Clinical and Radiographic Features of Cryptococcal Neoformans Meningitis-associated Immune Reconstitution Inflammatory Syndrome.

Cryptococcal meningitis is the most common intracranial infectious fungal disease. After a period of antifungal treatment, as the number of cells in the cerebrospinal fluid decreases, the biochemical indexes improve and the number of cryptococcus reduces, the patient's condition suddenly worsen. Most of the symptoms are severe headache, raised intracranial pressure, together with impaired clinical nerve function. These presentations are often mistaken for a failure of antifungal treatment. In fact it's an encephalitis syndrome which is unrecognized by most clinicians: Immune reconstitution inflammatory syndrome (IRIS). To increase awareness we retrospectively analyzed clinical data of 100 cases of cryptococcal neoformans meningitis, among which 26 patients develop CM-IRIS. All patients have been divided into three groups: Group 1, patients who were not treated with glucocorticoid and didn't experienced IRIS; Group 2, patients who were not treated with glucocorticoid although developed CM-IRIS; Group 3, patients started treatment with glucocorticoid for two weeks with new onset CM-IRIS. Compared with the group treated with glucocorticoid, treatment without glucocorticoid was subjected to a higher risk of incident IRIS. The difference was statistically significant (P < 0.05). Imaging findings demonstrated diseased area of the white matter area, and it looked like commonly in the supratentorial region. Moreover, if it appears in the infratentorial region then must be combined with supratentorial region.

Paradoxical worsening of chest radiographs secondary to immune reconstitution syndrome (IRIS) in a patient with advanced HIV infection and Rhodococcus pneumonia.

We present a rare case of post-antiretroviral therapy (ART) paradoxically worsening of radiological findings in a patient with advanced HIV-infection on treatment for Rhodococcus pneumonia who was misdiagnosed with pulmonary tuberculosis. Despite clinical improvement, serial chest radiographs showed deteriorations a month after starting ART. This was attributed to Immune Reconstitution Inflammatory Syndrome (IRIS) which spontaneously resolved without any treatment.

Case Report: A Case of Severe Cryptococcal Immune Reconstitution Inflammatory Syndrome Presenting with Brain and Intradural Abscesses in an HIV Patient.

Clinical worsening or new manifestation of cryptococcal disease following initiation of anti-retroviral therapy (ART) in an HIV patient is a hallmark of cryptococcal immune reconstitution inflammatory syndrome (C-IRIS). However, it can be difficult to distinguish IRIS from worsening or new infection. Here, we present a case of severe C-IRIS involving multiple cerebellar, spinal, and intradural abscesses and spinal arachnoiditis 7 months after ART initiation in an AIDS patient with uncertain prior ART compliance. He had multiple prior episodes of cryptococcal meningitis with complications necessitating ventriculoperitoneal shunt placement and was on suppressive fluconazole when he developed worsening brain manifestations. He received empiric anti-cryptococcal re-induction without improvement. All cerebrospinal fluid cultures remained sterile, with negative Cryptococcus PCR testing, and his condition continued to worsen prior to corticosteroid initiation. Ultimately, C-IRIS was diagnosed by brain biopsy. This case demonstrates an extreme in severity of C-IRIS and in the timeline of presentation after ART initiation.

Immune reconstruction inflammatory syndrome in HIV infection: beyond what meets the eye.

A high proportion of individuals with HIV infection currently are diagnosed at an advanced stage of disease (late presenters), increasing their risk for immune reconstitution inflammatory syndrome (IRIS). IRIS typically occurs within 6 months of initiation of antiretroviral therapy (ART) in patients with low CD4+ cell counts and can occur before any marked elevation in CD4+ count is achieved on ART. In addition to low CD4+ count at ART initiation, 2 other major clinical predictors of IRIS are preexisting opportunistic infection (including subclinical infection) and shorter treatment period for opportunistic infection prior to starting ART. Mycobacterial infection-associated IRIS, including tuberculosis (TB)-associated IRIS, and cryptococcal infection-associated IRIS are the most common forms of the syndrome. Corticosteroid prophylaxis and early treatment can be effective in reducing incidence of TB-IRIS and severity of symptoms in select patients. Sterilization of the cerebrospinal fluid should be achieved prior to starting ART in patients with TB meningitis and cryptococcal meningitis. This article summarizes a presentation by Irini Sereti, MD, MHS, at the International Antiviral Society-USA (IAS-USA) continuing education program held in Washington, DC, in April 2019.

CD8 + T-lymphocyte Encephalitis: A Systematic Review.

The increase of CD8 + T lymphocytes in the perivascular spaces of patients with HIV encephalopathy has been reported in some studies. CD8 + T lymphocyte encephalitis was first described in 2013 and then a few other similar cases were published. We proposed to analyze the clinical, MR imaging, and histopathology findings of CD8 + T lymphocyte encephalitis. A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyzes protocol using the PubMed, Scopus, Lilacs, and IBECS databases up to February 3, 2018. Seven articles were included, two case series and five case reports. A total of 19 individuals were evaluated. MRI showed alterations in the white matter signal in all cases. Histopathology showed a predominance of CD8 + T lymphocytes. The findings described so far may resemble the inflammatory immune reconstitution syndrome. New studies on the subject are needed in an attempt to characterize the differences between these two entities.

Extensive immune reconstitution inflammatory syndrome in Fingolimod-associated PML: a case report with 7 Tesla MRI data.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rare complication of patients treated with fingolimod. CASE PRESENTATION: Routine MRI eventually led to diagnosis of asymptomatic early PML that remained stable after discontinuation of fingolimod. As blood lymphocyte counts normalized, signs of immune reconstitution inflammatory syndrome (IRIS) and renewed MS activity developed. Both, advanced laboratory and ultrahigh field MRI findings elucidated differences between PML and MS. CONCLUSIONS: In our case, early discontinuation of fingolimod yielded a good outcome, lymphocyte counts reflected immune system activity, and paraclinical findings helped to differentiate between PML-IRIS and MS.

A case of immune reconstitution syndrome complicating progressive multifocal leukoencephalopathy after kidney transplant: Clinical, pathological, and radiographic features.

Progressive multifocal leukoencephalopathy (PML) is a life-threatening central nervous system (CNS) disorder, most commonly described in patients infected with the human immunodeficiency virus (HIV). Limited data exist on its natural history and treatment in solid organ transplant (SOT) recipients. A complication of PML is the immune reconstitution inflammatory syndrome (IRIS), which develops after T cell reconstitution and can have severe consequences when it occurs in the CNS. While well described in HIV-infected individuals, its clinical features, diagnosis, and treatment after SOT are largely unknown. We report a case of a kidney transplant recipient who was diagnosed with PML and developed significant worsening of her symptoms upon reduction of immunosuppression. Thallium SPECT showed avid uptake suggestive of lymphoma, but the diagnosis of PML-IRIS was ultimately established by brain biopsy. She survived with nearly complete restoration of her functional status after a prolonged steroid taper.

Chylous ascites in disseminated Kaposi sarcoma: an unusual manifestation as immune reconstitution inflammatory syndrome.

A 29-year-old man with diarrhoea, fever, abdominal pain and multiple purple papular lesions, neither pruriginous nor painful, was diagnosed with HIV-1 infection and disseminated Kaposi sarcoma (KS) with gastrointestinal involvement. He was started on highly active antiretroviral therapy immediately, as well as doxorubicin. Three weeks later, the patient developed bilateral moderate pleural effusion and large-volume ascites compatible with chylothorax and chylous ascites. An immune reconstitution inflammatory syndrome (IRIS) reaction was assumed. KS flare was associated with lymphatic obstruction and infiltration of thoracic duct by the tumour itself with leakage of chylous into pleural and peritoneal cavities. KS is the most common tumour in HIV patients and the existence of related effusions is not uncommon. KS-related chylothorax is an unusual manifestation of KS; there are only four cases described in the literature of chylous ascites related to KS-HIV. Overall survival is improving in KS but explosive and debilitating IRIS reactions can explain cases with poor prognosis.

Increased Metabolic Activity on 18F-Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography in Human Immunodeficiency Virus-Associated Immune Reconstitution Inflammatory Syndrome.

Background: Immune reconstitution inflammatory syndrome (IRIS) represents an unexpected inflammatory response shortly after initiation of antiretroviral therapy (ART) in some human immunodeficiency virus (HIV)-infected patients with underlying neoplasia or opportunistic infections, including tuberculosis. We hypothesized that IRIS is associated with increased glycolysis and that 18F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT) could help identify high-risk subjects. Methods: In this prospective cohort study, 30 HIV-infected patients (CD4+ count <100 cells/µL) underwent FDG-PET/CT scans at baseline and 4-8 weeks after ART initiation. Ten patients developed IRIS (6 mycobacterial). Results: At baseline, total glycolytic activity, total lesion volume, and maximum standardized uptake values (SUVs) of pathologic FDG uptake (reflective of opportunistic disease burden) were significantly higher in IRIS vs non-IRIS (P = .010, .017, and .029, respectively) and significantly correlated with soluble inflammatory biomarkers (interferon-γ, myeloperoxidase, tumor necrosis factor, interleukin 6, soluble CD14). Baseline bone marrow (BM) and spleen FDG uptake was higher in mycobacterial IRIS specifically. After ART initiation, BM and spleen mean SUV decreased in non-IRIS (P = .004, .013) but not IRIS subjects. Our results were supported by significantly higher glucose transporter 1 (Glut-1) expression of CD4+ cells and monocytes after ART initiation in IRIS/mycobacterial IRIS compared with non-IRIS patients. Conclusions: We conclude that increased pathologic metabolic activity on FDG-PET/CT prior to ART initiation is associated with IRIS development and correlates with inflammatory biomarkers. Abnormally elevated BM and spleen metabolism is associated with mycobacterial IRIS, HIV viremia, and Glut-1 expression on CD4+ cells and monocytes. Clinical Trials Registration: NCT02147405.

Tuberculosis-associated hemophagocytic lymphohistiocytosis with subsequent unmasking cryptococcal immune reconstitution inflammatory syndrome (IRIS) in an HIV-negative man.

A 22-year-old HIV-negative man from Ghana was diagnosed with severe hemophagocytic lymphohistiocytosis (HLH) induced by multiorgan tuberculosis with peritoneal, hepatic, pericardial, myocardial, pleural, pulmonary, and bone manifestation. His body mass index was 12.9 m2/kg. Bioptic material of a peritoneal biopsy grew M. tuberculosis, sensitive to all first-line antituberculous drugs. HLH resolved with antituberculous therapy, without additional anti-inflammatory therapy being given. The initial CT scan of his brain was normal. After 5 months of antituberculous treatment, he developed a paralysis of the left arm. A cerebral MRT showed ring-enhanced lesions. Blood cultures and lumbar puncture revealed Cryptococcus neoformans var. grubi. The HIV test was repeatedly negative. Antituberculous treatment was continued for a total of 9 months, and additional treatment with antifungal therapy was established. He recovered fully after 14 months of antifungal treatment.

Imaging spectrum of immunomodulating, chemotherapeutic and radiation therapy-related intracranial effects.

OBJECTIVE: A wide range of treatment-related side effects result in specific neurologic symptoms and signs and neuroimaging features. Even to the most seasoned neuroradiologist, elucidating therapy-related side effects from other common mimics can be challenging. We provide a pictorial survey of some common and uncommon medication-induced and therapy-related neuroimaging manifestations, discuss pathophysiology and common pitfalls in imaging and diagnosis. METHODS: A case-based review is utilized to depict scenarios on a routine basis in a general radiology or neuroradiology practice such as medication-induced posterior reversible encephalopathy syndrome to the more challenging cases of pseudoprogression and pseudoregression in temozolmide and bevacizumab therapy in gliobastoma treatment protocols. CONCLUSION: Knowledge of the treatment-induced imaging abnormalities is essential in the accurate interpretation and diagnosis from the most routine to most challenging of clinical situations. We provide a pictorial review for the radiologist to employ in order to be an invaluable provider to our clinical colleagues and patients.

Inflammatory natalizumab-associated PML: baseline characteristics, lesion evolution and relation with PML-IRIS.

BACKGROUND AND OBJECTIVE: Natalizumab-associated progressive multifocal leukoencephalopathy (NTZ-PML) patients may show imaging signs suggestive of inflammation at diagnosis ('inflammatory PML'), reminiscent of PML-immune reconstitution inflammatory syndrome (PML-IRIS). We investigated the imaging characteristics of inflammatory NTZ-PML lesions and PML-IRIS to determine differentiating and overlapping features. METHODS: We scored the presence, localisation and pattern of imaging characteristics of inflammation on brain MRI scans of inflammatory NTZ-PML patients. The imaging characteristics were followed up until the occurrence of PML-IRIS. RESULTS: Ten out of the 44 NTZ-PML patients included showed signs suggestive of inflammation at the time of diagnosis. The inflammation pattern at diagnosis was similar to the pattern seen at PML-IRIS, with contrast enhancement representing the most frequent sign of inflammation (90% at diagnosis, 100% at PML-IRIS). However, the severity of inflammation differed, with absence of swelling and low frequency of perilesional oedema (10%) at diagnosis, as compared with the PML-IRIS stage (40%). CONCLUSION: Patterns of inflammation at the time of PML diagnosis and at the PML-IRIS stage overlap but differ in their severity of inflammation. This supports histopathological evidence that the inflammation seen at both stages of the same disease shares a similar underlying pathophysiology, representing the immune response to the JC virus to a variable extend.

Contribution of arterial spin-labelling MRI in a case with immune reconstitution inflammatory syndrome.

Central nervous system immune reconstitution inflammatory syndrome (CNS-IRIS), which occurs most often in HIV-infected patients, is an exacerbation of inflammatory reactions related to opportunistic infections as well as primary CNS malignancies both of which mostly occur in HIV-infected patients. However, differential diagnoses are challenging both clinically and radiologically. We describe a patient with CNS-IRIS due to toxoplasmosis whose 11C-methionine uptake suggested lymphoma but whose arterial spin-labelling MRI led to the correct diagnosis.

Is maraviroc useful in multiple sclerosis patients with natalizumab-related progressive multifocal leukoencephalopathy?

BACKGROUND: Despite the recent advances in the understanding of natalizumab (NTZ) related progressive multifocal leukoencephalopathy (PML) and its associated immune reconstitution inflammatory syndrome (PML-IRIS), the therapeutic options are still under investigated. In this context, the beneficial use of maraviroc is still an anecdotal observation. OBJECTIVE: To evaluate the impact of maraviroc in modifying the course of PML preventing IRIS or blunting IRIS manifestations. METHODS: Three patients with NTZ PML included in the Italian dataset of PML were treated with maraviroc. Their longitudinal clinical and radiological course was described in detail. RESULTS: The three patients were characterized by a steady clinical worsening not controlled by maraviroc. All the three patients manifested PML-IRIS, which emerged, respectively, at 62, 64 and 90days post NTZ withdrawal. This is in accordance with the data of the Italian dataset. Clinical and radiological stabilization of PML-IRIS occurred only after corticosteroids administration. CONCLUSION: In these three cases, maraviroc did not show any clear effect in modulating the clinical course of PML preventing IRIS. Moreover, once PML-IRIS emerged, the clinical stabilization was achieved only with the use of corticosteroids. Thus, the use of maraviroc should be regarded with extreme caution due the potential adverse events associated with its use.

Toxoplasmosis-associated IRIS involving the CNS: a case report with longitudinal analysis of T cell subsets.

BACKGROUND: HIV-infected patients may present an unforeseen clinical worsening after initiating antiretroviral therapy known as immune reconstitution inflammatory syndrome (IRIS). This syndrome is characterized by a heightened inflammatory response toward infectious or non-infectious triggers, and it may affect different organs. Diagnosis of IRIS involving the central nervous system (CNS-IRIS) is challenging due to heterogeneous manifestations, absence of biomarkers to identify this condition, risk of long-term sequelae and high mortality. Hence, a deeper knowledge of CNS-IRIS pathogenesis is needed. CASE PRESENTATION: A 37-year-old man was diagnosed with AIDS and cerebral toxoplasmosis. Anti-toxoplasma treatment was initiated immediately, followed by active antiretroviral therapy (HAART) 1 month later. At 2 months of HAART, he presented with progressive hyposensitivity of the right lower limb associated with brain and dorsal spinal cord lesions, compatible with paradoxical toxoplasmosis-associated CNS-IRIS, a condition with very few reported cases. A stereotactic biopsy was planned but was postponed based on its inherent risks. Patient showed clinical improvement with no requirement of corticosteroid therapy. Routine laboratorial analysis was complemented with longitudinal evaluation of blood T cell subsets at 0, 1, 2, 3 and 6 months upon HAART initiation. A control group composed by 9 HIV-infected patients from the same hospital but with no IRIS was analysed for comparison. The CNS-IRIS patient showed lower percentage of memory CD4+ T cells and higher percentage of activated CD4+ T cells at HAART initiation. The percentage of memory CD4+ T cells drastically increased at 1 month after HAART initiation and became higher in comparison to the control group until clinical recovery onset; the percentage of memory CD8+ T cells was consistently lower throughout follow-up. Interestingly, the percentage of regulatory T cells (Treg) on the CNS-IRIS patient reached a minimum around 1 month before symptoms onset. CONCLUSION: Although both stereotactic biopsies and steroid therapy might be of use in CNS-IRIS cases and should be considered for these patients, they might be unnecessary to achieve clinical improvement as shown in this case. Immunological characterization of more CNS-IRIS cases is essential to shed some light on the pathogenesis of this condition.

Thalidomide for steroid-dependent chronic disseminated candidiasis after stem cell transplantation: A case report.

Chronic disseminated candidiasis (CDC) is a rare and difficult-to-treat invasive fungal disease occurring mainly after prolonged and profound neutropenia. We describe the case of a 59-year-old man successfully treated with thalidomide for CDC recurrences after an autologous transplantation. We add evidence of the effectiveness of immunomodulatory drugs to manage inflammatory reconstitution immune syndrome-related refractory CDC.

Incidence and prognosis of immune reconstitution inflammatory syndrome in HIV-associated progressive multifocal leucoencephalopathy.

BACKGROUND AND PURPOSE: Progressive multifocal leucoencephalopathy-associated immune reconstitution inflammatory syndrome (PML-IRIS) is the paradoxical worsening or unmasking of preexisting infection with JC virus attributable to a rapid recovery of the immune system after highly active antiretroviral therapy (HAART) initiation. We investigated the incidence and factors associated with PML-IRIS in HIV-infected patients. We also studied its influence on mortality of PML and the effect of corticosteroid therapy. METHODS: Single-center retrospective analysis of HIV-infected patients diagnosed with PML from 1996 to 2012 who received HAART. RESULTS: Among 59 PML patients treated with HAART, 18 (30.51%) developed PML-IRIS (five delayed PML-IRIS, 13 simultaneous PML-IRIS). Patients who developed IRIS had lower CD4 counts prior to treatment (102 vs. 68.5, P < 0.05) and experienced a greater decline in HIV-RNA levels in response to HAART (2.5log vs. 2.95log, P < 0.05). Gadolinium enhancement on MRI was observed in 31.25% of PML-IRIS cases versus 2.56% of PML non-IRIS (P < 0.01). Survival rates were higher in patients with PML-IRIS compared to those with PML non-IRIS. Eight patients received corticosteroids, five of which had a good outcome. Patients who died were severely ill when treatment was initiated whereas patients who survived were treated before major neurological deterioration occurred. CONCLUSIONS: Nearly one-third of HIV-infected patients with PML develop IRIS after initiating HAART. Patients severely immunocompromised who experience a rapid virological response to HAART have a higher risk for PML-IRIS. There was a trend for lower mortality in patients with IRIS. Early treatment with corticosteroids might be useful.