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Thomas S. Harrison - One of the best experts on this subject based on the ideXlab platform.

  • Recent advances in managing HIV-associated Cryptococcal Meningitis.
    F1000Research, 2019
    Co-Authors: Timothée Boyer-chammard, Thomas S. Harrison, Elvis Temfack, Alexandre Alanio, Joseph N. Jarvis, Olivier Lortholary
    Abstract:

    The recent development of highly sensitive and specific point-of-care tests has made it possible to diagnose HIV-associated Cryptococcal Meningitis within minutes. However, diagnostic advances have not been matched by new antifungal drugs and treatment still relies on old off-patent drugs: amphotericin B, flucytosine and fluconazole. Cryptococcal Meningitis treatment is divided in three phases: induction, consolidation and maintenance. The induction phase, aimed at drastically reducing cerebrospinal fluid fungal burden, is key for patient survival. The major challenge in Cryptococcal Meningitis management has been the optimisation of induction phase treatment using the limited number of available medications, and major progress has recently been made. In this review, we summarise data from key trials which form the basis of current treatment recommendations for HIV-associated Cryptococcal Meningitis.

  • Cryptococcal Meningitis epidemiology immunology diagnosis and therapy
    Nature Reviews Neurology, 2017
    Co-Authors: Peter R Williamson, Angela Loyse, Joseph N. Jarvis, Anil A Panackal, Matthew C Fisher, Sile F Molloy, Thomas S. Harrison
    Abstract:

    HIV-associated Cryptococcal Meningitis is by far the most common cause of adult Meningitis in many areas of the world that have high HIV seroprevalence. In most areas in Sub-Saharan Africa, the incidence of Cryptococcal Meningitis is not decreasing despite availability of antiretroviral therapy, because of issues of adherence and retention in HIV care. In addition, Cryptococcal Meningitis in HIV-seronegative individuals is a substantial problem: the risk of Cryptococcal infection is increased in transplant recipients and other individuals with defects in cell-mediated immunity, and cryptococcosis is also reported in the apparently immunocompetent. Despite therapy, mortality rates in these groups are high. Over the past 5 years, advances have been made in rapid point-of-care diagnosis and early detection of Cryptococcal antigen in the blood. These advances have enabled development of screening and pre-emptive treatment strategies aimed at preventing the development of clinical infection in patients with late-stage HIV infection. Progress in optimizing antifungal combinations has been aided by evaluation of the clearance rate of infection by using serial quantitative cultures of cerebrospinal fluid (CSF). Measurement and management of raised CSF pressure, a common complication, is a vital component of care. In addition, we now better understand protective immune responses in HIV-associated cases, immunogenetic predisposition to infection, and the role of immune-mediated pathology in patients with non-HIV associated infection and in the context of HIV-associated immune reconstitution reactions.

  • Cryptococcal Meningitis improving access to essential antifungal medicines in resource poor countries
    Lancet Infectious Diseases, 2013
    Co-Authors: Angela Loyse, Thomas S. Harrison, Nathan Ford, Tom Chiller, Harry Thangaraj, Philippa Easterbrook, Monika Roy, Nelesh P Govender, Tihana Bicanic
    Abstract:

    Cryptococcal Meningitis is the leading cause of adult Meningitis in sub-Saharan Africa, and contributes up to 20% of AIDS-related mortality in low-income and middle-income countries every year. Antifungal treatment for Cryptococcal Meningitis relies on three old, off -patent antifungal drugs: amphotericin B deoxycholate, fl ucytosine, and fl uconazole. Widely accepted treatment guidelines recommend amphotericin B and fl ucytosine as fi rst-line induction treatment for Cryptococcal Meningitis. However, fl ucytosine is unavailable in Africa and most of Asia, and safe amphotericin B administration requires patient hospitalisation and careful laboratory monitoring to identify and treat common sideeff ects. Therefore, fl uconazole monotherapy is widely used in low-income and middle-income countries for induction therapy, but treatment is associated with signifi cantly increased rates of mortality. We review the antifungal drugs used to treat Cryptococcal Meningitis with respect to clinical eff ectiveness and access issues specifi c to low-income and middle-income countries. Each drug poses unique access challenges: amphotericin B through cost, toxic eff ects, and insuffi ciently coordinated distribution; fl ucytosine through cost and scarcity of registration; and fl uconazole through challenges in maintenance of local stocks—eg, sustainability of donations or insuffi cient generic supplies. We advocate ten steps that need to be taken to improve access to safe and eff ective antifungal therapy for Cryptococcal Meningitis.

  • lumbar drainage for control of raised cerebrospinal fluid pressure in Cryptococcal Meningitis case report and review
    Journal of Infection, 2005
    Co-Authors: Karen F Macsween, Annemarie E Brouwer, Tihana Bicanic, Henry Marsh, Derek C Macallan, Thomas S. Harrison
    Abstract:

    Raised intracranial pressure in the absence of ventricular dilatation is common in Cryptococcal Meningitis and associated with increased mortality. We report the case of a patient with HIV-associated Cryptococcal Meningitis, who developed increasing CSF pressure and visual impairment on therapy despite serial lumbar punctures. Insertion of a temporary lumbar drain controlled the opening pressure and resulted in full visual recovery. The advantages and necessary precautions with this approach are reviewed, and alternative protocols for the use of lumbar drains discussed.

  • Baseline correlation and comparative kinetics of cerebrospinal fluid colony-forming unit counts and antigen titers in Cryptococcal Meningitis.
    The Journal of Infectious Diseases, 2005
    Co-Authors: Annemarie E Brouwer, Wirongrong Chierakul, Robert A Larsen, Paprit Teparrukkul, Supraphada Pinpraphaporn, Sharon J. Peacock, Nicholas P. J. Day, Nicholas J. White, Thomas S. Harrison
    Abstract:

    Cerebrospinal fluid (CSF) Cryptococcal colony-forming unit counts and CSF Cryptococcal antigen titers serve as alternative measures of organism load in Cryptococcal Meningitis. For these measures, we correlated baseline values and rates of decline during the first 2 weeks of therapy in 68 human immunodeficiency virus--seropositive patients with Cryptococcal Meningitis. At baseline, there was a strong correlation between CSF Cryptococcal colony-forming unit counts and CSF Cryptococcal antigen titers. During the first 2 weeks of therapy, CSF Cryptococcal colony-forming unit counts decreased by >5 logs, and CSF Cryptococcal antigen titers decreased by 1.5 dilutions. In individual patients, there was no correlation between the rate of decline in CSF Cryptococcal colony-forming unit counts and that in CSF Cryptococcal antigen titers.

Joseph N. Jarvis - One of the best experts on this subject based on the ideXlab platform.

  • Cryptococcal Meningitis a review of Cryptococcal antigen screening programs in africa
    Expert Review of Anti-infective Therapy, 2021
    Co-Authors: Greg Greene, Tom Chiller, David Lawrence, Joseph N. Jarvis, Alexander Jordan
    Abstract:

    Cryptococcal Meningitis remains a significant contributor to AIDS-related mortality despite widened access to antiretroviral therapy. Cryptococcal antigen (CrAg) can be detected in the blood prior ...

  • hiv associated Cryptococcal Meningitis a review of novel short course and oral therapies
    Current Treatment Options in Infectious Diseases, 2020
    Co-Authors: Letumile R Moeng, Joseph N. Jarvis, James Milburn, David S Lawrence
    Abstract:

    HIV-associated Cryptococcal Meningitis remains a significant public health problem in parts of Africa and Asia and a major cause of AIDS-related mortality, accounting for 15% of all AIDS-related deaths worldwide. Cryptococcal Meningitis is uniformly fatal if untreated, and access to antifungal therapy in regions with the highest burden is often limited. Outcomes with fluconazole monotherapy are poor, and induction treatment with amphotericin B and high-dose fluconazole for 2 weeks is associated with significant drug-related toxicities and prolonged hospital admissions. This review focuses on the potential of novel short-course and oral combination therapies for Cryptococcal Meningitis. Recent clinical trials have shown that shorter courses of amphotericin, if paired with oral flucytosine, rather than fluconazole, can achieve non-inferior mortality outcomes. In addition, an oral combination of fluconazole and flucytosine is a potential alternative. Liposomal amphotericin B may further simplify treatment; it is associated with fewer drug-related toxicities, and a recent phase II randomised controlled trial demonstrated that a single, high dose of liposomal amphotericin is non-inferior to 14 standard daily doses at clearing Cryptococcus from cerebrospinal fluid. This has been taken forward to an ongoing phase III, clinical endpoint study. The incidence and mortality associated with Cryptococcal Meningitis is still unacceptably high. There is evidence supporting the use of short-course amphotericin B and oral combination antifungal treatment regimens for Cryptococcal Meningitis (CM). Ongoing research into short-course, high-dose treatment with liposomal amphotericin may also help reduce the impact of this devastating disease.

  • Recent advances in managing HIV-associated Cryptococcal Meningitis.
    F1000Research, 2019
    Co-Authors: Timothée Boyer-chammard, Thomas S. Harrison, Elvis Temfack, Alexandre Alanio, Joseph N. Jarvis, Olivier Lortholary
    Abstract:

    The recent development of highly sensitive and specific point-of-care tests has made it possible to diagnose HIV-associated Cryptococcal Meningitis within minutes. However, diagnostic advances have not been matched by new antifungal drugs and treatment still relies on old off-patent drugs: amphotericin B, flucytosine and fluconazole. Cryptococcal Meningitis treatment is divided in three phases: induction, consolidation and maintenance. The induction phase, aimed at drastically reducing cerebrospinal fluid fungal burden, is key for patient survival. The major challenge in Cryptococcal Meningitis management has been the optimisation of induction phase treatment using the limited number of available medications, and major progress has recently been made. In this review, we summarise data from key trials which form the basis of current treatment recommendations for HIV-associated Cryptococcal Meningitis.

  • emerging concepts in hiv associated Cryptococcal Meningitis
    Current Opinion in Infectious Diseases, 2019
    Co-Authors: David Lawrence, Timothee Boyerchammard, Joseph N. Jarvis
    Abstract:

    Purpose of reviewHIV-associated Cryptococcal Meningitis remains a significant contributor to AIDS-related mortality despite widened access to antiretroviral therapy. Even in clinical trial settings 10-week mortality is roughly 40%. A number of important clinical trials have either recently concluded

  • treatment for hiv associated Cryptococcal Meningitis
    Cochrane Database of Systematic Reviews, 2018
    Co-Authors: Mark W Tenforde, Joseph N. Jarvis, Adrienne E Shapiro, Benjamin Rouse, Ingrid Eshunwilson, Nathan Ford
    Abstract:

    Background Cryptococcal Meningitis is a severe fungal infection that occurs primarily in the setting of advanced immunodeficiency and remains a major cause of HIV-related deaths worldwide. The best induction therapy to reduce mortality from HIV-associated Cryptococcal Meningitis is unclear, particularly in resource-limited settings where management of drug-related toxicities associated with more potent antifungal drugs is a challenge. Objectives To evaluate the best induction therapy to reduce mortality from HIV-associated Cryptococcal Meningitis; to compare side effect profiles of different therapies. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE (PubMed), Embase (Ovid), LILACS (BIREME), African Index Medicus, and Index Medicus for the South-East Asia Region (IMSEAR) from 1 January 1980 to 9 July 2018. We also searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), ClinicalTrials.gov, and the ISRCTN registry; and abstracts of select conferences published between 1 July 2014 and 9 July 2018. Selection criteria We included randomized controlled trials that compared antifungal induction therapies used for the first episode of HIV-associated Cryptococcal Meningitis. Comparisons could include different individual or combination therapies, or the same antifungal therapies with differing durations of induction (less than two weeks or two or more weeks, the latter being the current standard of care). We included data regardless of age, geographical region, or drug dosage. We specified no language restriction. Data collection and analysis Two review authors independently screened titles and abstracts identified by the search strategy. We obtained the full texts of potentially eligible studies to assess eligibility and extracted data using standardized forms. The main outcomes included mortality at 2 weeks, 10 weeks, and 6 months; mean rate of cerebrospinal fluid fungal clearance in the first two weeks of treatment; and Division of AIDS (DAIDS) grade three or four laboratory events. Using random-effects models we determined pooled risk ratio (RR) and 95% confidence interval (CI) for dichotomous outcomes and mean differences (MD) and 95% CI for continuous outcomes. For the direct comparison of 10-week mortality, we assessed the certainty of the evidence using the GRADE approach. We performed a network meta-analysis using multivariate meta-regression. We modelled treatment differences (RR and 95% CI) and determined treatment rankings for two-week and 10-week mortality outcomes using surface under the cumulative ranking curve (SUCRA). We assessed transitivity by comparing distribution of effect modifiers between studies, local inconsistency through a node-splitting approach, and global inconsistency using design-by-treatment interaction modelling. For the network meta-analysis, we applied a modified GRADE approach for assessing the certainty of the evidence for 10-week mortality. Main results We included 13 eligible studies that enrolled 2426 participants and compared 21 interventions. All studies were carried out in adults, and all but two studies were conducted in resource-limited settings, including 11 of 12 studies with 10-week mortality data.In the direct pairwise comparisons evaluating 10-week mortality, one study from four sub-Saharan African countries contributed data to several key comparisons. At 10 weeks these data showed that those on the regimen of one-week amphotericin B deoxycholate (AmBd) and flucytosine (5FC) followed by fluconazole (FLU) on days 8 to 14 had lower mortality when compared to (i) two weeks of AmBd and 5FC (RR 0.62, 95% CI 0.42 to 0.93; 228 participants, 1 study), (ii) two weeks of AmBd and FLU (RR 0.58, 95% CI 0.39 to 0.86; 227 participants, 1 study), (iii) one week of AmBd with two weeks of FLU (RR 0.49, 95% CI 0.34 to 0.72; 224 participants, 1 study), and (iv) two weeks of 5FC and FLU (RR 0.68, 95% CI 0.47 to 0.99; 338 participants, 1 study). The evidence for each of these comparisons was of moderate certainty. For other outcomes, this shortened one-week AmBd and 5FC regimen had similar fungal clearance (MD 0.05 log10 CFU/mL/day, 95% CI -0.02 to 0.12; 186 participants, 1 study) as well as lower risk of grade three or four anaemia (RR 0.31, 95% CI 0.16 to 0.60; 228 participants, 1 study) compared to the two-week regimen of AmBd and 5FC.For 10-week mortality, the comparison of two weeks of 5FC and FLU with two weeks of AmBd and 5FC (RR 0.92, 95% CI 0.69 to 1.23; 340 participants, 1 study) or two weeks of AmBd and FLU (RR 0.85, 95% CI 0.64 to 1.13; 339 participants, 1 study) did not show a difference in mortality, with moderate-certainty evidence for both comparisons.When two weeks of combination AmBd and 5FC was compared with AmBd alone, pooled data showed lower mortality at 10 weeks (RR 0.66, 95% CI 0.46 to 0.95; 231 participants, 2 studies, moderate-certainty evidence).When two weeks of AmBd and FLU was compared to AmBd alone, there was no difference in 10-week mortality in pooled data (RR 0.94, 95% CI 0.55 to 1.62; 371 participants, 3 studies, low-certainty evidence).One week of AmBd and 5FC followed by FLU on days 8 to 14 was the best induction therapy regimen after comparison with 11 other regimens for 10-week mortality in the network meta-analysis, with an overall SUCRA ranking of 88%. Authors' conclusions In resource-limited settings, one-week AmBd- and 5FC-based therapy is probably superior to other regimens for treatment of HIV-associated Cryptococcal Meningitis. An all-oral regimen of two weeks 5FC and FLU may be an alternative in settings where AmBd is unavailable or intravenous therapy cannot be safely administered. We found no mortality benefit of combination two weeks AmBd and FLU compared to AmBd alone. Given the absence of data from studies in children, and limited data from high-income countries, our findings provide limited guidance for treatment in these patients and settings.

Darlisha A Williams - One of the best experts on this subject based on the ideXlab platform.

  • cerebrospinal fluid lactate as a prognostic marker of disease severity and mortality in Cryptococcal Meningitis
    Clinical Infectious Diseases, 2021
    Co-Authors: Mahsa Abassi, Edwin Nuwagira, Edward Mpoza, Darlisha A Williams, Ananta S Bangdiwala, Kiiza Kandole Tadeo, Michael Okirwoth, Lillian Tugume
    Abstract:

    BACKGROUND Cerebrospinal fluid (CSF) lactate levels can be used to differentiate between bacterial and viral Meningitis. We measured CSF lactate in individuals with Cryptococcal Meningitis to determine its clinical significance. METHODS We measured point-of-care CSF lactate at the bedside of 319 Ugandan adults living with human immunodeficiency virus at diagnosis of Cryptococcal Meningitis. We summarized demographic variables and clinical characteristics by CSF lactate tertiles. We evaluated the association of CSF lactate with clinical characteristics and survival. RESULTS Individuals with high CSF lactate >5 mmol/L at Cryptococcal diagnosis more likely presented with altered mental status (P  5 mmol/L (35%; 38 of 109) compared with individuals with mid-range (22%; 25 of 112) or low CSF lactate (9%; 9 of 97; P = 5 mmol/L remained independently associated with excess mortality (adjusted hazard ratio = 3.41; 95% confidence interval, 1.55-7.51; P = .002). We found no correlation between baseline CSF lactate levels and blood capillary lactate levels. CONCLUSIONS Baseline point-of-care CSF lactate levels are a prognostic marker of disease severity and mortality in Cryptococcal Meningitis. Individuals with an elevated baseline CSF lactate level are more likely to present with altered mental status, seizures, and elevated CSF opening pressure and are at a greater risk of death. Future studies are needed to determine targeted therapeutic management strategies in persons with high CSF lactate.

  • correlation between blood and csf compartment cytokines and chemokines in subjects with Cryptococcal Meningitis
    Mediators of Inflammation, 2020
    Co-Authors: Elizabeth C Okafor, Joshua Rhein, Katherine Huppler Hullsiek, Abdu K Musubire, Darlisha A Williams, James E Scriven, Henry W Nabeta, Radha Rajasingham
    Abstract:

    Background: Though peripheral blood is a crucial sample to study immunology, it is unclear whether the immune environment in the peripheral vasculature correlates with that at the end-organ site of infection. Using Cryptococcal Meningitis as a model, we investigated the correlation between serum and cerebrospinal fluid biomarkers over time. Methods: We analyzed the cerebrospinal fluid and serum of 160 subjects presenting with first episode Cryptococcal Meningitis for soluble cytokines and chemokines measured by Luminex assay. Specimens were collected at Meningitis diagnosis, 1-week, and 2-week post Cryptococcal diagnosis. We compared paired samples by Spearman's correlation and the p value was set at <0.01. Results: Of the 21 analytes tested at baseline, there was no correlation detected between nearly all analytes. A weak negative correlation was found between serum and cerebrospinal fluid levels of interferon-gamma (Rho = -0.214; p = .007) and interleukin-4 (Rho = -0.232; p = .003). There was no correlation at 1-week post Cryptococcal diagnosis. However, at 2-week post Cryptococcal diagnosis, there was a weak positive correlation of granulocyte-macrophage colony-stimulating factor levels (Rho = 0.25; p = .007) in serum and cerebrospinal fluid. No cytokine or chemokine showed consistent correlation overtime. Conclusion: Based on our analysis of 21 biomarkers, serum and cerebrospinal fluid immune responses do not correlate. There appears to be a distinct immune environment in terms of soluble biomarkers in the vasculature versus end-organ site of infection. While this is a model of HIV-related Cryptococcal Meningitis, we postulate that assuming the blood compartment is representative of the immune function at the end-organ site of infection may not be appropriate.

  • cerebrospinal fluid lactate as a prognostic marker of disease severity and mortality in Cryptococcal Meningitis
    medRxiv, 2020
    Co-Authors: Mahsa Abassi, Lillian Tugume, Edwin Nuwagira, Kenneth Ssebambulidde, Edward Mpoza, Darlisha A Williams, Ananta S Bangdiwala, Kiiza Kandole Tadeo, Michael Okirwoth, Katherine Huppler Hullsiek
    Abstract:

    Background: Cerebrospinal fluid (CSF) lactate levels can differentiate between bacterial and viral Meningitis. We measured CSF lactate in individuals with Cryptococcal Meningitis to determine its clinical significance. Methods: We measured point-of-care CSF lactate at the bedside of 319 HIV-infected Ugandan adults at diagnosis of Cryptococcal Meningitis. We summarized demographic variables and clinical characteristics by CSF lactate tertiles. We evaluated the association of CSF lactate with clinical characteristics and survival. Results: Individuals with high CSF lactate >5 mmol/L at Cryptococcal diagnosis more likely presented with altered mental status (p 5 mmol/L (35%; 38/109) as compared to individuals with mid-range (22%; 25/112) or low CSF lactate (9%; 9/97; p= 5mmol/L remained independently associated with excess mortality (adjusted Hazard Ratio = 3.41; 95%CI, 1.55-7.51; p=.002). We found no correlation between baseline CSF lactate levels and blood capillary lactate levels (p=.72). Conclusions: Baseline point-of-care CSF lactate levels may be utilized as a prognostic marker of disease severity and mortality in Cryptococcal Meningitis. Individuals with an elevated baseline CSF lactate are more likely to present with altered mental status, seizures, elevated CSF opening pressures, and are at a greater risk of death. Future studies are needed to determine targeted therapeutic management strategy in persons with high CSF lactate.

  • correlation between blood and csf compartment cytokines and chemokines in subjects with Cryptococcal Meningitis
    medRxiv, 2020
    Co-Authors: Elizabeth C Okafor, Joshua Rhein, Katherine Huppler Hullsiek, Abdu K Musubire, Darlisha A Williams, Radha Rajasingham, James E Scriven, Henry W Nabeta, Conrad Muzoora, Charlotte Schutz
    Abstract:

    Background: Though peripheral blood is a crucial sample to study immunology, it is unclear whether the immune environment in the peripheral vasculature correlates with that at the end-organ site of infection. Utilizing Cryptococcal Meningitis as a model, we investigated the correlation between serum and cerebrospinal fluid biomarkers over time. Methodology and Principal Findings: We analyzed the cerebrospinal fluid and serum of 160 subjects presenting with first episode Cryptococcal Meningitis for soluble cytokines and chemokines measured by Luminex assay. Specimens were collected at Meningitis diagnosis, 1-week, and 2-weeks post Cryptococcal diagnosis. We compared paired samples by Spearman correlation and the p-value was set at <0.01. Of the 21 analytes tested at baseline, there was no correlation detected between nearly all analytes. A weak negative correlation was found between serum and cerebrospinal fluid levels of interferon-gamma (Rho= −0.214, p= .007) and interleukin- 4 (Rho= −0.232, p= .003). There was no correlation at 1-week post Cryptococcal diagnosis. However, at 2-weeks post diagnosis, there was a weak positive correlation between levels of granulocyte-macrophage colony-stimulating factor (Rho= 0.25, p= .007) between serum and cerebrospinal fluid. No cytokine or chemokine showed consistent correlation overtime. Conclusion and Significance: Based on our analysis of 21 biomarkers, serum and cerebrospinal fluid immune responses do not correlate. There appears to be a distinct immune environment in terms of soluble biomarkers in the vasculature versus end-organ site of infection. While this is a model of HIV-related Cryptococcal Meningitis, we postulate that assuming the blood compartment is representative of the immune function at the end-organ site of infection may not be appropriate.

  • baseline serum c reactive protein level predicts mortality in Cryptococcal Meningitis
    Open Forum Infectious Diseases, 2019
    Co-Authors: Supavit Chesdachai, Mahsa Abassi, Joshua Rhein, Lillian Tugume, Kenneth Ssebambulidde, Nicole Engen, Tadeo K Kandole, John Kasibante, Darlisha A Williams, Caleb P Skipper
    Abstract:

    Background C-reactive protein (CRP) is an acute phase protein produced by the liver in response to systemic inflammation. CRP is a helpful surrogate biomarker used for following the progression and resolution of infection. We aimed to determine the association of baseline CRP level and the temporal change in CRP over time with Cryptococcal Meningitis outcome. Methods We reviewed 168 prospectively enrolled HIV-infected Ugandans with confirmed first-episode Cryptococcal Meningitis. Baseline plasma CRP collected within 5 days of Meningitis diagnosis was categorized into quartiles. We compared baseline CRP with 18-week survival using time-to-event analysis. Results Of 168 participants, the baseline first quartile of serum CRP was 83.6 mg/L. Baseline CD4 count, HIV viral load, and cerebrospinal fluid results did not differ by CRP quartile. Participants with CRP >49.5 mg/L more likely presented with Glasgow Coma Scale (GCS) 49.5 mg/L), 41% (17/42) in the mid-range CRP group (29.0-49.5 mg/L), and 14% (6/42) in the low-CRP group (<29.0 mg/L; P < .001). After adjustment for possible confounding factors including GCS <15, CRP remained significantly associated with mortality (adjusted hazard ratio, 1.084 per 10 mg/L; 95% CI, 1.031-1.139; P = .0016). Conclusions Higher baseline CRP is associated with increased mortality in HIV-infected individuals with first-episode Cryptococcal Meningitis. CRP could be a surrogate marker for undiagnosed coinfections or may reflect immune dysregulation, leading to worse outcomes in persons with advanced AIDS and concomitant Cryptococcal Meningitis.

David R. Boulware - One of the best experts on this subject based on the ideXlab platform.

  • global burden of disease of hiv associated Cryptococcal Meningitis an updated analysis
    Lancet Infectious Diseases, 2017
    Co-Authors: Radha Rajasingham, Angela Loyse, Tom Chiller, Joseph N. Jarvis, Nelesh P Govender, Rachel M Smith, Benjamin J Park, David W Denning, David R. Boulware
    Abstract:

    Summary Background Cryptococcus is the most common cause of Meningitis in adults living with HIV in sub-Saharan Africa. Global burden estimates are crucial to guide prevention strategies and to determine treatment needs, and we aimed to provide an updated estimate of global incidence of HIV-associated Cryptococcal disease. Methods We used 2014 Joint UN Programme on HIV and AIDS estimates of adults (aged >15 years) with HIV and antiretroviral therapy (ART) coverage. Estimates of CD4 less than 100 cells per μL, virological failure incidence, and loss to follow-up were from published multinational cohorts in low-income and middle-income countries. We calculated those at risk for Cryptococcal infection, specifically those with CD4 less than 100 cells/μL not on ART, and those with CD4 less than 100 cells per μL on ART but lost to follow-up or with virological failure. Cryptococcal antigenaemia prevalence by country was derived from 46 studies globally. Based on Cryptococcal antigenaemia prevalence in each country and region, we estimated the annual numbers of people who are developing and dying from Cryptococcal Meningitis. Findings We estimated an average global Cryptococcal antigenaemia prevalence of 6·0% (95% CI 5·8–6·2) among people with a CD4 cell count of less than 100 cells per μL, with 278 000 (95% CI 195 500–340 600) people positive for Cryptococcal antigen globally and 223 100 (95% CI 150 600–282 400) incident cases of Cryptococcal Meningitis globally in 2014. Sub-Saharan Africa accounted for 73% of the estimated Cryptococcal Meningitis cases in 2014 (162 500 cases [95% CI 113 600–193 900]). Annual global deaths from Cryptococcal Meningitis were estimated at 181 100 (95% CI 119 400–234 300), with 135 900 (75%; [95% CI 93 900–163 900]) deaths in sub-Saharan Africa. Globally, Cryptococcal Meningitis was responsible for 15% of AIDS-related deaths (95% CI 10–19). Interpretation Our analysis highlights the substantial ongoing burden of HIV-associated Cryptococcal disease, primarily in sub-Saharan Africa. Cryptococcal Meningitis is a metric of HIV treatment programme failure; timely HIV testing and rapid linkage to care remain an urgent priority. Funding None.

  • flow cytometry to assess cerebrospinal fluid fungal burden in Cryptococcal Meningitis
    Journal of Clinical Microbiology, 2016
    Co-Authors: James E Scriven, David R. Boulware, Graeme Meintjes, Charlotte Schutz, David G Lalloo, Lisa M Graham, Thomas J Scriba, Robert J Wilkinson, Britta C Urban
    Abstract:

    Fungal burden in the cerebrospinal fluid is an important determinant of mortality in Cryptococcal Meningitis, but its use in aiding clinical decision making is hampered by the time involved to perform quantitative cultures. Here, we demonstrate the potential of flow cytometry as a novel and rapid technique to address this issue.

  • Cryptococcal Meningitis: Diagnosis and Management Update
    Current tropical medicine reports, 2015
    Co-Authors: Mahsa Abassi, David R. Boulware, Joshua Rhein
    Abstract:

    Recent advances in the diagnosis and management of Cryptococcal Meningitis are promising and have been improving long-term survival. Point of care testing has made diagnosing Cryptococcal Meningitis rapid, practical, and affordable. Targeted screening and treatment programs for Cryptococcal antigenemia are a cost effective method for reducing early mortality on antiretroviral therapy (ART). Optimal initial management with amphotericin and flucytosine improves survival against alternative therapies, although amphotericin is difficult to administer and flucytosine is not available in middle or low income countries, where Cryptococcal Meningitis is most prevalent. Controlling increased intracranial pressure with serial therapeutic lumbar punctures has a proven survival benefit. Delaying ART initiation for 4 weeks after the diagnosis of Cryptococcal Meningitis is associated with improved survival. Fortunately, new approaches have been leading the way toward improving care for Cryptococcal Meningitis patients. New trials utilizing different combinations of antifungal therapy are reviewed, and we summarize the efficacy of different regimens.

  • prognosis and management of Cryptococcal Meningitis in patients with human immunodeficiency virus infection
    Neurobehavioral HIV Medicine, 2012
    Co-Authors: Joshua Rhein, David R. Boulware
    Abstract:

    Correspondence: David R Boulware MTRF 3-222, 2001 6th Street SE, Minneapolis, MN 55455, USA Tel +1 612 625 9996 Fax +1 612 625 4410 Email boulw001@umn.edu Abstract: Cryptococcal Meningitis has emerged as one of the most frequent and deadly opportunistic infections in patients with human immunodeficiency virus (HIV). Cryptococcosis has become the most common cause of adult Meningitis in many parts of Africa, where it now rivals tuberculosis in all-cause mortality. While expanding access to antiretroviral therapy in many resource-limited settings has led to improvements in long-term prognosis, early mortality from HIV-associated Cryptococcal Meningitis remains unacceptably high. Successful management of Cryptococcal Meningitis is often hindered by unsatisfactory antifungal regimens or by poor control of elevated cerebrospinal fluid pressures. Immune reconstitution inflammatory syndrome also frequently complicates Cryptococcal Meningitis in patients with acquired immune deficiency syndrome (AIDS) initiating antiretroviral therapy, and the optimal timing of antiretroviral therapy remains unclear. The optimal initial regimen of amphotericin B and flucytosine is difficult to administer and is often not available in resource-limited settings, where Cryptococcal Meningitis is most prevalent. Fluid and electrolyte coadministration with amphotericin B is essential to minimizing iatrogenic comorbidities. Fortunately, several new approaches have been leading the way toward improving care for Cryptococcal Meningitis patients in resource-limited settings. Innovative trials utilizing different combinations of antifungal therapy are reviewed, and we summarize the efficacy of different induction regimens. Universal Cryptococcal antigen screening of AIDS patients, combined with new point-of-care testing, has the potential to improve the early diagnosis of Cryptococcal Meningitis markedly in resource-limited settings.

  • paucity of initial cerebrospinal fluid inflammation in Cryptococcal Meningitis is associated with subsequent immune reconstitution inflammatory syndrome
    The Journal of Infectious Diseases, 2010
    Co-Authors: David R. Boulware, David B Meya, Shulamith C Bonham, Darin L Wiesner, Gregory S Park, Andrew Kambugu, Edward N Janoff, Paul R Bohjanen
    Abstract:

    Background Cryptococcal Meningitis (CM)-related immune reconstitution inflammatory syndrome (IRIS) complicates antiretroviral therapy (ART) in 20–40% of ART-naive persons with AIDS and prior CM. Pathogenesis is unknown.

Annemarie E Brouwer - One of the best experts on this subject based on the ideXlab platform.

  • relationship of cerebrospinal fluid pressure fungal burden and outcome in patients with Cryptococcal Meningitis undergoing serial lumbar punctures
    AIDS, 2009
    Co-Authors: Tihana Bicanic, Annemarie E Brouwer, Wirongrong Chierakul, Nicholas J. White, Angela Loyse, Kevin Rebe, Graeme Meintjes, Direk Limmathurotsakul, Praprit Teparrakkul, Robin Wood
    Abstract:

    OBJECTIVES: To assess impact of serial lumbar punctures on association between cerebrospinal fluid (CSF) opening pressure and prognosis in HIV-associated Cryptococcal Meningitis; to explore time course and relationship of opening pressure with neurological findings, CSF fungal burden, immune response, and CD4 cell count. DESIGN: Evaluation of 163 HIV-positive ART-naive patients enrolled in three trials of amphotericin B-based therapy for Cryptococcal Meningitis in Thailand and South Africa. METHODS: Study protocols required four lumbar punctures with measurements of opening pressure over the first 2 weeks of treatment and additional lumbar punctures if opening pressure raised. Fungal burden and clearance, CSF immune parameters, CD4 cell count, neurological symptoms and signs, and outcome at 2 and 10 weeks were compared between groups categorized by opening pressure at Cryptococcal Meningitis diagnosis. RESULTS: Patients with higher baseline fungal burden had higher baseline opening pressure. High fungal burden appeared necessary but not sufficient for development of high pressure. Baseline opening pressure was not associated with CD4 cell count, CSF pro-inflammatory cytokines, or altered mental status. Day 14 opening pressure was associated with day 14 fungal burden. Overall mortality was 12% (20/162) at 2 weeks and 26% (42/160) at 10 weeks, with no significant differences between opening pressure groups. CONCLUSION: Studies are needed to define factors, in addition to fungal burden, associated with raised opening pressure. Aggressive management of raised opening pressure through repeated CSF drainage appeared to prevent any adverse impact of raised opening pressure on outcome in patients with Cryptococcal Meningitis. The results support increasing access to manometers in resource-poor settings and routine management of opening pressure in patients with Cryptococcal Meningitis.

  • lumbar drainage for control of raised cerebrospinal fluid pressure in Cryptococcal Meningitis case report and review
    Journal of Infection, 2005
    Co-Authors: Karen F Macsween, Annemarie E Brouwer, Tihana Bicanic, Henry Marsh, Derek C Macallan, Thomas S. Harrison
    Abstract:

    Raised intracranial pressure in the absence of ventricular dilatation is common in Cryptococcal Meningitis and associated with increased mortality. We report the case of a patient with HIV-associated Cryptococcal Meningitis, who developed increasing CSF pressure and visual impairment on therapy despite serial lumbar punctures. Insertion of a temporary lumbar drain controlled the opening pressure and resulted in full visual recovery. The advantages and necessary precautions with this approach are reviewed, and alternative protocols for the use of lumbar drains discussed.

  • Baseline correlation and comparative kinetics of cerebrospinal fluid colony-forming unit counts and antigen titers in Cryptococcal Meningitis.
    The Journal of Infectious Diseases, 2005
    Co-Authors: Annemarie E Brouwer, Wirongrong Chierakul, Robert A Larsen, Paprit Teparrukkul, Supraphada Pinpraphaporn, Sharon J. Peacock, Nicholas P. J. Day, Nicholas J. White, Thomas S. Harrison
    Abstract:

    Cerebrospinal fluid (CSF) Cryptococcal colony-forming unit counts and CSF Cryptococcal antigen titers serve as alternative measures of organism load in Cryptococcal Meningitis. For these measures, we correlated baseline values and rates of decline during the first 2 weeks of therapy in 68 human immunodeficiency virus--seropositive patients with Cryptococcal Meningitis. At baseline, there was a strong correlation between CSF Cryptococcal colony-forming unit counts and CSF Cryptococcal antigen titers. During the first 2 weeks of therapy, CSF Cryptococcal colony-forming unit counts decreased by >5 logs, and CSF Cryptococcal antigen titers decreased by 1.5 dilutions. In individual patients, there was no correlation between the rate of decline in CSF Cryptococcal colony-forming unit counts and that in CSF Cryptococcal antigen titers.

  • combination antifungal therapies for hiv associated Cryptococcal Meningitis a randomised trial
    The Lancet, 2004
    Co-Authors: Annemarie E Brouwer, Adul Rajanuwong, G E Griffin, Wirongrong Chierakul, Robert A Larsen, Thomas S. Harrison
    Abstract:

    Summary Background It frequently takes more than 2 weeks for drug treatments for Cryptococcal Meningitis to sterilise cerebrospinal fluid (CSF). In-vitro and animal studies lend support to the use of combinations of amphotericin B, flucytosine, and fluconazole for treatment of cryptococcosis. We compared the fungicidal activity of combinations of these drugs for initial treatment of patients with Cryptococcal Meningitis. Methods 64 patients with a first episode of HIV-associated Cryptococcal Meningitis were randomised to initial treatment with: amphotericin B (0·7 mg/kg daily); amphotericin B plus flucytosine (100 mg/kg daily); amphotericin B plus fluconazole (400 mg daily); or triple therapy with amphotericin B, flucytosine, and fluconazole. Our primary endpoint was fungicidal activity, measured by the rate of reduction in CSF Cryptococcal colony-forming units (CFU) from serial quantitative CSF cultures on days 3, 7, and 14 of treatment. Findings Baseline CSF CFU counts were an important prognostic factor. Clearance of cryptococci from the CSF was exponential and was significantly faster with amphotericin B plus flucytosine than with amphotericin B alone (p=0·0006), amphotericin B plus fluconazole ( p=0·02), or triple therapy (p=0·02).