Invasive Pulmonary Aspergillosis in Hospital and Ventilator-Associated Pneumonias

Abstract

Pneumonia is the commonest nosocomial infection complicating hospital stay, with both non-ventilated hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) occurring frequently amongst patients in intensive care. Aspergillus is an increasingly recognized pathogen amongst patients with HAP and VAP, and is associated with significantly increased mortality if left untreated.

Invasive pulmonary aspergillosis (IPA) was originally identified in patients who had been profoundly immunosuppressed, however, this disease can also occur in patients with relative immunosuppression such as critically ill patients in intensive care unit (ICU). Patients in ICU commonly have several risk factors for IPA, with the inflamed pulmonary environment providing a niche for aspergillus growth.

An understanding of the true prevalence of this condition amongst ICU patients, and its specific rate in patients with HAP or VAP is hampered by difficulties in diagnosis. Establishing a definitive diagnosis requires tissue biopsy, which is seldom practical in critically ill patients, so imperfect proxy measures are required. Clinical and radiological findings in ventilated patients are frequently non-specific. The best-established test is galactomannan antigen level in bronchoalveolar lavage fluid, although this must be interpreted in the clinical context as false positive results can occur. Acknowledging these limitations, the best estimates of the prevalence of IPA range from 0.3 to 5% amongst all ICU patients, 12% amongst patients with VAP and 7 to 28% amongst ventilated patients with influenza.

Antifungal triazoles including voriconazole are the first-line therapy choice in most cases. Amphotericin has excellent antimold coverage, but a less advantageous side effect profile. Echinocandins are less effective against IPA, but may play a role in rescue therapy, or as an adjuvant to triazole therapy.

A high index of suspicion for IPA should be maintained when investigating patients with HAP or VAP, especially when they have specific risk factors or are not responding to appropriate empiric antibacterial therapy.

Keywords

invasive pulmonary aspergillosis - ventilator-associated pneumonia - hospital-acquired pneumonia - fungal infections - critical care

Publikationsverlauf

Artikel online veröffentlicht:
18. Januar 2022

• References

• 1 Barnes E. A short history of invasive aspergillosis, 1920 to 1965. Published online 2004. Accessed September 24, 2021 at: https://www.aspergillus.org.uk
• 2 Kligman AM. Are fungus infections increasing as a result of antibiotic therapy?. J Am Med Assoc 1952; 149 (11) 979-983
• 3 Rankin NE. Disseminated aspergillosis and moniliasis associated with agranulocytosis and antibiotic therapy. BMJ 1953; 1 (4816): 918-919
• 4 Dimopoulos G, Piagnerelli M, Berré J, Eddafali B, Salmon I, Vincent J-L. Disseminated aspergillosis in intensive care unit patients: an autopsy study. J Chemother 2003; 15 (01) 71-75
• 5 Vincent J-L, Sakr Y, Singer M. et al; EPIC III Investigators. Prevalence and outcomes of infection among patients in intensive care units in 2017. JAMA 2020; 323 (15) 1478-1487
• 6 Hunter JD. Ventilator associated pneumonia. BMJ 2012; 344: e3325-e3325
• 7 Meduri GU, Mauldin GL, Wunderink RG. et al. Causes of fever and pulmonary densities in patients with clinical manifestations of ventilator-associated pneumonia. Chest 1994; 106 (01) 221-235
• 8 Ewig S, Torres A, El-Ebiary M. et al. Bacterial colonization patterns in mechanically ventilated patients with traumatic and medical head injury. Incidence, risk factors, and association with ventilator-associated pneumonia. Am J Respir Crit Care Med 1999; 159 (01) 188-198
• 9 Morris AC, Kefala K, Simpson AJ. et al. Evaluation of the effect of diagnostic methodology on the reported incidence of ventilator-associated pneumonia. Thorax 2009; 64 (06) 516-522
• 10 Montravers P, Gauzit R, Dombret MC, Blanchet F, Desmonts JM. Cardiopulmonary effects of bronchoalveolar lavage in critically ill patients. Chest 1993; 104 (05) 1541-1547
• 11 Taccone FS, Van den Abeele AM, Bulpa P. et al; AspICU Study Investigators. Epidemiology of invasive aspergillosis in critically ill patients: clinical presentation, underlying conditions, and outcomes. Crit Care 2015; 19: 7
• 12 Chung D, Barker BM, Carey CC. et al. ChIP-seq and in vivo transcriptome analyses of the Aspergillus fumigatus SREBP SrbA reveals a new regulator of the fungal hypoxia response and virulence. PLoS Pathog 2014; 10 (11) e1004487
• 13 Rodrigues AG, Araujo R, Pina-Vaz C. Human albumin promotes germination, hyphal growth and antifungal resistance by Aspergillus fumigatus . Med Mycol 2005; 43 (08) 711-717
• 14 Hoenigl M, Krause R. Antifungal therapy of aspergillosis of the central nervous system and aspergillus endophthalmitis. Curr Pharm Des 2013; 19 (20) 3648-3668
• 15 Sturtevant J, Latgé J-P. Participation of complement in the phagocytosis of the conidia of Aspergillus fumigatus by human polymorphonuclear cells. J Infect Dis 1992; 166 (03) 580-586
• 16 Madan T, Eggleton P, Kishore U. et al. Binding of pulmonary surfactant proteins A and D to Aspergillus fumigatus conidia enhances phagocytosis and killing by human neutrophils and alveolar macrophages. Infect Immun 1997; 65 (08) 3171-3179
• 17 Vogl G, Lesiak I, Jensen DB. et al. Immune evasion by acquisition of complement inhibitors: the mould Aspergillus binds both factor H and C4b binding protein. Mol Immunol 2008; 45 (05) 1485-1493
• 18 Werner JL, Metz AE, Horn D. et al. Requisite role for the dectin-1 β-glucan receptor in pulmonary defense against Aspergillus fumigatus . J Immunol 2009; 182 (08) 4938-4946
• 19 Langfelder K, Streibel M, Jahn B, Haase G, Brakhage AA. Biosynthesis of fungal melanins and their importance for human pathogenic fungi. Fungal Genet Biol 2003; 38 (02) 143-158
• 20 Langfelder K, Jahn B, Gehringer H, Schmidt A, Wanner G, Brakhage AA. Identification of a polyketide synthase gene (pksP) of Aspergillus fumigatus involved in conidial pigment biosynthesis and virulence. Med Microbiol Immunol (Berl) 1998; 187 (02) 79-89
• 21 Martinez J, Malireddi RKS, Lu Q. et al. Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins. Nat Cell Biol 2015; 17 (07) 893-906
• 22 Wood AJ, Vassallo AM, Ruchaud-Sparagano M-H. et al. C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodeling. JCI Insight 2020; 5 (15) 93
• 23 Bromley IM, Donaldson K. Binding of Aspergillus fumigatus spores to lung epithelial cells and basement membrane proteins: relevance to the asthmatic lung. Thorax 1996; 51 (12) 1203-1209
• 24 Tronchin G, Bouchara JP, Larcher G, Lissitzky JC, Chabasse D. Interaction between Aspergillus fumigatus and basement membrane laminin: binding and substrate degradation. Biol Cell 1993; 77 (02) 201-208
• 25 Roquilly A, McWilliam HEG, Jacqueline C. et al. Local modulation of antigen-presenting cell development after resolution of pneumonia induces long-term susceptibility to secondary infections. Immunity 2017; 47 (01) 135-147.e5
• 26 Roquilly A, Jacqueline C, Davieau M. et al. Alveolar macrophages are epigenetically altered after inflammation, leading to long-term lung immunoparalysis. Nat Immunol 2020; 21 (06) 636-648
• 27 Conway Morris A, Kefala K, Wilkinson TS. et al. C5a mediates peripheral blood neutrophil dysfunction in critically ill patients. Am J Respir Crit Care Med 2009; 180 (01) 19-28
• 28 Roilides E, Robinson T, Sein T, Pizzo PA, Walsh TJ. In vitro and ex vivo effects of cyclosporin A on phagocytic host defenses against Aspergillus fumigatus . Antimicrob Agents Chemother 1994; 38 (12) 2883-2888
• 29 Brummer E, Choi J-H, Stevens DA. Interaction between conidia, lung macrophages, immunosuppressants, proinflammatory cytokines and transcriptional regulation. Med Mycol 2005; 43 (Suppl. 01) S177-S179
• 30 Bassetti M, Peghin M, Vena A. Challenges and solution of invasive aspergillosis in non-neutropenic patients: a review. Infect Dis Ther 2018; 7 (01) 17-27
• 31 Loughlin L, Hellyer TP, White PL. et al. Pulmonary aspergillosis in patients with suspected ventilator-associated pneumonia in UK ICUs. Am J Respir Crit Care Med 2020; 202 (08) 1125-1132
• 32 Meersseman W, Vandecasteele SJ, Wilmer A, Verbeken E, Peetermans WE, Van Wijngaerden E. Invasive aspergillosis in critically ill patients without malignancy. Am J Respir Crit Care Med 2004; 170 (06) 621-625
• 33 Meersseman W, Lagrou K, Maertens J, Van Wijngaerden E. Invasive aspergillosis in the intensive care unit. Clin Infect Dis 2007; 45 (02) 205-216
• 34 Tudesq J-J, Peyrony O, Lemiale V, Azoulay E. Invasive pulmonary aspergillosis in nonimmunocompromised hosts. Semin Respir Crit Care Med 2019; 40 (04) 540-547
• 35 Lahmer T, Brandl A, Rasch S. et al. Prevalence and outcome of invasive pulmonary aspergillosis in critically ill patients with liver cirrhosis: an observational study. Sci Rep 2019; 9 (01) 11919
• 36 Schauwvlieghe AFAD, Rijnders BJA, Philips N. et al; Dutch-Belgian Mycosis study group. Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study. Lancet Respir Med 2018; 6 (10) 782-792
• 37 Verweij PE, Rijnders BJA, Brüggemann RJM. et al. Review of influenza-associated pulmonary aspergillosis in ICU patients and proposal for a case definition: an expert opinion. Intensive Care Med 2020; 46 (08) 1524-1535
• 38 Machado M, Valerio M, Álvarez-Uría A. et al; COVID-19 Study Group. Invasive pulmonary aspergillosis in the COVID-19 era: an expected new entity. Mycoses 2021; 64 (02) 132-143
• 39 Kula BE, Clancy CJ, Hong Nguyen M, Schwartz IS. Invasive mould disease in fatal COVID-19: a systematic review of autopsies. Lancet Microbe 2021; 2 (08) e405-e414
• 40 Maes M, Higginson E, Pereira-Dias J. et al. Ventilator-associated pneumonia in critically ill patients with COVID-19. Crit Care 2021; 25 (01) 25
• 41 Lansbury LE, Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam J, Shen Lim W. Corticosteroids as adjunctive therapy in the treatment of influenza: an updated Cochrane systematic review and meta-analysis. Crit Care Med 2020; 48 (02) e98-e106
• 42 Donnelly JP, Chen SC, Kauffman CA. et al. Revision and update of the consensus definitions of invasive fungal disease from the European Organization for research and treatment of cancer and the Mycoses Study Group Education and Research Consortium. Clin Infect Dis 2020; 71 (06) 1367-1376
• 43 Blot SI, Taccone FS, Van den Abeele AM. et al; AspICU Study Investigators. A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients. Am J Respir Crit Care Med 2012; 186 (01) 56-64
• 44 Koehler P, Bassetti M, Chakrabarti A. et al; European Confederation of Medical Mycology, International Society for Human Animal Mycology, Asia Fungal Working Group, INFOCUS LATAM/ISHAM Working Group, ISHAM Pan Africa Mycology Working Group, European Society for Clinical Microbiology, Infectious Diseases Fungal Infection Study Group, ESCMID Study Group for Infections in Critically Ill Patients, Interregional Association of Clinical Microbiology and Antimicrobial Chemotherapy, Medical Mycology Society of Nigeria, Medical Mycology Society of China Medicine Education Association, Infectious Diseases Working Party of the German Society for Haematology and Medical Oncology, Association of Medical Microbiology, Infectious Disease Canada. Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance. Lancet Infect Dis 2021; 21 (06) e149-e162
• 45 Bassetti M, Scudeller L, Giacobbe DR. et al; from the Study Group for Infections in Critically Ill Patients (ESGCIP) and the Fungal Infection Study Group (EFISG) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), European Society of Intensive Care Medicine (ESICM), European Confederation of Medical Mycology (ECMM), Mycoses Study Group Education and Research Consortium (MSGERC). Developing definitions for invasive fungal diseases in critically ill adult patients in intensive care units. Protocol of the FUNgal infections Definitions in ICU patients (FUNDICU) project. Mycoses 2019; 62 (04) 310-319
• 46 Huang L, He H, Ding Y, Jin J, Zhan Q. Values of radiological examinations for the diagnosis and prognosis of invasive bronchial-pulmonary aspergillosis in critically ill patients with chronic obstructive pulmonary diseases. Clin Respir J 2018; 12 (02) 499-509
• 47 Lee S, Yun NR, Kim K-H. et al. Discrepancy between histology and culture in filamentous fungal infections. Med Mycol 2010; 48 (06) 886-888
• 48 Jenks JD, Spiess B, Buchheidt D, Hoenigl M. (New) Methods for detection of Aspergillus fumigatus resistance in clinical samples. Curr Fungal Infect Rep 2019; 13 (03) 129-136
• 49 Bassetti M, Giacobbe DR, Grecchi C, Rebuffi C, Zuccaro V, Scudeller L. FUNDICU investigators. Performance of existing definitions and tests for the diagnosis of invasive aspergillosis in critically ill, adult patients: a systematic review with qualitative evidence synthesis. J Infect 2020; 81 (01) 131-146
• 50 Boonsarngsuk V, Niyompattama A, Teosirimongkol C, Sriwanichrak K. False-positive serum and bronchoalveolar lavage Aspergillus galactomannan assays caused by different antibiotics. Scand J Infect Dis 2010; 42 (6-7): 461-468
• 51 Heldt S, Prattes J, Eigl S. et al. Diagnosis of invasive aspergillosis in hematological malignancy patients: performance of cytokines, Asp LFD, and Aspergillus PCR in same day blood and bronchoalveolar lavage samples. J Infect 2018; 77 (03) 235-241
• 52 Heldt S, Hoenigl M. Lateral flow assays for the diagnosis of invasive aspergillosis: current status. Curr Fungal Infect Rep 2017; 11 (02) 45-51
• 53 Mercier T, Dunbar A, Veldhuizen V. et al. Point of care aspergillus testing in intensive care patients. Crit Care 2020; 24 (01) 642
• 54 Hoenigl M, Prattes J, Spiess B. et al. Performance of galactomannan, beta-d-glucan, Aspergillus lateral-flow device, conventional culture, and PCR tests with bronchoalveolar lavage fluid for diagnosis of invasive pulmonary aspergillosis. J Clin Microbiol 2014; 52 (06) 2039-2045
• 55 Prattes J, Flick H, Prüller F. et al. Novel tests for diagnosis of invasive aspergillosis in patients with underlying respiratory diseases. Am J Respir Crit Care Med 2014; 190 (08) 922-929
• 56 Eigl S, Hoenigl M, Spiess B. et al. Galactomannan testing and Aspergillus PCR in same-day bronchoalveolar lavage and blood samples for diagnosis of invasive aspergillosis. Med Mycol 2017; 55 (05) 528-534
• 57 Jones NK, Conway Morris A, Curran MD. et al. Evaluating the use of a 22-pathogen TaqMan array card for rapid diagnosis of respiratory pathogens in intensive care. J Med Microbiol 2020; 69 (07) 971-978
• 58 Echeverria-Esnal D, Martín-Ontiyuelo C, Navarrete-Rouco ME. et al. Pharmacological management of antifungal agents in pulmonary aspergillosis: an updated review. Expert Rev Anti Infect Ther 2021; 1-19
• 59 Felton T, Troke PF, Hope WW. Tissue penetration of antifungal agents. Clin Microbiol Rev 2014; 27 (01) 68-88
• 60 Simitsopoulou M, Roilides E, Paliogianni F. et al. Immunomodulatory effects of voriconazole on monocytes challenged with Aspergillus fumigatus: differential role of toll-like receptors. Antimicrob Agents Chemother 2008; 52 (09) 3301-3306
• 61 Bellocchio S, Gaziano R, Bozza S. et al. Liposomal amphotericin B activates antifungal resistance with reduced toxicity by diverting Toll-like receptor signalling from TLR-2 to TLR-4. J Antimicrob Chemother 2005; 55 (02) 214-222
• 62 Moretti S, Bozza S, Massi-Benedetti C. et al. An immunomodulatory activity of micafungin in preclinical aspergillosis. J Antimicrob Chemother 2014; 69 (04) 1065-1074