Cellular immune activation in cerebrospinal fluid from ugandans with cryptococcal meningitis and immune reconstitution inflammatory syndrome.

BACKGROUND: Human immunodeficiency virus (HIV)-associated cryptococcal meningitis (CM) is characterized by high fungal burden and limited leukocyte trafficking to cerebrospinal fluid (CSF). The immunopathogenesis of CM immune reconstitution inflammatory syndrome (IRIS) after initiation of antiretroviral therapy at the site of infection is poorly understood. METHODS: We characterized the lineage and activation status of mononuclear cells in blood and CSF of HIV-infected patients with noncryptococcal meningitis (NCM) (n = 10), those with CM at day 0 (n = 40) or day 14 (n = 21) of antifungal therapy, and those with CM-IRIS (n = 10). RESULTS: At diagnosis, highly activated CD8(+) T cells predominated in CSF in both CM and NCM. CM-IRIS was associated with an increasing frequency of CSF CD4(+) T cells (increased from 2.2% to 23%; P = .06), a shift in monocyte phenotype from classic to an intermediate/proinflammatory, and increased programmed death ligand 1 expression on natural killer cells (increased from 11.9% to 61.6%, P = .03). CSF cellular responses were distinct from responses in peripheral blood. CONCLUSIONS: After CM, T cells in CSF tend to evolve with the development of IRIS, with increasing proportions of activated CD4(+) T cells, migration of intermediate monocytes to the CSF, and declining fungal burden. These changes provide insight into IRIS pathogenesis and could be exploited to more effectively treat CM and prevent CM-IRIS

AIDS-related mycoses: the way forward.

The contribution of fungal infections to the morbidity and mortality of HIV-infected individuals is largely unrecognized. A recent meeting highlighted several priorities that need to be urgently addressed, including improved epidemiological surveillance, increased availability of existing diagnostics and drugs, more training in the field of medical mycology, and better funding for research and provision of treatment, particularly in developing countries

Cryptococcal Meningitis Treatment Strategies in Resource-Limited Settings: A Cost-Effectiveness Analysis

<div><h3>Background</h3><p>Cryptococcal meningitis (CM) is the most common form of meningitis in Africa. World Health Organization guidelines recommend 14-d amphotericin-based induction therapy; however, this is impractical for many resource-limited settings due to cost and intensive monitoring needs. A cost-effectiveness analysis was performed to guide stakeholders with respect to optimal CM treatment within resource limitations.</p> <h3>Methods and Findings:</h3><p>We conducted a decision analysis to estimate the incremental cost-effectiveness ratio (ICER) of six CM induction regimens: fluconazole (800–1,200 mg/d) monotherapy, fluconazole + flucytosine (5FC), short-course amphotericin (7-d) + fluconazole, 14-d of amphotericin alone, amphotericin + fluconazole, and amphotericin + 5FC. We computed actual 2012 healthcare costs in Uganda for medications, supplies, and personnel, and average laboratory costs for three African countries. A systematic review of cryptococcal treatment trials in resource-limited areas summarized 10-wk survival outcomes. We modeled one-year survival based on South African, Ugandan, and Thai CM outcome data, and survival beyond one-year on Ugandan and Thai data. Quality-adjusted life years (QALYs) were determined and used to calculate the cost-effectiveness ratio and ICER. The cost of hospital care ranged from $154 for fluconazole monotherapy to$467 for 14 d of amphotericin + 5FC. Based on 18 studies investigating outcomes for HIV-infected individuals with CM in resource-limited settings, the estimated mean one-year survival was lowest for fluconazole monotherapy, at 40%. The cost-effectiveness ratio ranged from $20 to$44 per QALY. Overall, amphotericin-based regimens had higher costs but better survival. Short-course amphotericin (1 mg/kg/d for 7 d) with fluconazole (1,200 mg/d for14 d) had the best one-year survival (66%) and the most favorable cost-effectiveness ratio, at $20.24/QALY, with an ICER of$15.11 per additional QALY over fluconazole monotherapy. The main limitation of this study is the pooled nature of a systematic review, with a paucity of outcome data with direct comparisons between regimens.</p> <h3>Conclusions</h3><p>Short-course (7-d) amphotericin induction therapy coupled with high-dose (1,200 mg/d) fluconazole is “very cost effective” per World Health Organization criteria and may be a worthy investment for policy-makers seeking cost-effective clinical outcomes. More head-to-head clinical trials are needed on treatments for this neglected tropical disease.</p> <h3></h3><p> <em>Please see later in the article for the Editors' Summary.</em></p> </div

Estimated clinical outcomes by cryptococcal meningitis induction treatment regimen.

<p>5FC dosed at 100 mg/kg/d; amphotericin B deoxycholate dosed at 0.7–1.0 mg/kg/d. <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001316#pmed.1001316.s007" target="_blank">Figure S2</a> displays the data.</p>a<p>Mayanja-Kizza et al. used fluconazole doses of 200 mg/d and 5FC doses of 150 mg/kg/d <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001316#pmed.1001316-MayanjaKizza1" target="_blank">[30]</a>.</p>b<p>Muzoora et al. <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001316#pmed.1001316-Muzoora1" target="_blank">[13]</a> used 5 d of amphotericin and Jackson et al. <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001316#pmed.1001316-Jackson1" target="_blank">[15]</a> used 7 d of amphotericin at 1.0 mg/kg/d with fluconazole at 1,200 mg/d, whereas 7 d of amphotericin was used by Bicanic et al. <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001316#pmed.1001316-Bicanic1" target="_blank">[9]</a> (1.0 mg/kg/d) and Tansuphaswadikul et al. <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001316#pmed.1001316-Tansuphaswadikul1" target="_blank">[31]</a> (0.7 mg/kg/d).</p

Input costs of cryptococcal meningitis induction therapy and medical care.

<p>LP includes initial diagnostic CSF analysis; 5FC dosed at 100 mg/kg/d; amphotericin B deoxycholate dosed at 0.7–1.0 mg/kg/d. Cost components displayed in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001316#pmed.1001316.s006" target="_blank">Figure S1</a>.</p>a<p>Assumes 7 d of hospitalization, with additional phlebotomy for 5FC monitoring.</p

Estimating Risk to Responders Exposed to Avian Influenza A H5 and H7 Viruses in Poultry, United States, 2014–2017

In the United States, outbreaks of avian influenza H5 and H7 virus infections in poultry have raised concern about the risk for infections in humans. We reviewed the data collected during 2014–2017 and found no human infections among 4,555 exposed responders who were wearing protection

Supply of neuraminidase inhibitors related to reduced influenza A (H1N1) mortality during the 2009-2010 H1N1 pandemic: an ecological study.

BACKGROUND: The influenza A (H1N1) pandemic swept across the globe from April 2009 to August 2010 affecting millions. Many WHO Member States relied on antiviral drugs, specifically neuraminidase inhibitors (NAIs) oseltamivir and zanamivir, to treat influenza patients in critical condition. Such drugs have been found to be effective in reducing severity and duration of influenza illness, and likely reduced morbidity during the pandemic. However, it is less clear whether NAIs used during the pandemic reduced H1N1 mortality. METHODS: Country-level data on supply of oseltamivir and zanamivir were used to predict H1N1 mortality (per 100,000 people) from July 2009 to August 2010 in forty-two WHO Member States. Poisson regression was used to model the association between NAI supply and H1N1 mortality, with adjustment for economic, demographic, and health-related confounders. RESULTS: After adjustment for potential confounders, each 10% increase in kilograms of oseltamivir, per 100,000 people, was associated with a 1.6% reduction in H1N1 mortality over the pandemic period (relative rate (RR) = 0.84 per log increase in oseltamivir supply). While the supply of zanamivir was considerably less than that of oseltamivir in each Member State, each 10% increase in kilogram of active zanamivir, per 100,000, was associated with a 0.3% reduction in H1N1 mortality (RR = 0.97 per log increase). CONCLUSION: While there are limitations to the ecologic nature of these data, this analysis offers evidence of a protective relationship between antiviral drug supply and influenza mortality and supports a role for influenza antiviral use in future pandemics

Respiratory virus circulation during the first year of the COVID-19 pandemic in the Household Influenza Vaccine Evaluation (HIVE) cohort

BackgroundThe annual reappearance of respiratory viruses has been recognized for decades. COVID-19 mitigation measures taken during the pandemic were targeted at respiratory transmission and broadly impacted the burden of acute respiratory illnesses (ARIs).MethodsWe used the longitudinal Household Influenza Vaccine Evaluation (HIVE) cohort in southeast Michigan to characterize the circulation of respiratory viruses from March 1, 2020, to June 30, 2021, using RT-PCR of respiratory specimens collected at illness onset. Participants were surveyed twice during the study period, and SARS-CoV-2 antibodies were measured in serum by electrochemiluminescence immunoassay. Incidence rates of ARI reports and virus detections were compared between the study period and a preceding pre-pandemic period of similar duration.ResultsOverall, 437 participants reported a total of 772 ARIs; 42.6% had respiratory viruses detected. Rhinoviruses were the most frequent virus, but seasonal coronaviruses, excluding SARS-CoV-2, were also common. Illness reports and percent positivity were lowest from May to August 2020, when mitigation measures were most stringent. Seropositivity for SARS-CoV-2 was 5.3% in summer 2020 and increased to 11.3% in spring 2021. The incidence rate of total reported ARIs for the study period was 50% lower (95% CI: 0.5, 0.6; p < 0.001) than the incidence rate from a pre-pandemic comparison period (March 1, 2016, to June 30, 2017).ConclusionsThe burden of ARI in the HIVE cohort during the COVID-19 pandemic fluctuated, with declines occurring concurrently with the widespread use of public health measures. Rhinovirus and seasonal coronaviruses continued to circulate even when influenza and SARS-CoV-2 circulation was low.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/175944/1/irv13106_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/175944/2/irv13106.pd