Epidemiology and clinical manifestations of invasive aspergillosis
- Kieren A Marr, MD
Kieren A Marr, MD
- Section Editor — Compromised Host Infections; Fungal Infections
- Professor of Medicine and Oncology
- Johns Hopkins University School of Medicine
The term "aspergillosis" refers to illness due to allergy, airway or lung invasion, cutaneous infection, or extrapulmonary dissemination caused by species of Aspergillus, most commonly A. fumigatus, A. flavus, and A. terreus. Aspergillus species are ubiquitous in nature, and inhalation of infectious conidia is a frequent event. Tissue invasion is uncommon and occurs most frequently in the setting of immunosuppression associated with therapy for hematologic malignancies, hematopoietic cell transplantation, or solid organ transplantation.
The pathogenesis, epidemiology, clinical manifestations, and differential diagnosis of invasive aspergillosis (specifically that occurring in people who are immunocompromised after transplant and/or treatment of hematologic malignancies) will be reviewed here. The diagnosis and treatment of invasive aspergillosis are discussed separately; other syndromes caused by Aspergillus species, including invasive aspergillosis in HIV-infected patients, are also presented elsewhere. (See "Diagnosis of invasive aspergillosis" and "Treatment and prevention of invasive aspergillosis" and "Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis" and "Clinical manifestations and diagnosis of chronic pulmonary aspergillosis" and "Treatment of chronic pulmonary aspergillosis" and "Epidemiology and clinical manifestations of pulmonary aspergillosis and invasive disease in HIV-infected patients" and "Diagnosis and treatment of invasive pulmonary aspergillosis in HIV-infected patients".)
Inhaled conidia are met by the innate defenses provided by resident phagocytes, specifically airway epithelial cells and alveolar macrophages [1,2]. Little is known about the contribution of epithelial cells in clearing conidia. Relatively more is known about macrophages, which contribute to both conidial clearance and the production of secondary inflammation. These cells secrete inflammatory mediators after recognition of key cell wall components (eg, beta-D-glucan) exposed after conidial germination into hyphal forms. These mediators result in neutrophil recruitment and the activation of cellular immunity, which are important in killing potentially invasive microbial forms (hyphae) and determining the extent and nature of the immune response. Hence, risks for disease and the type of disease that occurs are the combined result of multiple cellular functions that impact proximal events in conidial clearance, production of inflammation, and killing of invasive forms .
Microbial factors that impact disease potential include toxins, proteases, and secondary metabolites that exert multiple effects on the host's local pulmonary and systemic defense. These include cellular products that:
●Inhibit phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, a key component in host defense against filamentous fungi
- Segal BH. Aspergillosis. N Engl J Med 2009; 360:1870.
- Ben-Ami R, Lewis RE, Kontoyiannis DP. Enemy of the (immunosuppressed) state: an update on the pathogenesis of Aspergillus fumigatus infection. Br J Haematol 2010; 150:406.
- Balajee SA, Marr KA. Phenotypic and genotypic identification of human pathogenic aspergilli. Future Microbiol 2006; 1:435.
- Marr KA, Carter RA, Crippa F, et al. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 2002; 34:909.
- Kanamori H, Rutala WA, Sickbert-Bennett EE, Weber DJ. Review of fungal outbreaks and infection prevention in healthcare settings during construction and renovation. Clin Infect Dis 2015; 61:433.
- Lambourne J, Agranoff D, Herbrecht R, et al. Association of mannose-binding lectin deficiency with acute invasive aspergillosis in immunocompromised patients. Clin Infect Dis 2009; 49:1486.
- Bulpa P, Dive A, Sibille Y. Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease. Eur Respir J 2007; 30:782.
- Meersseman W, Lagrou K, Maertens J, Van Wijngaerden E. Invasive aspergillosis in the intensive care unit. Clin Infect Dis 2007; 45:205.
- Marr KA, Carter RA, Boeckh M, et al. Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood 2002; 100:4358.
- Stuehler C, Kuenzli E, Jaeger VK, et al. Immune Reconstitution After Allogeneic Hematopoietic Stem Cell Transplantation and Association With Occurrence and Outcome of Invasive Aspergillosis. J Infect Dis 2015; 212:959.
- Camargo JF, Husain S. Immune correlates of protection in human invasive aspergillosis. Clin Infect Dis 2014; 59:569.
- Camargo JF, Bhimji A, Kumar D, et al. Impaired T cell responsiveness to interleukin-6 in hematological patients with invasive aspergillosis. PLoS One 2015; 10:e0123171.
- Bochud PY, Chien JW, Marr KA, et al. Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N Engl J Med 2008; 359:1766.
- Wójtowicz A, Gresnigt MS, Lecompte T, et al. IL1B and DEFB1 Polymorphisms Increase Susceptibility to Invasive Mold Infection After Solid-Organ Transplantation. J Infect Dis 2015; 211:1646.
- Cunha C, Aversa F, Lacerda JF, et al. Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation. N Engl J Med 2014; 370:421.
- Wójtowicz A, Lecompte TD, Bibert S, et al. PTX3 Polymorphisms and Invasive Mold Infections After Solid Organ Transplant. Clin Infect Dis 2015; 61:619.
- Cunha C, Di Ianni M, Bozza S, et al. Dectin-1 Y238X polymorphism associates with susceptibility to invasive aspergillosis in hematopoietic transplantation through impairment of both recipient- and donor-dependent mechanisms of antifungal immunity. Blood 2010; 116:5394.
- Chai LY, de Boer MG, van der Velden WJ, et al. The Y238X stop codon polymorphism in the human β-glucan receptor dectin-1 and susceptibility to invasive aspergillosis. J Infect Dis 2011; 203:736.
- Iversen M, Burton CM, Vand S, et al. Aspergillus infection in lung transplant patients: incidence and prognosis. Eur J Clin Microbiol Infect Dis 2007; 26:879.
- Luong ML, Chaparro C, Stephenson A, et al. Pretransplant Aspergillus colonization of cystic fibrosis patients and the incidence of post-lung transplant invasive aspergillosis. Transplantation 2014; 97:351.
- Fortún J, Martín-Dávila P, Moreno S, et al. Risk factors for invasive aspergillosis in liver transplant recipients. Liver Transpl 2002; 8:1065.
- Rosenhagen M, Feldhues R, Schmidt J, et al. A risk profile for invasive aspergillosis in liver transplant recipients. Infection 2009; 37:313.
- Heylen L, Maertens J, Naesens M, et al. Invasive aspergillosis after kidney transplant: case-control study. Clin Infect Dis 2015; 60:1505.
- Horger M, Hebart H, Einsele H, et al. Initial CT manifestations of invasive pulmonary aspergillosis in 45 non-HIV immunocompromised patients: association with patient outcome? Eur J Radiol 2005; 55:437.
- Cornillet A, Camus C, Nimubona S, et al. Comparison of epidemiological, clinical, and biological features of invasive aspergillosis in neutropenic and nonneutropenic patients: a 6-year survey. Clin Infect Dis 2006; 43:577.
- Georgiadou SP, Sipsas NV, Marom EM, Kontoyiannis DP. The diagnostic value of halo and reversed halo signs for invasive mold infections in compromised hosts. Clin Infect Dis 2011; 52:1144.
- Caillot D, Casasnovas O, Bernard A, et al. Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery. J Clin Oncol 1997; 15:139.
- Caillot D, Couaillier JF, Bernard A, et al. Increasing volume and changing characteristics of invasive pulmonary aspergillosis on sequential thoracic computed tomography scans in patients with neutropenia. J Clin Oncol 2001; 19:253.
- Gavalda J, Len O, San Juan R, et al. Risk factors for invasive aspergillosis in solid-organ transplant recipients: a case-control study. Clin Infect Dis 2005; 41:52.
- Burgos A, Zaoutis TE, Dvorak CC, et al. Pediatric invasive aspergillosis: a multicenter retrospective analysis of 139 contemporary cases. Pediatrics 2008; 121:e1286.
- Stanzani M, Battista G, Sassi C, et al. Computed tomographic pulmonary angiography for diagnosis of invasive mold diseases in patients with hematological malignancies. Clin Infect Dis 2012; 54:610.
- Stanzani M, Sassi C, Lewis RE, et al. High resolution computed tomography angiography improves the radiographic diagnosis of invasive mold disease in patients with hematological malignancies. Clin Infect Dis 2015; 60:1603.
- Fernández-Ruiz M, Silva JT, San-Juan R, et al. Aspergillus tracheobronchitis: report of 8 cases and review of the literature. Medicine (Baltimore) 2012; 91:261.
- van Assen S, Bootsma GP, Verweij PE, et al. Aspergillus tracheobronchitis after allogeneic bone marrow transplantation. Bone Marrow Transplant 2000; 26:1131.
- Sivak-Callcott JA, Livesley N, Nugent RA, et al. Localised invasive sino-orbital aspergillosis: characteristic features. Br J Ophthalmol 2004; 88:681.
- McCarthy M, Rosengart A, Schuetz AN, et al. Mold infections of the central nervous system. N Engl J Med 2014; 371:150.
- 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.
- Levin LA, Avery R, Shore JW, et al. The spectrum of orbital aspergillosis: a clinicopathological review. Surv Ophthalmol 1996; 41:142.
- Riddell Iv J, McNeil SA, Johnson TM, et al. Endogenous Aspergillus endophthalmitis: report of 3 cases and review of the literature. Medicine (Baltimore) 2002; 81:311.
- Ellis ME, Al-Abdely H, Sandridge A, et al. Fungal endocarditis: evidence in the world literature, 1965-1995. Clin Infect Dis 2001; 32:50.
- El-Hamamsy I, Dürrleman N, Stevens LM, et al. Aspergillus endocarditis after cardiac surgery. Ann Thorac Surg 2005; 80:359.
- van Burik JA, Colven R, Spach DH. Cutaneous aspergillosis. J Clin Microbiol 1998; 36:3115.
- Eggimann P, Chevrolet JC, Starobinski M, et al. Primary invasive aspergillosis of the digestive tract: report of two cases and review of the literature. Infection 2006; 34:333.
- González-Vicent M, Díaz MA, Colmenero I, et al. Primary gastrointestinal aspergillosis after autologous peripheral blood progenitor cell transplantation: an unusual presentation of invasive aspergillosis. Transpl Infect Dis 2008; 10:193.
- Kontoyiannis DP, Mathur M, Chen YB, et al. Case records of the Massachusetts General Hospital. Case 13-2014. A 41-year-old man with fever and abdominal pain after stem-cell transplantation. N Engl J Med 2014; 370:1637.
- Kim SH, Kim MY, Hong SI, et al. Invasive Pulmonary Aspergillosis-mimicking Tuberculosis. Clin Infect Dis 2015; 61:9.
- MICROBIAL EPIDEMIOLOGY
- Species prevalence
- RISK FACTORS
- CLINICAL FEATURES
- Pulmonary aspergillosis
- - Imaging
- Chronic necrotizing and chronic cavitary pulmonary aspergillosis
- Disseminated infection
- Central nervous system infection
- Cutaneous aspergillosis
- Gastrointestinal aspergillosis
- DIFFERENTIAL DIAGNOSIS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS