Post-infectious Inflammatory Response Syndrome Research Articles

Post-infectious inflammatory response syndrome in an HIV-negative patient after Cryptococcus gattii meningoencephalitis: a case report and review of the literature

BackgroundCryptococcal meningitis (CM) is an inflammatory mycosis of the central nervous system caused by meninge infection or brain parenchyma with Cryptococcus species. It is associated with high morbidity and mortality, and patients with acquired immune deficiency syndrome are particularly susceptible. There have been increasing reports of CM in HIV-negative patients in China over the last few years.Case presentationA 31-year-old healthy Chinese male presented with fever and gradually developed headache, projectile vomiting, and other manifestations that were later confirmed as Cryptococcus gattii meningoencephalitis. However, multiple disease changes occurred during the course of treatment, and the regimen was accordingly modified after the diagnosis of post-infectious inflammatory response syndrome (PIIRS). The patient eventually recovered.ConclusionThere has been a growing trend in the incidence of C. gattii meningoencephalitis in HIV-negative patients. It shows rapid onset and severe prognosis. This case report can provide a reference to treat PIIRS following CM in HIV-negative patients.

Cryptococcal Meningitis in Young, Immunocompetent Patients: A Single-Center Retrospective Case Series and Review of the Literature.

Cryptococcal meningitis is an uncommon but serious infection with high mortality and morbidity. Classically described in immunocompromised patients, including those with solid organ transplants or HIV/AIDS, cryptococcosis has also been reported in young and otherwise healthy patients, albeit rarely. We retrospectively searched for all cases of cryptococcal meningitis in young (≤50 years) and previously healthy patients with no known immunocompromising conditions from January 2015 to January 2022 at Indiana University Health (IU Health). Additionally, a PubMed literature review was performed with the keywords "cryptococcal meningitis" and "immunocompetent" from January 1988 to January 2022. Clinical courses, including outcomes and treatment regimens, were evaluated. We identified 4 local cases of cryptococcal meningitis in otherwise healthy patients age ≤50 years. Three cases were due to Cryptococcus neoformans, with 1 experiencing a postinfectious inflammatory response syndrome (PIIRS). The PubMed search identified 51 additional cases, with 32 (63%) being caused by Cryptococcus neoformans and 8 (17%) by Cryptococcus gattii. Of the 51 cases, only 2 resulted in death directly due to cryptococcosis. Fifteen (29%) had PIIRS, with steroid treatment documented in 11 of 15. Antifungal induction regimens and duration were varied but predominately consisted of amphotericin and flucytosine, with a mean induction duration of 5.0 weeks. Cryptococcal meningitis in young, previously healthy patients is likely under-recognized. PIIRS (akin to immune reconstitution inflammatory syndrome observed in HIV/AIDS) with prolonged recovery should be of concern. Determining risk factors for cryptococcosis in these patients remains elusive.

Persistent neurological symptoms and elevated intracranial pressures in a previously healthy host with cryptococcal meningitis

Cryptococcal meningoencephalitis can occur in both previously healthy and immunocompromised hosts. Here, we describe a 55 year-old HIV-negative male with no known prior medical problems, who presented with three months of worsening headaches, confusion, and memory changes without fever. Magnetic resonance imaging of the brain demonstrated bilateral enlargement/enhancement of the choroid plexi, with hydrocephalus, temporal and occipital horn entrapments, as well as marked periventricular transependymal cerebrospinal fluid (CSF) seepage. CSF analysis yielded a lymphocytic pleocytosis and cryptococcal antigen titer of 1:160 but sterile fungal cultures. Despite standard antifungal therapy and CSF drainage, the patient had worsening confusion and persistently elevated intracranial pressures. External ventricular drainage led to improved mental status but only with valve settings at negative values. Ventriculoperitoneal shunt placement could thus not be considered due to a requirement for drainage into the positive pressure venous system. Due to this persistent CSF inflammation and cerebral circulation obstruction, the patient required transfer to the National Institute of Health. He was treated for cryptococcal post-infectious inflammatory response syndrome with pulse-taper corticosteroid therapy, with resultant reductions in CSF pressures along with decreased protein and obstructive material, allowing successful shunt placement. After tapering of corticosteroids, the patient recovered without sequelae. This case highlights (1) the necessity to consider cryptococcal meningitis as a rare cause of neurological deterioration in the absence of fever even in apparently immunocompetent individuals and (2) the potential for obstructive phenomena from inflammatory sequelae and the prompt response to corticosteroid therapy.

The effect of serum uric acid, bilirubin and albumin levels on antioxidant status in HIV-negative immunocompetent cryptococcal meningitis patients with post-infectious inflammatory response syndrome.

Oxidative imbalances have been observed in various neurological diseases. Despite the microbiological control in cryptococcal meningitis (CM), a proportion of previously healthy patients experience a clinical deterioration known as post-infectious inflammatory response syndrome (PIIRS). However, the antioxidant status in PIIRS remains unclear. In this study, we found that the serum antioxidant status of HIV-negative immunocompetent CM patients during PIIRS episodes was lower than that of healthy controls. There was a relationship between baseline serum indirect bilirubin levels and the development of PIIRS, and serum uric acid levels may indicate the severity of the disease during PIIRS episodes. Oxidative stress may play a role in the development of PIIRS.

Post-infectious inflammatory response syndrome related to cryptococcal meningoencephalitis.

Post-infectious inflammatory response syndrome related to cryptococcal meningoencephalitis.

Cryptococcal Immune Reconstitution Inflammatory Syndrome: From Clinical Studies to Animal Experiments.

Cryptococcus neoformans is an encapsulated pathogenic fungus that initially infects the lung but can migrate to the central nervous system (CNS), resulting in meningoencephalitis. The organism causes the CNS infection primarily in immunocompromised individuals including HIV/AIDS patients, but also, rarely, in immunocompetent individuals. In HIV/AIDS patients, limited inflammation in the CNS, due to impaired cellular immunity, cannot efficiently clear a C. neoformans infection. Antiretroviral therapy (ART) can rapidly restore cellular immunity in HIV/AIDS patients. Paradoxically, ART induces an exaggerated inflammatory response, termed immune reconstitution inflammatory syndrome (IRIS), in some HIV/AIDS patients co-infected with C. neoformans. A similar excessive inflammation, referred to as post-infectious inflammatory response syndrome (PIIRS), is also frequently seen in previously healthy individuals suffering from cryptococcal meningoencephalitis. Cryptococcal IRIS and PIIRS are life-threatening complications that kill up to one-third of affected people. In this review, we summarize the inflammatory responses in the CNS during HIV-associated cryptococcal meningoencephalitis. We overview the current understanding of cryptococcal IRIS developed in HIV/AIDS patients and cryptococcal PIIRS occurring in HIV-uninfected individuals. We also describe currently available animal models that closely mimic aspects of cryptococcal IRIS observed in HIV/AIDS patients.

A Case of Cryptococcal Meningitis Complicated by Postinfectious Inflammatory Response Syndrome in an Apparently Immunocompetent Patient

Abstract Cryptococcal meningitis (CM) is a fungal infection most commonly seen in immunocompromised patients and rarely affecting immunocompetent patients. Cryptococcal meningitis can present with varying complications, such as disseminated disease and neurological complications that include intracranial hypertension, cerebral infarcts, and vision loss. Delayed diagnosis of CM contributes to the disease's mortality in the immunocompetent patient. We would like to present the case of a 27-year-old apparently immunocompetent woman admitted for CM with initial improvement and then neurological decline concerning for cryptococcal–postinfectious inflammatory response syndrome.

Treatment recommendations for non-HIV associated cryptococcal meningoencephalitis including management of post-infectious inflammatory response syndrome.

Cryptococcal meningoencephalitis (CM) continues to cause major morbidity and mortality in a range of patients such as those immunosuppressed from HIV and with biologic immunosuppressants, including treatments of autoimmunity, malignancies, and conditioning regimens for transplantation. It is currently the most common cause of non-viral meningitis in the United States. Infections in previously healthy patients also develop with autoantibodies to granulocyte-macrophage colony stimulating factor or with monogenetic defects. In all populations, mortality and significant long-term morbidity occur in 30-50% despite therapy, and immune reconstitution and post-infectious inflammatory response syndromes complicate management. To help with these difficult cases, we present here a practical tutorial of the care of a range of patients with CM in the absence of HIV/AIDS.

The effect on brain volume in HIV-negative and non-transplant cryptococcal meningitis

To explore the brain volume (BV) changes of HIV-negative and non-transplant cryptococcal meningitis (CM) in 1 year after initial therapy. Case data were collected from 78 CM patients who underwent magnetic resonance imaging (MRI) scanning at least 3 times in 1-year interval after initial therapy. The assessment of BV was measured by a non-commercial software, uAI Research Portal. Linear mixed model was used to investigate the association between clinical characteristics and the changes in BV. Longitudinal study showed a decrease in total brain volume (-4.65 cm3, P=.005), regional brain volume including white matter (-2.86 cm3, P=.031) and basal ganglia (-0.25 cm3, P=.007), and increase in cerebrospinal fluid (CSF) volume (3.58 cm3, P=.013) in CM patients in 1 year after initial therapy. Ventricular volume in patients with ventriculoperitoneal shunts (VPS) was lower than that in patients without VPS (-7.5 cm3, P<.05). Ventricular volume in patients with post-infectious inflammatory response syndrome (PIIRS) was larger than that in patients without PIIRS (7.1 cm3, P<.01). In addition, temporal lobe atrophy was associated with corticosteroid therapy (-6.8 cm3, P<.01). The present study suggested that brain atrophy, especially regional BV decrease, could happen in HIV-negative and non-transplant CM patients over a 1-year interval.

Analysis of the association of HLA subtypes with cryptococcal meningitis in HIV-negative immunocompetent patients.

Objective: We aimed to study the possible relationship between cryptococcal meningitis (CM) and HLA genotypes in HIV-negative immunocompetent patients. Methods: HLA loci of 53 HIV-negative immunocompetent Han Chinese CM patients were compared with those in 481 healthy individuals. Results: We found a significant association between DQB1*05:02 and CM patients compared with controls. There were no significant differences in the frequencies of HLA alleles between CM with and without postinfectious inflammatory response syndrome and controls. Correlation analysis showed DQB1*05:02 was correlated with susceptibility to CM. CM patients carrying the DQB1*05:02 allele had more severe focal neurological deficit, higher initial modified Rankin Scale and British Medical Research Council staging scores. Conclusion: This study provides the first evidence for the interaction between specific HLA class II alleles and HIV-negative immunocompetent CM patients.

P.058 Spinal arachnoiditis as a complication of cryptococcal meningitis

Background: Spinal arachnoiditis is a rare condition involving progressive fibrosis of the spinal arachnoid membrane and can be secondary to multiple spinal surgeries, intrathecal chemotherapy, or infection. This condition can manifest as lumbosacral radiculopathy, cauda equina syndrome, myelopathy, or syringomyelia. Methods: We present a case of a 38-year-old female with recent cryptococcal meningitis treated with amphotericin B and flucytosine, who re-presented to hospital several weeks after discharge with decreased mobility requiring a wheelchair, falls, and urinary and fecal incontinence. Results: Examination revealed lower extremity pyramidal weakness, hyperreflexia, and upgoing plantar responses. CSF analysis showed white blood cells of 147x106 cells/L, protein of 4.07 g/L, and glucose of 0.4 mmol/L. Cryptococcal antigen was positive, but fungal culture was negative x 5 days, suggesting adequate initial treatment of cryptococcal meningitis. MRI spine revealed tethering of the cervical cord posteriorly at C4-5 and tethering of the midthoracic cord anteriorly. The patient was treated with IV methylprednisolone 1 g/kg daily for 5 days without significant improvement. Conclusions: Spinal arachnoiditis secondary to infection is thought to be caused by post-infectious inflammatory response syndrome (PIRIS) and is treated with IV methylprednisolone. In spinal arachnoiditis secondary to cryptococcus, the clinical findings may be confounded by the presence of hydrocephalus or myelopathy.

Immunological Predictors of Post Infectious Inflammatory Response Syndrome in HIV-Negative Immunocompetent Cryptococcal Meningitis.

ObjectiveThis research aims to study the correlation between serum immune factors and post-infectious inflammatory response syndrome (PIIRS) in immunocompetent cryptococcal meningitis (CM), and explore whether serum immune factors could be used to predict the development of PIIRS.MethodsA cohort of 30 patients with PIIRS and 87 patients without PIIRS was selected from 347 CM patients. We analyzed the general clinical information and immunological indexes (cytokines, complement, immunoglobulin, inflammation, related cytological and biochemical indexes). Spearman correlation analysis and principal component analysis were used to explore the effects of the variables on PIIRS. Additionally, the variables were identified by a random forest-based classifier for predicting the development of PIIRS. The clinical value of predictors was verified by survival analysis.ResultsCompared with patients without PIIRS, patients with PIIRS had lower baseline serum interleukin-6 (IL-6, P = 0.006), immunoglobulin M (IgM, P = 0.004), and a higher baseline neutrophil ratio (P <0.001). The baseline neutrophil ratio (r = 0.359, P = 0.001), IgM (r = −0.272, P = 0.025), and IL-6 (r = −0.259, P = 0.027) were significantly correlated with PIIRS. Combining principal component analysis and random forest results, neutrophil ratio, neutrophil count, IgM, IL-6, and D-dimer were useful predictors. The accuracy of random forest prediction was 75.00%, AUC, and sensitivity were 0.76 and 70%, respectively. Further survival analysis of the time from treatment to PIIRS revealed that the development of PIIRS was associated with IgM (more than 98 days of treatment) and neutrophil ratio/count.ConclusionBaseline neutrophils ratio, neutrophil count, IgM, IL-6, and D-dimer may be clinically useful predictors of PIIRS in HIV-negative immunocompetent CM patients.

Tocilizumab as steroid-sparing agent for post-infectious inflammatory response syndrome in two non-HIV cryptococcal meningitis patients

Non-HIV Cryptococcal Meningitis (CM) is often complicated by a post-infectious inflammatory response syndrome (PIIRS), characterized by neurologic deterioration in previously-healthy patients with CM after appropriate antifungal therapy and conversion of CSF fungal cultures to negative. PIIRS is due to an appropriate inflammatory response to fungal antigen released during therapy, mediated by IFN-gamma and IL-6 stimulating T-helper cells, leading to immune-mediated host damage. At the National Institutes of Health (NIH), patients with non-HIV CM-related PIIRS have been successfully treated with methylprednisolone burst and slow prednisone taper.

Cryptococcal Meningitis and Post-Infectious Inflammatory Response Syndrome in a Patient With X-Linked Hyper IgM Syndrome: A Case Report and Review of the Literature

The hyper IgM syndromes are a rare group of primary immunodeficiency. The X-linked Hyper IgM syndrome (HIGM), due to a gene defect in CD40L, is the commonest variant; it is characterized by an increased susceptibility to a narrow spectrum of opportunistic infection. A few cases of HIGM patients with Cryptococcal meningoencephalitis (CM) have been described in the literature. Herein we report the case of a young male diagnosed in infancy with HIGM who developed CM complicated by a post-infectious inflammatory response syndrome (PIIRS), despite regular immunoglobulin replacement therapy and appropriate antimicrobial prophylaxis. The patient was admitted because of a headache and CM was diagnosed through detection of Cryptococcus neoformans in the cerebrospinal fluid. Despite the antifungal therapy resulting to negative CSF culture, the patient exhibited persistent headaches and developed diplopia. An analysis of inflammatory cytokines on CSF, as well as the brain MRI, suggested a diagnosis of PIIRS. Therefore, a prolonged corticosteroids therapy was started obtaining a complete resolution of symptoms without any relapse.

Outcomes in Previously Healthy Cryptococcal Meningoencephalitis Patients Treated With Pulse Taper Corticosteroids for Post-infectious Inflammatory Syndrome.

Cryptococcal meningoencephalitis (CM) is a major cause of mortality in immunosuppressed patients and previously healthy individuals. In the latter, a post-infectious inflammatory response syndrome (PIIRS) is associated with poor clinical response despite antifungal therapy and negative cerebrospinal fluid (CSF) cultures. Data on effective treatment are limited. Between March 2015 and March 2020, 15 consecutive previously healthy patients with CM and PIIRS were treated with adjunctive pulse corticosteroid taper therapy (PCT) consisting of intravenous methylprednisolone 1 gm daily for 1 week followed by oral prednisone 1 mg/kg/day, tapered based on clinical and radiological response plus oral fluconazole. Montreal cognitive assessments (MOCA), Karnofsky performance scores, magnetic resonance imaging (MRI) brain scanning, ophthalmic and audiologic exams, and CSF parameters including cellular and soluble immune responses were compared at PIIRS diagnosis and after methylprednisolone completion. The median time from antifungal treatment to steroid initiation was 6 weeks. The most common symptoms at PIIRS diagnosis were altered mental status and vision changes. All patients demonstrated significant improvements in MOCA and Karnofsky scores at 1 month (P < .0003), which was accompanied by improvements in CSF glucose, white blood cell (WBC) count, protein, cellular and soluble inflammatory markers 1 week after receiving corticosteroids (CS) (P < .003). All patients with papilledema and visual field deficits also exhibited improvement (P < .0005). Five out of 7 patients who underwent audiological testing demonstrated hearing improvement. Brain MRI showed significant improvement of radiological findings (P = .001). CSF cultures remained negative. PCT in this small cohort of PIIRS was associated with improvements in CM-related complications with minimal toxicity in the acute setting.

47. Long Term Outcomes of Pulse-taper Corticosteroid Therapy (PCT) for Refractory Non-HIV Cryptococcal Meningoencephalitis

BackgroundCryptococcal meningoencephalitis (CM) is a major cause of mortality in HIV/AIDS, transplant recipients and previously healthy individuals. In the latter, a post-infectious inflammatory response syndrome (PIIRS) is associated with poor clinical response despite prior amphotericin therapy and CSF culture conversion. Data on effective treatment is limited.MethodsBetween March 2015 and March 2020, 15 patients with CM/PIIRS were treated with adjunctive pulse – taper corticosteroid therapy (PCT) consisting of intravenous methylprednisolone 1 gm daily for 1 week followed by oral prednisone 1 mg/kg/d, tapered based on clinical and radiological response plus oral fluconazole. Montreal cognitive assessments (MOCA), Karnofsky Performance scores, MRI brain scans, eye and audiologic exams were conducted at baseline and after pulse completion. CSF parameters were assessed prior to and after the pulse.Results80% of patients were male, median age 51 years. Median time from antifungal treatment to steroid initiation was 6 weeks. The most common symptoms at PIIRS diagnosis were progressive deterioration in mental status and vision changes. There was a significant improvement in MOCA(n=14) and Karnofsky(n=15) scores at 3 weeks (p< 0.0003), which was accompanied by improvements in CSF: serum, glucose ratios, CSF WBC, protein and activated CD4 T cells (n=14) post-pulse (p< 0.003). Additionally, soluble CSF IL-6 and sCD25 levels improved (p = 0.03). Neurofilament light chain levels (NFL), a biomarker of axonal damage, showed significant reductions over a 30-month period (Generalized Estimating Equation coefficient = 0.128) and a negative correlation with post pulse MOCA scores (r = - 0.8; p = 0.01).Papilledema (n=8) and visual field deficits (n=11) improved significantly (p< 0.0005) after 2 months of pulse completion. Brain MRI showed improvement of radiological findings in 11 patients (p=0.001). Five out of 7 patients who underwent audiological testing demonstrated hearing improvement after 3 weeks post-pulse. CSF cultures remained negative. ConclusionPCT in this small cohort of PIIRS patients was associated with persistent improvements in CM-related complications with minimal toxicity and no recurrence of infection.Disclosures All Authors: No reported disclosures

1176. Quality of Life of Previously Healthy Subjects following Cryptococcal Meningoencephalitis

BackgroundCryptococcal meningoencephalitis (CM) causes significant morbidity and mortality in HIV-negative, previously healthy populations. This group has significant disease sequalae including a fronto-subcortical syndrome, hearing loss, vision loss, and spinal arachnoiditis. However, the health-related quality of life (HRQOL) of this group of patients following microbial recovery from infection has not been reported.MethodsWe cross-sectionally defined the HRQOL of previously healthy individuals with CM seen at the NIH Clinical Center since 2013 and at least one year past diagnosis using the Quality of Life in Neurological Disorders (Neuro-QoL) project short forms. These forms assess domains such as anxiety, fatigue, depression, dexterity and mobility in patients with chronic neurological disease. Form scores were calculated for each domain and centered to a general or clinical United States population reference. Impairment was considered a subject score of least one half a standard deviation (SD) lower than the population reference average.ResultsOf 43 subjects with CM (mean age 48 years, 56% male, mean time from diagnosis 5.7 years), 91% had evidence of impairment in at least one HRQOL domain. Notable findings included self-reported impaired cognitive function in 53% and sleep disturbance in 56%. Impaired satisfaction with social roles and activities was present in 44%. Mobility and dexterity were impaired in 30% respectively. The number of impaired HRQOL domains was not significantly different in subjects with a history of neurosurgical intervention during hospitalization (mean no. impaired domains 4.4 vs. 3.3, P=0.43) or methylprednisolone treatment for post-infectious inflammatory response syndrome (4.3 vs. 3.4, P=0.63). Cerebrospinal fluid glucose levels on admission were negatively correlated with the number of impaired functional domains (rs=-0.33, P=0.05, n=38).Patient reported quality of life domains following microbial recovery from cryptococcal meningoencephalitis. Box plots show median, 25th, and 75th percentiles.The gray dotted line represents the mean T-score (50) of the U.S. population reference for each Neuro-QoL domain. The yellow region designates mild symptoms or impairment (0.5-1.0 std below the population mean), orange, moderate (1.0-2.0), and red, severe (2.0-3.0). The asterisk* indicates measures that were centered to U.S. clinical reference population. All other domains were centered to a U.S. general population reference. Abbreviations: CNS, central nervous system, U.S., United States, ADL, activities of daily living, SRA, social roles and activities ConclusionThis is the first report of HRQOL deficits in previously healthy individuals following microbial recovery from CM. These data reinforce and quantify the long-term morbidity of this disease and identify patient-centered outcomes for future interventional trials.Disclosures All Authors: No reported disclosures

Postinfectious inflammatory response syndrome in HIV-uninfected and nontransplant men after cryptococcal meningitis.

Aim: The aim of our study was to describe the characteristics of postinfectious inflammatory response syndrome (PIIRS) in HIV-uninfected and nontransplant men after cryptococcal meningitis (CM).Patients & methods: A case-control study was designed to compare HIV-uninfected and nontransplant male CM patients with and without PIIRS. Results: CM-PIIRS patients had increased rates of hearing loss, V-P shunt placement, amphotericin B treatment, higher cerebrospinal fluid pressures and Cryptococcus counts in the first CM episode. CM-PIIRS episode was characterized by higher frequencies of headache and fever, higher C-reactive protein, erythrocyte sedimentation rate, cerebrospinal fluid white blood cell(WBC) counts and modified Rankin Score. Brain MRI scans revealed the high signal lesions on axial flair imaging. Receipt of corticosteroid therapy was associated with lower rates of fever and better modified Rankin Score scores at 1month after treatment. Conclusion: CM-PIIRS episode differs to the initial presentation, may help to identify which patients are at risk to develop PIIRS. Steroids therapy could be beneficial.

1820. Efficacy of Pulse-Taper Corticosteroid Adjunctive Therapy for Refractory Non-HIV Cryptococcal Meningoencephalitis

BackgroundCryptococcal meningoencephalitis (CM) affects individuals with AIDS, transplants recipients and those previously healthy, with 30–50% mortality in most groups despite anti-fungal treatment. In the previously healthy, a post-infectious inflammatory response syndrome (PIIRS) analogous to cryptococcal IRIS in AIDS patients has recently been described. PIIRS is defined as a deterioration in mental status and/or audio-visual capacity despite optimal treatment for CM and negative CSF cultures. Pathophysiology is related to excessive T-cell responses to lysed fungal cells during therapy but data on effective treatment regimens are limited.MethodsBetween March 2015 and February 2019, 11 consecutive patients with PIIRS who evidenced clinical deterioration over a period of up to 10 weeks despite effective antifungals were referred to the NIH clinical center. Patients were prospectively treated with adjunctive pulse solumedrol 1 g daily for 1 week followed by prednisone 1 mg/kg/day, tapered based on clinical and radiological response plus oral fluconazole. Montreal cognitive assessments (MOCA) scores at baseline and 1 month were the primary endpoints and CSF parameters including WBC, glucose, HLA DR4+ CD4 and CD8 cells and cytokines were also determined at baseline and after 1 week of solumedrol. Paired nonparametric t-tests were conducted using GraphPad Prism 7.0.ResultsAll patients demonstrated clinical improvement despite 7 being initiated at the point of stupor and 6 having received ventriculoperitoneal shunts without clinical response. MOCA scores at 1 month showed significant improvement (P = 0.002), accompanied by significant improvements in CSF: serum glucose ratios, CSF WBC, protein and HLADR4 positive T cells 1 week after receiving corticosteroids (P < 0.02). Patients with hearing or visual deficits exhibited clinical improvement. CSF cultures remained negative.ConclusionOur findings in this small observational cohort of refractory non-HIV CM with PIIRS demonstrated significant clinical benefit of high dose adjunctive pulse-taper corticosteroids. The study also demonstrates the utility of physiology-based immunophenotyping to guide therapy in neuroinflammation associated with infectious diseases.Disclosures All Authors: No reported Disclosures.

Immunology of Cryptococcal Infections: Developing a Rational Approach to Patient Therapy.

Cryptococcal meningoencephalitis is responsible for upwards of 15% of HIV-related deaths worldwide and is currently the most common cause of non-viral meningitis in the US, affecting both previously healthy and people with immune suppression caused by cancer chemotherapy, transplantation, and biologic therapies. Despite a continued 30–50% attributable mortality, recommended therapeutic strategies have remained largely unchanged since the 1950s. Recent murine models and human studies examining the role of the immune system in both susceptibility to the infection as well as host damage have begun to influence patient care decisions. The Damage Framework Response, originally proposed in 1999, was recently used to discuss dichotomous etiologies of host damage in cryptococcal disease. These include patients suffering microbiological damage with low host immunity (especially those immunosuppressed with HIV) and those having low (live) microbiological burden but high immune-mediated damage (HIV-related immune reconstitution syndrome and non-HIV-related postinfectious inflammatory response syndrome). Cryptococcal disease in previously healthy hosts, albeit rare, has been known for a long time. Immunophenotyping and dendritic cell-T cell signaling studies on cerebral spinal fluid of these rare patients reveal immune capacity for recognition and T-cell activation pathways including increased levels of HLA-DR and CD56. However, despite effective T-cell signals, brain biopsy and autopsy specimens demonstrated an M2 alternative macrophage polarization and poor phagocytosis of fungal cells. These studies expand the paradigm for cryptococcal disease susceptibility to include a prominent role for immune-mediated damage and suggest a need for careful individual consideration of immune activation during therapy of cryptococcal disease in diverse hosts.