17 (SD: ± 0,11); TARGA inicial: 90% utilizaron 3TC, 60% AZT, 40% ABC y 80% inhibidores de proteasa. Las manifestaciones clínicas más frecuentemente observadas fueron BCGitis (30%), tuberculosis (30%) y neumocistosis (20%). En un 90% las manifestaciones de SIRI ocurrieron en los primeros 3 meses de iniciado TARGA. Al momento del SIRI se observó en promedio un aumento del contaje de linfocitos T CD4+ en 411 células/mL y disminución de CV en 2 log. El SIRI es frecuente en pacientes pediátricos con VIH/SIDA y debe ser tomado en cuenta cuando se inicia tratamiento en estados severos de inmunodepresión

The World Health Organization defines the Immune Reconstitution Inflammatory Syndrome (IRIS) as a group of signs and symptoms as a result of the HIV/AIDS patients’ immune recovery after initiation of highly active antiretroviral therapy (HAART), being the incidence 10% to 25%. To study patients with HIV infection in control at the Pediatric Infectious Service of University Hospital of Caracas who developed IRIS. Retrospective data review of pediatric patients diagnosed with HIV who presented SIRI was performed. It was collected from 2010 Access - designed HIV/AIDS consultation database and analyzed with EPIINFO 3.5.4. 15% of patients diagnosed with HIV had IRIS, being 80% male, 60% were initially classified C3 stage. The average age was 5.26 years (SD: +4.34). Viral load (VL) starting HAART: 320 318 copies/mL (SD: ± 260,727), CD4 ± count: 127 cells/mm³ (SD: +148), CD4/CD8: 0.17 (SD: +0.11); initial HAART used: 90% 3TC,60% AZT, 40% ABC and 80% protease inhibitors. The most frequently clinical features observed were: BCGitis (30%), tuberculosis (30%) and pneumocystosis (20%). SIRI manifestations occurred, in 90% of cases, in the first 3 months after initiation of HAART. At the moment of IRIS diagnosis, an average CD4 + T count at 411 cells/ml increase and 2 log VL decreases were recorded. SIRI is common in HIV pediatric patients and should be considered when treatment is started in severe immunosuppression state

Immune reconstitution disorders in patients with HIV infection: from pathogenesis to prevention and treatment.

An immune reconstitution disorder occurs in up to 40 % of severely immunodeficient HIV patients who commence antiretroviral therapy (ART), with an immune reconstitution inflammatory syndrome (IRIS) being encountered most commonly. Differences in the immunopathogenesis of an IRIS associated with different types of pathogen have become apparent but common features have also been defined. These include severe immunodeficiency prior to commencing ART associated with a high pathogen load and 'compensatory' immune responses, particularly innate immune responses, which inadequately control the pathogen and increase the risk of immunopathology as the immune system recovers on ART. Prevention of an IRIS may be achieved by optimising therapy for opportunistic infections before ART is commenced, delaying ART or using immunomodulatory therapy to prevent or suppress the immune response that causes the immunopathology. However, further clinical studies are required to examine these options in a systematic manner for the various types of IRIS.