Cryptococcal meningitis: epidemiology, immunology, diagnosis and therapy

• Published in: Nature reviews. Neurology Vol. 13; no. 1; pp. 13 - 24
• Main Authors: Williamson, Peter R., Jarvis, Joseph N., Panackal, Anil A., Fisher, Matthew C., Molloy, Síle F., Loyse, Angela, Harrison, Thomas S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2017; Nature Publishing Group
• Subjects: 692/699/249/1570/1901; 692/699/255/1672; 692/699/375/1367; Acquired immune deficiency syndrome; AIDS; Autoimmune diseases; Care and treatment; Complications and side effects; Cryptococcal meningitis; Development and progression; Diagnosis; Epidemiology; Health aspects; HIV; HIV infections; Human immunodeficiency virus; Humans; Immunocompetence; Infections; Infectious diseases; Medicine & Public Health; Meningitis; Meningitis, Cryptococcal; Neurology; Pathogens; review-article; Steroids; United Kingdom > UK; United States > US; North America; Botswana; Pacific Northwest
• ISSN: 1759-4758; 1759-4766; 1759-4766
• DOI: 10.1038/nrneurol.2016.167

Key Points In most clinical centres in Africa, despite access to antiretroviral therapies, cases of HIV-associated cryptococcal meningitis (CM) are not decreasing owing to challenges with retention and adherence to HIV care CM in HIV-negative individuals is relatively rare, but carries a mortality at least as high as in HIV-associated disease; therefore, CM must be considered in all cases of lymphocytic meningitis — even in the apparently immunocompetent A point-of-care, lateral flow 'dipstick' test to detect cryptococcal antigen in the blood or cerebrospinal fluid (CSF) is a significant advance: it is highly specific, sensitive, and easy to use Amphotericin B (in conventional or liposomal formulation) combined with flucytosine remains the induction therapy of choice, and is associated with a survival advantage over amphotericin B alone Measurement of CSF opening pressure and appropriate management of raised CSF pressure can reduce mortality Any future attempts at adjunctive immunotherapies will need to be closely guided by the specific immune status of the host at the time of any intervention Cryptococcal meningitis is a major cause of morbidity and mortality in immunocompromized individuals, and, even in apparently immunocompetent individuals, carries a high risk of mortality. Treatment in immunocompromized patients is challenging because these patients are at risk of immune reconstitution inflammatory syndrome (IRIS). This Review summarizes the diagnosis and treatment of cryptococcal disease in various disease. 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.