Post-infection inflammatory syndromes have been increasingly recognized as a cause of host damage in a variety of infectious diseases including tuberculosis, bacterial meningitis, and COVID-19. Recently, a post-infectious inflammatory response syndrome (PIIRS) was described in non-HIV-infected cryptococcal fungal meningoencephalitis (CM) as a major cause of mortality. Inflammatory syndromes are particularly severe in neurological infections due to the skull's rigid structure which limits unchecked tissue expansion from inflammatory-induced edema. In the present studies, neurologic transcriptional pathway analysis utilizing a murine PIIRS model demonstrated a predominance of Janus kinase/signal transducer and activator of transcription (JAK/STAT) activation. JAK/STAT inhibitor treatment resulted in improvements in CNS damage markers, reductions in intrathecal CD44hiCD62lo CD4+ effector CD4+ T-cells and MHC II+ inflammatory myeloid cells, and weight gains in mice, the latter after treatment with antifungals. Based on these data, pathway-driven steroid-sparing human treatment for steroid-refractory PIIRS was initiated using short courses of the JAK/STAT inhibitor ruxolitinib. These were well tolerated and reduced activated HLA-DR+ CD4+ and CD8+ cells and inflammatory monocytes as well as improved brain imaging. Together, these findings support the role of JAK/STAT in PIIRS as well as further study of JAK/STAT inhibitors as potential adjunctive therapy for PIRS and other neural inflammatory syndromes.
Abstract Background Cryptococcal 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. Methods Between 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. Results 80% 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. Conclusion PCT 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
Cryptococcosis is a serious opportunistic fungal disease, and the proportion of cases among patients with immunosuppressive conditions other than HIV or organ transplant has increased. Understanding laboratory testing patterns for cryptococcosis is useful for estimating its true burden and developing testing guidance.We identified cryptococcosis tests (cryptococcal antigen [CrAg], cryptococcal antibody, and fungal cultures) performed at a major national commercial laboratory ordered during March 1, 2019-October 1, 2021, and analyzed test results, patient and provider features, reasons for testing, geography, and temporal trends.Among 29 180 serum CrAg tests, 4422 (15.2%) were positive, and among 10 724 cerebrospinal fluid (CSF) CrAg tests, 492 (4.6%) were positive. Frequent reasons for serum CrAg testing in nonhospital settings (10 882 tests) were HIV (44.6%) and cryptococcosis (17.0%); other underlying conditions were uncommonly listed (<10% total). Serum CrAg positivity declined from 25.6% in October 2019 to 11.3% in September 2021. The South had the highest positivity for serum CrAg tests (16.6%), CSF CrAg tests (4.7%), and fungal cultures (0.15%). Among 5009 cryptococcal antibody tests, 5 (0.1%) were positive.Few outpatient serum CrAg tests were performed for patients with immunocompromising conditions other than HIV, suggesting potential missed opportunities for early detection. Given the high positive predictive value of CrAg testing, research is needed to improve early diagnosis, particularly in patients without HIV. Conversely, the low yield of antibody testing suggests that it may be of low value. The decline in CrAg positivity during the COVID-19 pandemic warrants further investigation.
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.
Abstract Background Cryptococcal 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. Methods We 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. Results Of 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 Conclusion This 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
Abstract Background Cryptococcal 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. Methods Between 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. Results All 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. Conclusion Our 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.
Patients with cryptococcal meningitis (CM) often have ocular manifestations; although data are describing these findings in nonimmunosuppressed, previously healthy individuals are scarce.
