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.

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.

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.

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.

Disease course and outcome of 15 monocentrically treated natalizumab-associated progressive multifocal leukoencephalopathy patients.

OBJECTIVE: Although the prognosis of natalizumab-associated progressive multifocal leukoencephalopathy (PML) seems to be better than HIV-associated PML, little is known about the long-term functional outcome in multiple sclerosis (MS) patients and the subsequent return of MS disease activity. We evaluated retrospectively 15 patients with natalizumab-associated PML treated at our centre. PATIENTS AND METHODS: Fifteen MS-PML patients (nine women, six men) were referred to us from adjacent local centres. The patients had a median natalizumab exposure of 34 months at PML diagnosis. They received standardised treatment as described in previous work. Expanded Disability Status Scale (EDSS) and Karnofsky score in the year pre-PML, at PML-diagnosis (pre-immune reconstitution inflammatory syndrome (IRIS)) and post-PML were determined in 3-6 monthly intervals. RESULTS: The median follow-up of these 15 patients was 21.5 months. None of the 15 patients died. Three patients had a Karnofsky score of 80 or higher, nine patients between 50-70 and three patients of 40 or lower at latest examination. Eight of the 15 patients developed seizures during acute PML phase. Fifty percent of those patients were not seizure-free one year post PML, despite continuation of antiepileptic treatment. The median EDSS in the year pre-PML was 2.5, 4.5 at PML diagnosis, 6.5 post-IRIS and 5.5 at latest examination. CSF became virus-free in eight of the 15 patients after a median time of 4.5 months. In nine patients, disease reappeared after a median time of seven months from PML diagnosis. CONCLUSIONS: Although the clinical outcome of natalizumab-treated PML patients is much better than in patients with HIV-associated PML, this may be further improved by treatment at reference centres using standardised therapy regimens and transient intensive care if needed. Systematic studies of appropriate MS immunotherapies after PML are critically needed.

[The Spanish AIDS Study Group and Spanish National AIDS Plan (GESIDA/Secretaría del Plan Nacional sobre el Sida) recommendations for the treatment of tuberculosis in HIV-infected individuals (Updated January 2013)]. / Recomendaciones de GESIDA/Secretaría del Plan Nacional sobre el Sida para el tratamiento de la tuberculosis en adultos infectados por el virus de la inmunodeficiencia humana (actualización enero de 2013).

This consensus document was prepared by an expert panel of the Grupo de Estudio de Sida (GESIDA [Spanish AIDS Study Group]) and the Plan Nacional sobre el Sida (PNS [Spanish National AIDS Plan]). The document updates current guidelines on the treatment of tuberculosis (TB) in HIV-infected individuals contained in the guidelines on the treatment of opportunistic infections published by GESIDA and PNS in 2008. The document aims to facilitate the management and treatment of HIV-infected patients with TB in Spain, and includes specific sections and recommendations on the treatment of drug-sensitive TB, multidrug-resistant TB, and extensively drug-resistant TB, in this population. The consensus guidelines also make recommendations on the treatment of HIV-infected patients with TB in special situations, such as chronic liver disease, pregnancy, kidney failure, and transplantation. Recommendations are made on the timing and initial regimens of antiretroviral therapy in patients with TB, and on immune reconstitution syndrome in HIV-infected patients with TB who are receiving antiretroviral therapy. The document does not cover the diagnosis of TB, diagnosis/treatment of latent TB, or treatment of TB in children. The quality of the evidence was evaluated and the recommendations graded using the approach of the Grading of Recommendations Assessment, Development and Evaluation Working Group.

The changing spectrum of rheumatic disease in HIV infection.

BACKGROUND: Rheumatic manifestations were described soon after human immunodeficiency virus (HIV) was discovered. Since however, combination anti-retroviral therapy (cART) has revolutionized the course of the infection. Less clear is what effect cART has had on rheumatic manifestations. SOURCES OF DATA: References were retrieved from the PubMed database using keywords including: 'HIV' and 'arthritis'; 'myalgia'; 'arthralgia' and other disease-specific terms, e.g. 'rheumatoid arthritis'. AREAS OF AGREEMENT: Musculoskeletal pain was common in HIV and increased with AIDS. Immune restoration inflammatory syndrome on initiation of cART causes de novo autoimmune inflammatory rheumatic disorders. Seronegative inflammatory arthritis with/without axial involvement has been reported widely with HIV. AREAS OF CONTROVERSY: It is unclear if HIV causes these conditions, creates an environmental milieu supportive of these conditions or acts as a marker of other risk factors. It is unclear what effect cART has had on these conditions. GROWING POINTS: Variable diagnostic classification criteria have caused this literature to be poorly comparable. AREAS TIMELY FOR DEVELOPING RESEARCH: High-quality controlled epidemiological studies using standardized criteria are needed among cART users. Treatment of active autoimmune disease in HIV patients needs to be evaluated formally.

Immune reconstitution inflammatory syndrome: immune restoration disease 20 years on.

Restoration of immune responses against opportunistic pathogens after commencing antiretroviral therapy (ART) may cause immune restoration disease (IRD) in about 10%-40% of HIV patients with low CD4(+) T-cell counts and usually presents clinically as a type of immune reconstitution inflammatory syndrome (IRIS). IRIS may be associated with many different opportunistic pathogens, but types associated with Mycobacterium tuberculosis, BCG, cryptococci, JC polyomavirus (the cause of progressive multifocal leukoencephalopathy [PML]), hepatitis C virus and hepatitis B virus infection are the most informative about disease pathogenesis and management. A CD4(+) T-cell count of < 50/µL and a high pathogen load are the most commonly identified risk factors for IRIS. Recovery of pathogen-specific T-cell responses and perturbations of innate immune responses before and after ART appear to cause immunopathological abnormality in tissues infected by the pathogen. Prevention of IRIS may be influenced by the timing of ART: The risk of tuberculosis (TB)-associated-IRIS can be reduced by commencing ART after 8 weeks of TB treatment, but rates of AIDS or death are lower if ART is commenced during the first 4 weeks of TB treatment. Outcomes for patients with HIV and treated cryptococcal or TB meningitis may be improved by deferring ART until the opportunistic infection is fully suppressed, but data are inadequate. As ART is currently the only effective treatment for PML in patients with HIV, PML-associated IRIS cannot be prevented by manipulating the timing of ART. A greater understanding of the immunopathogenesis of IRIS may lead to targeted therapies.

[With the scalpel against the immune system: HIV infection complicated by an unclear colitis]. / Mit dem Skalpell gegen das Immunsystem: eine unklare Kolitis bei HIV-Infektion.

A 35-year-old Kenian lady with advanced immunodeficiency due to HIV infection started on an antiretroviral therapy. Five months later, a severe colitis was diagnosed, however, no causal pathogen could be found. In order to avoid imminent perforation, a hemicolectomy became necessary, and immediately the symptoms and inflammation markers normalized rapidly. M. tuberculosis could be proven in culture in a draining abdominal lymph node. We assume that the severe inflammation was caused by an immune restoration inflammatory syndrome (IRIS). Essentials in diagnosis, pathogenesis and therapy of IRIS are discussed.

[Immune reconstitution syndrome]. / Immunrekonstitutionssyndrome.

The immune reconstitution inflammatory syndrome (IRIS) represents a heterogeneous group of conditions. Whilst they typically present in HIV-infected patients with advanced immunodeficiency, IRIS have also been described in HIV-negative patients with immune reconstitution due to other causes of immunosuppression. Frequently IRIS results from an immune response against underlying infection (pathogen-associated IRIS). However, IRIS might become evident during immune reconstitution without an underlying pathogen such as a sarcoid-like illness or an autoimmune thyropathy. Here we report on the epidemiology and risk factors of IRIS along with diagnosis and management of this clinically important inflammatory syndrome.

Immune reconstitution syndrome and fungal infections.

PURPOSE OF REVIEW: Fungal infections-related immune reconstitution syndrome (IRS) poses challenging diagnostic and management issues in immunocompromised hosts. This review summarizes the current state of knowledge regarding its pathophysiologic basis, presentation, and treatment strategies. RECENT FINDINGS: Existing evidence suggests that IRS is a state of an imbalance between protective immunity and inflammatory pathology versus anti-inflammatory responses that restrain inflammation. IRS has been observed in diverse hosts including HIV-infected patients initiating potent antiretroviral therapy, transplant recipients, pregnant women, and recipients of iatrogenic biologic agents. Among the most common fungal infections associated with IRS is cryptococcosis, although this entity has been documented during the course of invasive aspergillosis, histoplasmosis, and candidiasis. Unique risk factors for IRS have been recognized in specific hosts. SUMMARY: IRS is a culmination of immunologic sequelae of host-pathogen interaction during evolution of an opportunistic infection, and as such the development of biomarkers that differentiate it from progressive disease would represent an important advance. Optimal management of immunosuppression and immunomodulatory approaches that target precise regulatory pathways for IRS warrant future investigations.

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.

Immune reconstitution inflammatory syndrome after highly active antiretroviral therapy: a review.

The use of highly active antiretroviral therapy (HAART) in the management of human immunodeficiency virus (HIV) restores immune responses against pathogens and has greatly decreased mortality. However, in about 25% to 35% of patients receiving HAART, the reconstituted immune system leads to a pathological inflammatory response, commonly known as immune reconstitution inflammatory syndrome (IRIS), which causes substantial short-term morbidity or even mortality. Although we have gleaned some knowledge on IRIS in the past few years, a number of unanswered questions remain. In this review, we discuss the definition, diagnostic criteria, pathogenesis, risk factors, clinical spectrum including oral manifestations, and management of IRIS.

[Management of immune reconstitution inflammatory syndrome].

While antiretroviral therapy(ART) in HIV-infected patients results in dramatic reductions in HIV viral load and subsequent improvements in CD4 cell count, part of patients experience clinical deterioration as a direct consequence of rapid and dysregulated restoration of antigen-specific immune responses. This is termed "immune reconstitution inflammatory syndrome (IRIS)." Because there is no single agreed upon definition for IRIS, the diagnosis of IRIS is clinical. Several studies have demonstrated that lower CD4 cell count and higher viral load at the initiation of ART increase the risk of developing IRIS. Management of IRIS consists of appropriate treatment for the diseases of IRIS, control of the excessive inflammation (NSAIDs or corticosteroids), and interrupting ART.

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.

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.

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.

Management of patients with the immune reconstitution inflammatory syndrome.

A significant proportion of patients present with the immune reconstitution inflammatory syndrome (IRIS) after commencing antiretroviral therapy (ART). This syndrome is most frequently associated with infective causes. The lack of evidence-based treatment guidelines poses challenges in the management of these patients. Alternative causes for deterioration should be excluded, and optimization of treatment for the underlying opportunistic infection is essential. In addition, anti-inflammatory or immunomodulatory therapy may be considered, particularly in severe cases. Corticosteroids, the only treatment for which clinical trial data exist (for treating paradoxical tuberculosis-associated IRIS), are the treatment most frequently used in IRIS. Limited anecdotal reports of benefit exist for other agents, including NSAIDs, pentoxifylline, montelukast, thalidomide, and hydroxychloroquine. Therapeutic procedures (eg, aspiration of pus collections) play an important role in some patients. Interruption of ART may be considered in life-threatening forms of IRIS.

Pulmonary complications of immune reconstitution inflammatory syndromes in HIV-infected patients.

Immune reconstitution inflammatory syndrome (IRIS) describes a paradoxical worsening of clinical status related to recovery of the immune system, as can occur after the initiation of highly active antiretroviral therapy (HAART) in HIV-infected patients. Most commonly, IRIS results from opportunistic infections that can unmask or develop paradoxical worsening following HAART. Cancers, autoimmune conditions and sarcoidosis have also been associated with IRIS. Pulmonary complications may be frequently encountered. This article reviews the types and clinical presentation of IRIS, with a focus on the pulmonary manifestations. Management and outcome of IRIS are considered.