Cerebral Fungal Infection in Pediatric Cancer Patients
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Abstract
Invasive fungal disease (IFD) significantly contributes to morbidity and mortality in pediatric cancer patients, especially in those with acute leukemia and allogeneic hematopoietic stem cell transplantation. Cerebral fungal infections are a particular severe form of IFD, as they are difficult to diagnose and require aggressive treatment, and cure rates are still unacceptably low. Here, we review the current data on epidemiology, diagnosis, and the management of cerebral fungal infection in pediatric cancer patients and outline important questions which have to be addressed by further research.
Keywords
Invasive fungal infection Central nervous system Cancer Child Hematopoietic stem cell transplantationNotes
Compliance with Ethics Guidelines
Conflict of Interest
Angela Haßler and Luciana Porto have no disclosures. Thomas Lehrnbecher served in the speaker’s bureau of Astellas, Gilead Sciences, GlaxoSmithKline, Merck/MSD, and Pfizer; he also received a research grant from Gilead Sciences and is a consultant to Astellas, Gilead Sciences, and Merck/MSD.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
References
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- 1.Nieves DJ, Antonio C. Recent studies on invasive fungal diseases in children and adolescents: an update. Curr Fungal Infect Rep. 2014;8:56–66.CrossRefGoogle Scholar
- 2.Benjamin Jr DK, Miller WC, Bayliff S, et al. Infections diagnosed in the first year after pediatric stem cell transplantation. Pediatr Infect Dis J. 2002;21:227–34.CrossRefPubMedGoogle Scholar
- 3.Castagnola E, Rossi MR, Cesaro S, et al. Incidence of bacteremias and invasive mycoses in children with acute non-lymphoblastic leukemia: results from a multi-center Italian study. Pediatr Blood Cancer. 2010;55:1103–7.CrossRefPubMedGoogle Scholar
- 4.Groll AH, Kurz M, Schneider W, et al. Five-year-survey of invasive aspergillosis in a paediatric cancer centre. Epidemiology, management and long-term survival. Mycoses. 1999;42:431–42.CrossRefPubMedGoogle Scholar
- 5.Hale KA, Shaw PJ, Dalla-Pozza L, et al. Epidemiology of paediatric invasive fungal infections and a case-control study of risk factors in acute leukaemia or post stem cell transplant. Br J Haematol. 2010;149:263–72.CrossRefPubMedGoogle Scholar
- 6.Hovi L, Saarinen-Pihkala UM, Vettenranta K, et al. Invasive fungal infections in pediatric bone marrow transplant recipients: single center experience of 10 years. Bone Marrow Transplant. 2000;26:999–1004.CrossRefPubMedGoogle Scholar
- 7.Kaya Z, Gursel T, Kocak U, et al. Invasive fungal infections in pediatric leukemia patients receiving fluconazole prophylaxis. Pediatr Blood Cancer. 2009;52:470–5.CrossRefPubMedGoogle Scholar
- 8.Kobayashi R, Kaneda M, Sato T, et al. The clinical feature of invasive fungal infection in pediatric patients with hematologic and malignant diseases: a 10-year analysis at a single institution at Japan. J Pediatr Hematol Oncol. 2008;30:886–90.CrossRefPubMedGoogle Scholar
- 9.Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis. 2001;32:358–66.CrossRefPubMedGoogle Scholar
- 10.Mor M, Gilad G, Kornreich L, et al. Invasive fungal infections in pediatric oncology. Pediatr Blood Cancer. 2011;56:1092–7.CrossRefPubMedGoogle Scholar
- 11.Rosen GP, Nielsen K, Glenn S, et al. Invasive fungal infections in pediatric oncology patients: 11-year experience at a single institution. J Pediatr Hematol Oncol. 2005;27:135–40.CrossRefPubMedGoogle Scholar
- 12.Zaoutis TE, Argon J, Chu J, et al. The epidemiology and attributable outcomes of candidemia in adults and children hospitalized in the United States: a propensity analysis. Clin Infect Dis. 2005;41:1232–9.CrossRefPubMedGoogle Scholar
- 13.Besnard M, Hartmann O, Valteau-Couanet D, et al. Systemic Candida infection in pediatric BM autotransplantation: clinical signs, outcome and prognosis. Bone Marrow Transplant. 1993;11:465–70.PubMedGoogle Scholar
- 14.Dvorak CC, Steinbach WJ, Brown JM, et al. Risks and outcomes of invasive fungal infections in pediatric patients undergoing allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2005;36:621–9.CrossRefPubMedGoogle Scholar
- 15.Flynn PM, Marina NM, Rivera GK, et al. Candida tropicalis infections in children with leukemia. Leuk Lymphoma. 1993;10:369–76.CrossRefPubMedGoogle Scholar
- 16.Vogiatzi L, Ilia S, Sideri G, et al. Invasive candidiasis in pediatric intensive care in Greece: a nationwide study. Intensive Care Med. 2013;39:2188–95.CrossRefPubMedGoogle Scholar
- 17.Dehority W, Willert J, Pong A. Zygomycetes infections in pediatric hematology oncology patients: a case series and review of the literature. J Pediatr Hematol Oncol. 2009;31:911–9.CrossRefPubMedGoogle Scholar
- 18.Zaoutis TE, Greves HM, Lautenbach E, et al. Risk factors for disseminated candidiasis in children with candidemia. Pediatr Infect Dis J. 2004;23:635–41.CrossRefPubMedGoogle Scholar
- 19.Castagnola E, Faraci M, Moroni C, et al. Invasive mycoses in children receiving hemopoietic SCT. Bone Marrow Transplant. 2008;41 Suppl 2:S107–11.CrossRefPubMedGoogle Scholar
- 20.MacDonald L, Baker C, Chenoweth C. Risk factors for candidemia in a children’s hospital. Clin Infect Dis. 1998;26:642–5.CrossRefPubMedGoogle Scholar
- 21.Mahul P, Piens MA, Guyotat D, et al. Disseminated Geotrichum capitatum infection in a patient with acute myeloid leukemia. Mycoses. 1989;32:573–7.CrossRefPubMedGoogle Scholar
- 22.Menezes EA, Marinho JA, Angelo MR, et al. Isolation and antifungal susceptibility testing of Trichosporon asahii in Ceara, Brazil. Rev Inst Med Trop Sao Paulo. 2012;54:1–3.CrossRefPubMedGoogle Scholar
- 23.Severo CB, Xavier MO, Gazzoni AF, et al. Cryptococcosis in children. Paediatr Respir Rev. 2009;10:166–71.CrossRefPubMedGoogle Scholar
- 24.Zaoutis TE, Heydon K, Chu JH, et al. Epidemiology, outcomes, and costs of invasive aspergillosis in immunocompromised children in the United States, 2000. Pediatrics. 2006;117:e711–6.CrossRefPubMedGoogle Scholar
- 25.Abbasi S, Shenep JL, Hughes WT, et al. Aspergillosis in children with cancer: a 34-year experience. Clin Infect Dis. 1999;29:1210–9.CrossRefPubMedGoogle Scholar
- 26.Denning DW. Invasive aspergillosis. Clin Infect Dis. 1998;26:781–803. quiz 804–5.CrossRefPubMedGoogle Scholar
- 27.Dotis J, Iosifidis E, Roilides E. Central nervous system aspergillosis in children: a systematic review of reported cases. Int J Infect Dis. 2007;11:381–93.CrossRefPubMedGoogle Scholar
- 28.Kourkoumpetis TK, Desalermos A, Muhammed M, et al. Central nervous system aspergillosis: a series of 14 cases from a general hospital and review of 123 cases from the literature. Medicine (Baltimore). 2012;91:328–36.CrossRefGoogle Scholar
- 29.Odio CM, Navarrete M, Carrillo JM, et al. Disseminated histoplasmosis in infants. Pediatr Infect Dis J. 1999;18:1065–8.CrossRefPubMedGoogle Scholar
- 30.Fischer GB, Mocelin H, Severo CB, et al. Histoplasmosis in children. Paediatr Respir Rev. 2009;10:172–7.CrossRefPubMedGoogle Scholar
- 31.Bariola JR, Perry P, Pappas PG, et al. Blastomycosis of the central nervous system: a multicenter review of diagnosis and treatment in the modern era. Clin Infect Dis. 2010;50:797–804.CrossRefPubMedGoogle Scholar
- 32.Drake KW, Adam RD. Coccidioidal meningitis and brain abscesses: analysis of 71 cases at a referral center. Neurology. 2009;73:1780–6.CrossRefPubMedGoogle Scholar
- 33.Fanella S, Skinner S, Trepman E, et al. Blastomycosis in children and adolescents: a 30-year experience from Manitoba. Med Mycol. 2011;49:627–32.PubMedGoogle Scholar
- 34.Fisher BT, Chiller TM, Prasad PA, et al. Hospitalizations for coccidioidomycosis at 41 children’s hospitals in the United States. Pediatr Infect Dis J. 2010;29:243–7.CrossRefPubMedGoogle Scholar
- 35.Karageorgopoulos DE, Vouloumanou EK, Ntziora F, et al. Beta-D-glucan assay for the diagnosis of invasive fungal infections: a meta-analysis. Clin Infect Dis. 2011;52:750–70.CrossRefPubMedGoogle Scholar
- 36.Zaoutis TE, Roilides E, Chiou CC, et al. Zygomycosis in children: a systematic review and analysis of reported cases. Pediatr Infect Dis J. 2007;26:723–7.CrossRefPubMedGoogle Scholar
- 37.Raman Sharma R. Fungal infections of the nervous system: current perspective and controversies in management. Int J Surg. 2010;8:591–601.CrossRefPubMedGoogle Scholar
- 38.Gamaletsou MN, Sipsas NV, Roilides E, et al. Rhino-orbital-cerebral mucormycosis. Curr Infect Dis Rep. 2012;14:423–34.CrossRefPubMedGoogle Scholar
- 39.Sanchez-Portocarrero J, Perez-Cecilia E, Corral O, et al. The central nervous system and infection by Candida species. Diagn Microbiol Infect Dis. 2000;37:169–79.CrossRefPubMedGoogle Scholar
- 40.Walsh TJ, Hier DB, Caplan LR. Fungal infections of the central nervous system: comparative analysis of risk factors and clinical signs in 57 patients. Neurology. 1985;35:1654–7.CrossRefPubMedGoogle Scholar
- 41.••Groll AH, Schrey D, Tragiannidis A, et al. Invasive aspergillosis in children and adolescents. Curr Pharm Des. 2013;19:3545–68. This is a recent comprehensive review on invasive aspergillosis which focuses on pediatric patients.CrossRefPubMedGoogle Scholar
- 42.McCullers JA, Vargas SL, Flynn PM, et al. Candidal meningitis in children with cancer. Clin Infect Dis. 2000;31:451–7.CrossRefPubMedGoogle Scholar
- 43.Blyth CC, Palasanthiran P, O’Brien TA. Antifungal therapy in children with invasive fungal infections: a systematic review. Pediatrics. 2007;119:772–84.CrossRefPubMedGoogle Scholar
- 44.••Lehrnbecher T, Phillips R, Alexander S, et al. Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation. J Clin Oncol. 2012;30:4427–38. These are first international guidelines on the management of fever and neutropenia in pediatric cancer patients.CrossRefPubMedGoogle Scholar
- 45.Pollack E, Bhaya A, Law M. Differentiating intracranial aspergillosis from a high grade glioma using MRI and MR spectroscopic imaging. J Neuroimaging. 2007;17:361–6.CrossRefPubMedGoogle Scholar
- 46.Ashdown BC, Tien RD, Felsberg GJ. Aspergillosis of the brain and paranasal sinuses in immunocompromised patients: CT and MR imaging findings. AJR Am J Roentgenol. 1994;162:155–9.CrossRefPubMedGoogle Scholar
- 47.Nickerson JP, Richner B, Santy K, et al. Neuroimaging of pediatric intracranial infection—part 2: TORCH, viral, fungal, and parasitic infections. J Neuroimaging. 2012;22:e52–63.CrossRefPubMedGoogle Scholar
- 48.Lindsley MD. The future of fungal serology. Curr Fungal Infect Rep 2013;in press.Google Scholar
- 49.••Groll AH, Castagnola E, Cesaro S, et al. Fourth European Conference on Infections in Leukaemia (ECIL-4): guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or allogeneic haemopoietic stem-cell transplantation. Lancet Oncol. 2014;15:e327–40. These are the first international guidelines for the prevention and management of invasive fungal diseases in pediatric cancer patients.CrossRefPubMedGoogle Scholar
- 50.De Pauw B, Walsh TJ, Donnelly JP, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008;46:1813–21.CrossRefPubMedCentralPubMedGoogle Scholar
- 51.Marr KA, Laverdiere M, Gugel A, et al. Antifungal therapy decreases sensitivity of the Aspergillus galactomannan enzyme immunoassay. Clin Infect Dis. 2005;40:1762–9.CrossRefPubMedGoogle Scholar
- 52.Roilides E, Pavlidou E, Papadopoulos F, et al. Cerebral aspergillosis in an infant with corticosteroid-resistant nephrotic syndrome. Pediatr Nephrol. 2003;18:450–3.PubMedGoogle Scholar
- 53.Viscoli C, Machetti M, Gazzola P, et al. Aspergillus galactomannan antigen in the cerebrospinal fluid of bone marrow transplant recipients with probable cerebral aspergillosis. J Clin Microbiol. 2002;40:1496–9.CrossRefPubMedCentralPubMedGoogle Scholar
- 54.Oz Y, Kiraz N. Diagnostic methods for fungal infections in pediatric patients: microbiological, serological and molecular methods. Expert Rev Anti Infect Ther. 2011;9:289–98.CrossRefPubMedGoogle Scholar
- 55.Mikulska M, Furfaro E, Del Bono V, et al. (1-3)-beta-D-glucan in cerebrospinal fluid is useful for the diagnosis of central nervous system fungal infections. Clin Infect Dis. 2013;56:1511–2.CrossRefPubMedGoogle Scholar
- 56.Smith PB, Benjamin Jr DK, Alexander BD, et al. Quantification of 1,3-beta-D-glucan levels in children: preliminary data for diagnostic use of the beta-glucan assay in a pediatric setting. Clin Vaccine Immunol. 2007;14:924–5.CrossRefPubMedCentralPubMedGoogle Scholar
- 57.Hummel M, Spiess B, Kentouche K, et al. Detection of Aspergillus DNA in cerebrospinal fluid from patients with cerebral aspergillosis by a nested PCR assay. J Clin Microbiol. 2006;44:3989–93.CrossRefPubMedCentralPubMedGoogle Scholar
- 58.Skladny H, Buchheidt D, Baust C, et al. Specific detection of Aspergillus species in blood and bronchoalveolar lavage samples of immunocompromised patients by two-step PCR. J Clin Microbiol. 1999;37:3865–71.PubMedCentralPubMedGoogle Scholar
- 59.Landlinger C, Preuner S, Baskova L, et al. Diagnosis of invasive fungal infections by a real-time panfungal PCR assay in immunocompromised pediatric patients. Leukemia. 2010;24:2032–8.CrossRefPubMedGoogle Scholar
- 60.Cesaro S, Stenghele C, Calore E, et al. Assessment of the lightcycler PCR assay for diagnosis of invasive aspergillosis in paediatric patients with onco-haematological diseases. Mycoses. 2008;51:497–504.CrossRefPubMedGoogle Scholar
- 61.•Reinwald M, Buchheidt D, Hummel M, et al. Diagnostic performance of an Aspergillus-specific nested PCR assay in cerebrospinal fluid samples of immunocompromised patients for detection of central nervous system aspergillosis. PLoS One. 2013;8:e56706. This is an important study on PCR-based Aspergillus detection in cerebrospinal fluid samples. The study includes a large number of patients, and the results may have an important impact on the diagnostic procedure in suspected IFD affecting the CNS.CrossRefPubMedCentralPubMedGoogle Scholar
- 62.Dornbusch HJ, Groll A, Walsh TJ. Diagnosis of invasive fungal infections in immunocompromised children. Clin Microbiol Infect. 2010;16:1328–34.CrossRefPubMedGoogle Scholar
- 63.••Vermeulen E, Lagrou K, Verweij PE. Azole resistance in Aspergillus fumigatus: a growing public health concern. Curr Opin Infect Dis. 2013;26:493–500. This is a key review on the emergence of azole resistance in Aspergillus fumigatus which has important implications for future prevention and treatment strategies of invasive aspergillosis.CrossRefPubMedGoogle Scholar
- 64.Sorensen J, Becker M, Porto L, et al. Rhinocerebral zygomycosis in a young girl undergoing allogeneic stem cell transplantation for severe aplastic anaemia. Mycoses. 2006;49 Suppl 1:31–6.CrossRefPubMedGoogle Scholar
- 65.Lescar J, Meyer I, Akshita K, et al. Aspergillus fumigatus harbouring the sole Y121F mutation shows decreased susceptibility to voriconazole but maintained susceptibility to itraconazole and posaconazole. J Antimicrob Chemother 2014.Google Scholar
- 66.Montesinos I, Dodemont M, Lagrou K, et al. New case of azole-resistant Aspergillus fumigatus due to TR46/Y121F/T289A mutation in Belgium. J Antimicrob Chemother 2014.Google Scholar
- 67.Spiess B, Postina P, Reinwald M, et al. Incidence of Cyp51 A key mutations in Aspergillus fumigatus-a study on primary clinical samples of immunocompromised patients in the period of 1995-2013. PLoS One. 2014;9:e103113.CrossRefPubMedCentralPubMedGoogle Scholar
- 68.Antinori S, Corbellino M, Meroni L, et al. Aspergillus meningitis: a rare clinical manifestation of central nervous system aspergillosis. Case report and review of 92 cases. J Infect. 2013;66:218–38.CrossRefPubMedGoogle Scholar
- 69.McGinnis MR. Detection of fungi in cerebrospinal fluid. Am J Med. 1983;75:129–38.CrossRefPubMedGoogle Scholar
- 70.Lehrnbecher T, Aplenc R, Rivas Pereira F, et al. Variations in non-pharmacological anti-infective measures in childhood leukemia—results of an international survey. Haematologica. 2012;97:1548–52.CrossRefPubMedCentralPubMedGoogle Scholar
- 71.Oren I, Haddad N, Finkelstein R, et al. Invasive pulmonary aspergillosis in neutropenic patients during hospital construction: before and after chemoprophylaxis and institution of HEPA filters. Am J Hematol. 2001;66:257–62.CrossRefPubMedGoogle Scholar
- 72.•Akan H, Antia VP, Kouba M, et al. Preventing invasive fungal disease in patients with haematological malignancies and the recipients of haematopoietic stem cell transplantation: practical aspects. J Antimicrob Chemother. 2013;68 Suppl 3:iii5–16. This recent article nicely reviews the practical aspects of preventing fungal infections in hematologic cancer patients.PubMedGoogle Scholar
- 73.Charalampos D, Athanassiadou F. Primary and secondary antifungal prophylaxis in the immunocompromised child: where do we stand? Curr Fungal Infect Rep. 2013;7:1–7.CrossRefGoogle Scholar
- 74.Science M, Robinson PD, MacDonald T, et al. Guideline for primary antifungal prophylaxis for pediatric patients with cancer or hematopoietic stem cell transplant recipients. Pediatr Blood Cancer. 2014;61:393–400.CrossRefPubMedGoogle Scholar
- 75.Bochennek K, Tramsen L, Schedler N, et al. Liposomal amphotericin B twice weekly as antifungal prophylaxis in paediatric haematological malignancy patients. Clin Microbiol Infect. 2011;17:1868–74.CrossRefPubMedGoogle Scholar
- 76.Foot AB, Veys PA, Gibson BE. Itraconazole oral solution as antifungal prophylaxis in children undergoing stem cell transplantation or intensive chemotherapy for haematological disorders. Bone Marrow Transplant. 1999;24:1089–93.CrossRefPubMedGoogle Scholar
- 77.Roman E, Osunkwo I, Militano O, et al. Liposomal amphotericin B prophylaxis of invasive mold infections in children post allogeneic stem cell transplantation. Pediatr Blood Cancer. 2008;50:325–30.CrossRefPubMedGoogle Scholar
- 78.van Burik JA, Ratanatharathorn V, Stepan DE, et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis. 2004;39:1407–16.CrossRefPubMedGoogle Scholar
- 79.Wingard JR, Carter SL, Walsh TJ, et al. Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood. 2010;116:5111–8.CrossRefPubMedCentralPubMedGoogle Scholar
- 80.Andes D. Optimizing antifungal choice and administration. Curr Med Res Opin. 2013;29 Suppl 4:13–8.CrossRefPubMedGoogle Scholar
- 81.Black KE, Baden LR. Fungal infections of the CNS: treatment strategies for the immunocompromised patient. CNS Drugs. 2007;21:293–318.CrossRefPubMedGoogle Scholar
- 82.S. CK, Bariola JR. Current antifungal agents for treatment of central nervous system infections. Curr Fungal Infect Rep 2014;8:146–52Google Scholar
- 83.Schwartz S, Ruhnke M, Ribaud P, et al. Improved outcome in central nervous system aspergillosis, using voriconazole treatment. Blood. 2005;106:2641–5.CrossRefPubMedGoogle Scholar
- 84.Mikulska M, Novelli A, Aversa F, et al. Voriconazole in clinical practice. J Chemother. 2012;24:311–27.CrossRefPubMedGoogle Scholar
- 85.Morris AM. Review: voriconazole for prevention or treatment of invasive fungal infections in cancer with neutropenia. Ann Intern Med. 2014;161:JC8.CrossRefPubMedGoogle Scholar