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
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.
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Durski, K. N. et al. Cost-effective diagnostic checklists for meningitis in resource-limited settings. J. Acquir. Immune Defic. Syndr. 63, e101–e108 (2013).
Rajasingham, R. et al. Epidemiology of meningitis in an HIV-infected Ugandan cohort. Am. J. Trop. Med. Hyg. 92, 274–279 (2015).
Jarvis, J. N. et al. Adult meningitis in a setting of high HIV and TB prevalence: findings from 4961 suspected cases. BMC Infect. Dis. 10, 67 (2010).
Zhu, L. P. et al. Cryptococcal meningitis in non-HIV-infected patients in a Chinese tertiary care hospital, 1997–2007. Med. Mycol. 48, 570–579 (2010).
Pyrgos, V. et al. Epidemiology of cryptococcal meningitis in the US: 1997–2009. PLoS ONE 8, e56269 (2013).
Phillips, P. et al. Longitudinal clinical findings and outcome among patients with Cryptococcus gattii infection in British Columbia. Clin. Infect. Dis. 60, 1368–1376 (2015).
May, R. C. et al. Cryptococcus: from environmental saprophyte to global pathogen. Nat. Rev. Microbiol. 14, 106–117 (2016).
Alanio, A. et al. Cryptococcus neoformans host adaptation: toward biological evidence of dormancy. mBio 6, e02580-14 (2015).
Fisher, M. C. et al. Emerging fungal threats to animal, plant and ecosystem health. Nature 484, 186–194 (2012).
Park, B. J. et al. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS 23, 525–530 (2009).
French, N. et al. Cryptococcal infection in a cohort of HIV-1-infected Ugandan adults. AIDS 16, 1031–1038 (2002).
Boulware, D. R. et al. Update on the global burden of disease of HIV-associated cryptococcal meningitis. Oral Abstract presented at: 9th International Conference on Cryptococcus and Cryptococcosis; 2014 May; Amsterdam.
National Institute of Communicable Diseases. RapidGerms South Africa Annual Report 2014. [online] http://www.nicd.ac.za/assets/files/GERMS-SA%20AR%202014.pdf pages 8–11 (2014).
Wall, E. C. et al. Bacterial meningitis in Malawian adults, adolescents, and children during the era of antiretroviral scale-up and Haemophilus influenzae type b vaccination, 2000–2012. Clin. Infect. Dis. 58, e137–e145 (2014).
Tenforde, M. et al. HIV-associated cryptococcal meningitis in Botswana: national incidence and temporal trends following ART rollout. [online] http://www.aids2016.org/Portals/0/File/AIDS2016_Abstracts_LOW.pdf?ver=2016-08-10-154247-087 Abstract presented at: 21st International AIDS Conference; July 2016; Durban.
Beardsley, J. et al. Adjunctive dexamethasone in HIV-associated cryptococcal meningitis. N. Engl. J. Med. 374, 542–554 (2016).
Rhein, J. et al. Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: an open-label dose-ranging study. Lancet Infect. Dis. 16, 809–818 (2016).
Pappas, P. G. et al. Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy. Clin. Infect. Dis. 33, 690–699 (2001).
Bernard, C. et al. Cryptococcosis in sarcoidosis: cryptOsarc, a comparative study of 18 cases. QJM 106, 523–539 (2013).
Jarvis, J. N. et al. Is HIV-associated tuberculosis a risk factor for the development of cryptococcal disease? AIDS 24, 612–614 (2010).
Speed, B. & Dunt, D. Clinical and host differences between infections with the two varieties of Cryptococcus neoformans. Clin. Infect. Dis. 21, 28–34 (1995).
Ahmad, D. S., Esmadi, M. & Steinmann, W. C. Idiopathic CD4 lymphocytopenia: spectrum of opportunistic infections, malignancies, and autoimmune diseases. Avicenna J. Med. 3, 37–47 (2013).
Gorska, M. M. & Alam, R. A mutation in the human Uncoordinated 119 gene impairs TCR signaling and is associated with CD4 lymphopenia. Blood 119, 1399–1406 (2012).
Lee, Y. C., Chew, G. T. & Robinson, B. W. Pulmonary & meningeal cryptococcosis in pulmonary alveolar proteinosis. Aust. N. Z. J. Med. 29, 843–844 (1999).
Rosen, L. B. et al. Anti-GM-CSF autoantibodies in patients with cryptococcal meningitis. J. Immunol. 190, 3959–3966 (2013).
Saijo, T. et al. Anti-granulocyte-macrophage colony-stimulating factor autoantibodies are a risk factor for central nervous system infection by Cryptococcus gattii in otherwise immunocompetent patients. mBio 5, e00912-14 (2014).
Browne, S. K. et al. Adult-onset immunodeficiency in Thailand and Taiwan. N. Engl. J. Med. 367, 725–734 (2012).
Vinh, D. C. et al. Autosomal dominant and sporadic monocytopenia with susceptibility to mycobacteria, fungi, papillomaviruses, and myelodysplasia. Blood 115, 1519–1529 (2010).
Hsu, A. P. et al. Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood 118, 2653–2655 (2011).
Spinner, M. A. et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood 123, 809–821 (2014).
Jacobs, D. H. et al. Esophageal cryptococcosis in a patient with the hyperimmunoglobulin E-recurrent infection (Job's) syndrome. Gastroenterology 87, 201–203 (1984).
Holland, S. M. et al. STAT3 mutations in the hyper-IgE syndrome. N. Engl. J. Med. 357, 1608–1619 (2007).
Winkelstein, J. A. et al. The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine (Baltimore) 82, 373–384 (2003).
Iseki, M. et al. Hyper-IgM immunodeficiency with disseminated cryptococcosis. Acta Paediatr. 83, 780–782 (1994).
Hu, X. P. et al. Association of Fcγ receptor IIB polymorphism with cryptococcal meningitis in HIV-uninfected Chinese patients. PLoS ONE 7, e42439 (2012).
Coelho, C., Bocca, A. L. & Casadevall, A. The tools for virulence of Cryptococcus neoformans. Adv. Appl. Microbiol. 87, 1–41 (2014). This review discusses virulence factors specific to Cryptococcus.
Moodley, A. et al. Early clinical and subclinical visual evoked potential and Humphrey's visual field defects in cryptococcal meningitis. PLoS ONE 7, e52895 (2012).
Jarvis, J. N. et al. Pulmonary cryptococcosis misdiagnosed as smear-negative pulmonary tuberculosis with fatal consequences. Int. J. Infect. Dis. 14 (Suppl. 3), e310–e312 (2010).
Sun, H. Y. et al. Predictors of immune reconstitution syndrome in organ transplant recipients with cryptococcosis: implications for the management of immunosuppression. Clin. Infect. Dis. 60, 36–44 (2015).
Mitchell, D. H. et al. Cryptococcal disease of the CNS in immunocompetent hosts: influence of cryptococcal variety on clinical manifestations and outcome. Clin. Infect. Dis. 20, 611–616 (1995).
Schoffelen, T. et al. Cryptococcus gattii induces a cytokine pattern that is distinct from other cryptococcal species. PLoS ONE 8, e55579 (2013).
Lee, S. C., Dickson, D. W. & Casadevall, A. Pathology of cryptococcal meningoencephalitis: analysis of 27 patients with pathogenetic implications. Hum. Pathol. 27, 839–847 (1996).
Panackal, A. A. et al. Paradoxical immune responses in non-HIV cryptococcal meningitis. PLoS Pathog. 11, e1004884 (2015).
Lee, S. C., Casadevall, A. & Dickson, D. W. Immunohistochemical localization of capsular polysaccharide antigen in the central nervous system cells in cryptococcal meningoencephalitis. Am. J. Pathol. 148, 1267–1274 (1996).
Loyse, A. et al. Neurological, visual, and MRI brain scan findings in 87 South African patients with HIV-associated cryptococcal meningoencephalitis. J. Infect. 70, 668–675 (2015).
Charlier, C. et al. Cryptococcal neuroradiological lesions correlate with severity during cryptococcal meningoencephalitis in HIV-positive patients in the HAART era. PLoS ONE 3, e1950 (2008).
Rothe, C. et al. A prospective longitudinal study of the clinical outcomes from cryptococcal meningitis following treatment induction with 800 mg oral fluconazole in Blantyre, Malawi. PLoS ONE 8, e67311 (2013).
Gaskell, K. M. et al. A prospective study of mortality from cryptococcal meningitis following treatment induction with 1200 mg oral fluconazole in Blantyre, Malawi. PLoS ONE 9, e110285 (2014).
Longley, N. et al. Dose response effect of high-dose fluconazole for HIV-associated cryptococcal meningitis in southwestern Uganda. Clin. Infect. Dis. 47, 1556–1561 (2008).
Loyse, A. et al. Comparison of the early fungicidal activity of high-dose fluconazole, voriconazole, and flucytosine as second-line drugs given in combination with amphotericin B for the treatment of HIV-associated cryptococcal meningitis. Clin. Infect. Dis. 54, 121–128 (2012).
Bicanic, T. et al. High-dose amphotericin B with flucytosine for the treatment of cryptococcal meningitis in HIV-infected patients: a randomized trial. Clin. Infect. Dis. 47, 123–130 (2008).
Jarvis, J. N. et al. Adjunctive interferon-γ immunotherapy for the treatment of HIV-associated cryptococcal meningitis: a randomized controlled trial. AIDS 26, 1105–1113 (2012).
Dromer, F. et al. Determinants of disease presentation and outcome during cryptococcosis: the CryptoA/D study. PLoS Med. 4, e21 (2007).
Lortholary, O. et al. Long-term outcome of AIDS-associated cryptococcosis in the era of combination antiretroviral therapy. AIDS 20, 2183–2191 (2006).
Robinson, P. A. et al. Early mycological treatment failure in AIDS-associated cryptococcal meningitis. Clin. Infect. Dis. 28, 82–92 (1999).
Brizendine, K. D., Baddley, J. W. & Pappas, J. W. Predictors of mortality and differences in clinical features among patients with Cryptococcosis according to immune status. PLoS ONE 8, e60431 (2013).
Panackal, A. A. et al. Fighting the monster: applying the host damage framework to human central nervous system infections. mBio 7, e01906-15 (2016).
Chen, S. C. et al. Clinical manifestations of Cryptococcus gattii infection: determinants of neurological sequelae and death. Clin. Infect. Dis. 55, 789–798 (2012).
Steele, K. T. et al. In-hospital mortality of HIV-infected cryptococcal meningitis patients with C. gattii and C. neoformans infection in Gaborone, Botswana. Med. Mycol. 48, 1112–1115 (2010).
Jarvis, J. N. et al. Determinants of mortality in a combined cohort of 501 patients with HIV-associated cryptococcal meningitis: implications for improving outcomes. Clin. Infect. Dis. 58, 736–745 (2014).
Bicanic, T. et al. Independent association between rate of clearance of infection and clinical outcome of HIV-associated cryptococcal meningitis: analysis of a combined cohort of 262 patients. Clin. Infect. Dis. 49, 702–709 (2009).
Diamond, R. D. & Bennett, J. E. Prognostic factors in cryptococcal meningitis: a study in 111 cases. Ann. Intern. Med. 80, 176–181 (1974).
Dismukes, W. E. et al. Treatment of cryptococcal meningitis with combination amphotericin B and flucytosine for four as compared with six weeks. N. Engl. J. Med. 317, 334–341 (1987).
Jarvis, J. N. et al. The phenotype of the Cryptococcus-specific CD4+ memory T-cell response is associated with disease severity and outcome in HIV-associated cryptococcal meningitis. J. Infect. Dis. 207, 1817–1828 (2013).
Jarvis, J. N. et al. Cerebrospinal fluid cytokine profiles predict risk of early mortality and immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis. PLoS Pathog. 11, e1004754 (2015).
Siddiqui, A. A. et al. IFN-γ at the site of infection determines rate of clearance of infection in cryptococcal meningitis. J. Immunol. 174, 1746–1750 (2005).
Scriven, J. E. et al. A glucuronoxylomannan-associated immune signature, characterized by monocyte deactivation and an increased interleukin 10 level, is a predictor of death in cryptococcal meningitis. J. Infect. Dis. 213, 1725–1734 (2016).
Peeling, R. W. et al. Rapid tests for sexually transmitted infections (STIs): the way forward. Sex. Transm. Infect. 82 (Suppl. 5). v1–v6 (2006).
Jarvis, J. N. et al. Evaluation of a novel point-of-care cryptococcal antigen test on serum, plasma, and urine from patients with HIV-associated cryptococcal meningitis. Clin. Infect. Dis. 53, 1019–1023 (2011).
Percival, A., Thorkildson, P. & Kozel, T. R. Monoclonal antibodies specific for immunorecessive epitopes of glucuronoxylomannan, the major capsular polysaccharide of Cryptococcus neoformans, reduce serotype bias in an immunoassay for cryptococcal antigen. Clin. Vaccine Immunol. 18, 1292–1296 (2011).
Williams, D. A. et al. Evaluation of fingerstick cryptococcal antigen lateral flow assay in HIV-infected persons: a diagnostic accuracy study. Clin. Infect. Dis. 61, 464–467 (2015).
Tenforde, M. W. et al. Poor specificity of urinary cryptococcal antigen testing: Reply to Drain et al. Prevalence of cryptococcal antigenuria at initial HIV diagnosis in KwaZulu-Natal. HIV Med. http://dx.doi.org/10.1111/hiv.12319 (2015).
Longley, N. et al. Cryptococcal antigen screening in patients initiating ART in South Africa: a prospective cohort study. Clin. Infect. Dis. 62, 581–587 (2016).
Berlin, L. & Pincus, J. H. Cryptococcal meningitis. False-negative antigen test results and cultures in nonimmunosuppressed patients. Arch. Neurol. 46, 1312–1316 (1989).
Jitmuang, A. et al. Performance of the cryptococcal antigen lateral flow assay in non-HIV-related cryptococcosis. J. Clin. Microbiol. 54, 460–463 (2016).
Tintelnot, K. et al. Pitfalls in serological diagnosis of Cryptococcus gattii infections. Med. Mycol. 53, 874–879 (2015).
World Health Organization. Rapid Advice: Diagnosis, Prevention and Management of Cryptococcal Disease in HIV-Infected Adults, Adolescents and Children. http://apps.who.int/iris/bitstream/10665/44786/1/9789241502979_eng.pdf (2011)
Perfect, J. R. et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin. Infect. Dis. 50, 291–322 (2010).
Govender, N. P. et al. Guideline for the prevention, diagnosis and management of cryptococcal meningitis among HIV-infected persons: 2013 update. South Afr. J. HIV Med. 14, 76–86 (2013).
van der Horst, C. M. et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. N. Engl. J. Med. 337, 15–21 (1997).
Brouwer, A. E. et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet 363, 1764–1767 (2004).
Day, J. N. et al. Combination antifungal therapy for cryptococcal meningitis. N. Engl. J. Med. 368, 1291–1302 (2013).
Loyse, A. et al. Flucytosine and cryptococcosis: time to urgently address the worldwide accessibility of a 50-year-old antifungal. J. Antimicrob. Chemother. 68, 2435–2444 (2013).
Bicanic, T. et al. Toxicity of amphotericin B deoxycholate-based induction therapy in patients with HIV-associated cryptococcal meningitis. Antimicrob. Agents Chemother. 59, 7224–7231 (2015).
Brouwer, A. E. et al. Oral versus intravenous flucytosine in patients with human immunodeficiency virus-associated cryptococcal meningitis. Antimicrob. Agents Chemother. 51, 1038–1042 (2007).
Girmenia, C. et al. Effects of hydration with salt repletion on renal toxicity of conventional amphotericin B empirical therapy: a prospective study in patients with hematological malignancies. Support. Care Cancer 13, 987–992 (2005).
Thakur, C. P. et al. Improving outcome of treatment of kala-azar by supplementation of amphotericin B with physiologic saline and potassium chloride. Am. J. Trop. Med. Hyg. 83, 1040–1043 (2010).
Hamill, R. J. et al. Comparison of 2 doses of liposomal amphotericin B and conventional amphotericin B deoxycholate for treatment of AIDS-associated acute cryptococcal meningitis: a randomized, double-blind clinical trial of efficacy and safety. Clin. Infect. Dis. 51, 225–232 (2010).
Molefi, M. et al. AMBITION-cm: intermittent high dose AmBisome on a high dose fluconazole backbone for cryptococcal meningitis induction therapy in sub-Saharan Africa: study protocol for a randomized controlled trial. Trials 16, 276 (2015).
Nussbaum, J. C. et al. Combination flucytosine and high-dose fluconazole compared with fluconazole monotherapy for the treatment of cryptococcal meningitis: a randomized trial in Malawi. Clin. Infect. Dis. 50, 338–344 (2009).
Jackson, A. et al. A phase II randomised controlled trial adding oral flucytosine to high dose fluconazole, with short-course amphotericin B, for cryptococcal meningitis in Malawi. AIDS 26, 1363–1370 (2012).
Muzoora, C. K. et al. Short course amphotericin B with high dose fluconazole for HIV-associated cryptococcal meningitis. J. Infect. 64, 76–81 (2011).
Livermore, J. et al. Efficacy of an abbreviated induction regimen of amphotericin B deoxycholate for cryptococcal meningoencephalitis: 3 days of therapy is equivalent to 14 days. mBio 5, e00725-13 (2013).
ISRCTN registry. ISRCTN.com [online] http://www.isrctn.com/ISRCTN45035509, (2015).
US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01802385 (2016).
Butts, A. et al. Estrogen receptor antagonists are anti-cryptococcal agents that directly bind EF hand proteins and synergize with fluconazole in vivo. mBio 5, e00765-13 (2014).
Chen, S. C. et al. Antifungal therapy and management of complications of cryptococcosis due to Cryptococcus gattii. Clin. Infect. Dis. 57, 543–551 (2013).
Singh, N. How I treat cryptococcosis in organ transplant recipients. Transplantation 93, 17–21 (2012).
Kontoyiannis, D. P. et al. Calcineurin inhibitor agents interact synergistically with antifungal agents in vitro against Cryptococcus neoformans isolates: correlation with outcome in solid organ transplant recipients with cryptococcosis. Antimicrob. Agents Chemother. 52, 735–738 (2008).
Graybill, J. R. et al. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. Clin. Infect. Dis. 30, 47–54 (2000).
Loyse, A. et al. Histopathology of the arachnoid granulations and brain in HIV-associated cryptococcal meningitis: correlation with cerebrospinal fluid pressure. AIDS 24, 405–410 (2010).
Bicanic, T. et al. Relationship of cerebrospinal fluid pressure, fungal burden and outcome in patients with cryptococcal meningitis undergoing serial lumbar punctures. AIDS 23, 701–706 (2009).
Shoham, S. et al. Cryptococcus neoformans meningitis at hospitals in Washington, D. C.: adherence of health care providers to published practice guidelines for the management of cryptococcal disease. Clin. Infect. Dis. 40, 477–479 (2005).
Rolfes, M. A. et al. The effect of therapeutic lumbar punctures on acute mortality from cryptococcal meningitis. Clin. Infect. Dis. 59, 1607–1614 (2014).
Macsween, K. F. et al. Lumbar drainage for control of raised cerebrospinal fluid pressure in cryptococcal meningitis: case report and review. J. Infect. 51, e221–e224 (2005).
Manosuthi, W. et al. Temporary external lumbar drainage for reducing elevated intracranial pressure in HIV-infected patients with cryptococcal meningitis. Int. J. STD AIDS 19, 268–271 (2008).
Park, M. K., Hospenthal, D. R. & Bennett, J. E. Treatment of hydrocephalus secondary to cryptococcal meningitis by use of shunting. Clin. Infect. Dis. 28, 629–633 (1999).
Haddow, L. J. et al. Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions. Lancet Infect. Dis. 10, 791–802 (2010).
Bicanic, T. et al. Immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis: a prospective study. J. Acquir. Immune Defic. Syndr. 51, 130–134 (2009).
Boulware, D. R. et al. Clinical features and serum biomarkers in HIV immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study. PLoS Med. 7, e1000384 (2010).
Muller, M. et al. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect. Dis. 10, 251–261 (2010).
Longley, N., Harrison, T. S. & Jarvis, J. N. Cryptococcal immune reconstitution inflammatory syndrome. Curr. Opin. Infect. Dis. 26, 26–34 (2013).
Boulware, D. R. et al. Paucity of initial cerebrospinal fluid inflammation in cryptococcal meningitis is associated with subsequent immune reconstitution inflammatory syndrome. J. Infect. Dis. 202, 962–970 (2010).
Chang, C. C. et al. Cryptococcosis-IRIS is associated with lower cryptococcus-specific IFN-γ responses before antiretroviral therapy but not higher T-cell responses during therapy. J. Infect. Dis. 208, 898–906 (2013).
Chang, C. C. et al. Chemokine levels and chemokine receptor expression in the blood and the cerebrospinal fluid of HIV-infected patients with cryptococcal meningitis and cryptococcosis-associated immune reconstitution inflammatory syndrome. J. Infect. Dis. 208, 1604–1612 (2013).
Worsley, C. M. et al. Multi-analyte profiling of ten cytokines in South African HIV-infected patients with immune reconstitution inflammatory syndrome (IRIS). AIDS Res. Ther. 7, 36 (2010).
Meya, D. B. et al. Cellular immune activation in cerebrospinal fluid from Ugandans with cryptococcal meningitis and immune reconstitution inflammatory syndrome. J. Infect. Dis. 211, 1597–1606 (2015).
Makadzange, A. T. et al. Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-saharan Africa. Clin. Infect. Dis. 50, 1532–1538 (2010).
Boulware, D. R. et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N. Engl. J. Med. 370, 2487–2498 (2014).
Zolopa, A. et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS ONE 4, e5575 (2009).
Scriven, J. E. et al. Early ART after cryptococcal meningitis is associated with cerebrospinal fluid pleocytosis and macrophage activation in a multisite randomized trial. J. Infect. Dis. 212, 769–778 (2015).
Scemla, A. et al. Dramatic improvement of severe cryptococcosis-induced immune reconstitution syndrome with adalimumab in a renal transplant recipient. Am. J. Transplant. 15, 560–564 (2015).
Brunel, A. S. et al. Thalidomide for steroid-dependent immune reconstitution inflammatory syndromes during AIDS. AIDS 26, 2110–2112 (2012).
Jarvis, J. N., Meintjes, G. & Harrison, T. S. Outcomes of cryptococcal meningitis in antiretroviral naive and experienced patients in South Africa. J. Infect. 60, 496–498 (2010).
Hardison, S. E. et al. Pulmonary infection with an interferon-gamma-producing Cryptococcus neoformans strain results in classical macrophage activation and protection. Am. J. Pathol. 176, 774–785 (2010).
Phillips, P. et al. Dexamethasone in Cryptococcus gattii central nervous system infection. Clin. Infect. Dis. 49, 591–595 (2009).
Casadevall, A. & Pirofski, L. A. The damage-response framework of microbial pathogenesis. Nat. Rev. Microbiol. 1, 17–24 (2003).
Tazawa, R. et al. Inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis. Am. J. Respir. Crit. Care Med. 181, 1345–1354 (2010).
Tazawa, R. et al. Duration of benefit in patients with autoimmune pulmonary alveolar proteinosis after inhaled granulocyte-macrophage colony-stimulating factor therapy. Chest 145, 729–737 (2014).
Pappas, P. G. et al. Recombinant interferon-γ1b as adjunctive therapy for AIDS-related acute cryptococcal meningitis. J. Infect. Dis. 189, 2185–2191 (2004).
Jarvis, J. N. et al. Screening for cryptococcal antigenemia in patients accessing an antiretroviral treatment program in South Africa. Clin. Infect. Dis. 48, 856–862 (2009).
Jarvis, J. N. et al. Cost effectiveness of cryptococcal antigen screening as a strategy to prevent HIV-associated cryptococcal meningitis in South Africa. PLoS ONE 8, e69288 (2013).
Meya, D. B. et al. Cost-effectiveness of serum cryptococcal antigen screening to prevent deaths among HIV-infected persons with a CD4+ cell count < or = 100 cells/microL who start HIV therapy in resource-limited settings. Clin. Infect. Dis. 51, 448–455 (2010).
Govender, N. P. et al. Phased implementation of screening for cryptococcal disease in South Africa. S. Afr. Med. J. 102, 914–917 (2012).
Mfinanga, S. et al. Cryptococcal meningitis screening and community-based early adherence support in people with advanced HIV infection starting antiretroviral therapy in Tanzania and Zambia: an open-label, randomised controlled trial. Lancet 385, 2173–2182 (2015).
Morawski, B. M. et al. Pre-ART cryptococcal antigen titer associated with preemptive fluconazole failure. [online] http://www.croiconference.org/sessions/pre-art-cryptococcal-antigen-titer-associated-preemptive-fluconazole-failure Abstract presented at: CROI; February 2016; Boston.
Loyse, A. et al. Cryptococcal meningitis: improving access to essential antifungal medicines in resource-poor countries. Lancet Infect. Dis. 13, 629–637 (2013).
Kuris, A. M., Lafferty, K. D. & Sokolow, S. H. Sapronosis: a distinctive type of infectious agent. Trends Parasitol. 30, 386–393 (2014).
Casadevall, A. Evolution of intracellular pathogens. Annu. Rev. Microbiol. 62, 19–33 (2008).
McDonald, T., Wiesner, D. L. & Nielsen, K. Cryptococcus. Curr. Biol. 22, R554–R555 (2012).
Casadevall, A., Steenbergen, J. N. & Nosanchuk, J. D. 'Ready made' virulence and 'dual use' virulence factors in pathogenic environmental fungi — the Cryptococcus neoformans paradigm. Curr. Opin. Microbiol. 6, 332–337 (2003).
Zaragoza, O. et al. The capsule of the fungal pathogen Cryptococcus neoformans. Adv. Appl. Microbiol. 68, 133–216 (2009).
Xu, J. Fundamentals of fungal molecular population genetic analyses. Curr. Issues Mol. Biol. 8, 75–89 (2006).
Hagen, F. et al. Recognition of seven species in the Cryptococcus gattii/Cryptococcus neoformans species complex. Fungal Genet. Biol. 78, 16–48 (2015).
Farrer, R. A. et al. Genome evolution and innovation across the four major lineages of Cryptococcus gattii. mBio 6, e00868-15 (2015).
Engelthaler, D. M. et al. Cryptococcus gattii in North American Pacific Northwest: whole-population genome analysis provides insights into species evolution and dispersal. mBio 5, e01464–14 (2014).
P.W. has a CRADA (cooperative research and development agreement) with Matinas BioPharma regarding an oral amphotericin formulation. J.J. has received an Investigator Award (to institution) from Gilead Sciences. T.H. has received an Investigator Award (to institution) from Gilead Sciences and has received a donation of cryptococcosis test kits for research purposes from Immuno-Mycologics, received honoraria from Pfizer, and is on the advisory board for Viamet.
- Idiopathic CD4+ lymphopenia
Repeated presence of a CD4+ T lymphocyte count of <300 cells/ml without a predisposing cause.
- Hyperimmunoglobulin E recurrent infection syndrome
This syndrome, also known as Job syndrome, is caused by mutations in the signal transducer and activator of transcription (STAT3). Patients typically have eosinophilia, eczema, and recurrent skin and pulmonary infections.
- Colony forming unit
A measure to quantify viable fungal cells on the basis of the cells' ability to grow to form visible colonies on an agar plate.
- Rate of infection clearance
The rate of decrease in viable organisms in the cerebrospinal fluid (CSF) during treatment, derived from quantitative cultures of the CSF obtained from serial lumbar punctures done over the first 14 days of treatment. For a particular drug regimen, the early fungicidal activity is the mean rate of infection clearance for patients on that regimen.
- ASSURED criteria
Originally developed by the WHO Sexually Transmitted Diseases Diagnostics Initiative as a benchmark to determine whether new diagnostic tests addressed the needs of their disease control programmes in resource-limited settings: the ASSURED criteria include the test being affordable, sensitive, specific, user-friendly, rapid and robust, equipment-free, and deliverable to end-users.
- Paradoxical IRIS
Clinical deterioration in HIV-positive patients with cryptococcal meningitis who have responded to initial antifungal therapy, but then relapse after starting antiretroviral therapy owing to the resultant immune restoration and enhanced inflammatory immune response to residual cryptococcal antigens.
- Unmasking IRIS
Individuals with HIV infection can present for the first time with cryptococcal meningitis after effective antiretroviral therapy (ART) has been initiated. These patients may have a mixture of active infection and immune-mediated pathology as a result of ART-mediated immune restoration.
- Macrophage–T-cell dissociation
Despite appropriate T-cell signalling, macrophages fail to become classically activated and clear infection but rather remain in an alternatively activated state that is less effective at controlling infection and clearing antigen.
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Williamson, P., Jarvis, J., Panackal, A. et al. Cryptococcal meningitis: epidemiology, immunology, diagnosis and therapy. Nat Rev Neurol 13, 13–24 (2017). https://doi.org/10.1038/nrneurol.2016.167
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