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Id Subject Object Predicate Lexical cue
T1 0-124 Sentence denotes Review of influenza-associated pulmonary aspergillosis in ICU patients and proposal for a case definition: an expert opinion
T2 126-134 Sentence denotes Abstract
T3 135-142 Sentence denotes Purpose
T4 143-270 Sentence denotes Invasive pulmonary aspergillosis is increasingly reported in patients with influenza admitted to the intensive care unit (ICU).
T5 271-526 Sentence denotes Classification of patients with influenza-associated pulmonary aspergillosis (IAPA) using the current definitions for invasive fungal diseases has proven difficult, and our aim was to develop case definitions for IAPA that can facilitate clinical studies.
T6 528-535 Sentence denotes Methods
T7 536-733 Sentence denotes A group of 29 international experts reviewed current insights into the epidemiology, diagnosis and management of IAPA and proposed a case definition of IAPA through a process of informal consensus.
T8 735-742 Sentence denotes Results
T9 743-845 Sentence denotes Since IAPA may develop in a wide range of hosts, an entry criterion was proposed and not host factors.
T10 846-1007 Sentence denotes The entry criterion was defined as a patient requiring ICU admission for respiratory distress with a positive influenza test temporally related to ICU admission.
T11 1008-1132 Sentence denotes In addition, proven IAPA required histological evidence of invasive septate hyphae and mycological evidence for Aspergillus.
T12 1133-1440 Sentence denotes Probable IAPA required the detection of galactomannan or positive Aspergillus culture in bronchoalveolar lavage (BAL) or serum with pulmonary infiltrates or a positive culture in upper respiratory samples with bronchoscopic evidence for tracheobronchitis or cavitating pulmonary infiltrates of recent onset.
T13 1441-1690 Sentence denotes The IAPA case definitions may be useful to classify patients with COVID-19-associated pulmonary aspergillosis (CAPA), while awaiting further studies that provide more insight into the interaction between Aspergillus and the SARS-CoV-2-infected lung.
T14 1692-1702 Sentence denotes Conclusion
T15 1703-1918 Sentence denotes A consensus case definition of IAPA is proposed, which will facilitate research into the epidemiology, diagnosis and management of this emerging acute and severe Aspergillus disease, and may be of use to study CAPA.
T16 1920-1937 Sentence denotes Take-home message
T17 1938-2054 Sentence denotes Invasive pulmonary aspergillosis is an emerging co-infection in patients with influenza who are admitted to the ICU.
T18 2055-2303 Sentence denotes An international team of experts proposed consensus case definitions of influenza-associated pulmonary aspergillosis in order to facilitate clinical studies and the definition may also be useful to study COVID-19-associated pulmonary aspergillosis.
T19 2305-2317 Sentence denotes Introduction
T20 2318-2623 Sentence denotes Invasive pulmonary aspergillosis (IPA) is a well-recognized disease affecting immunocompromised individuals with prolonged neutropenia, inherited neutrophil disorders or T cell defects, with the risk depending on the patients’ underlying disease and the type and duration of immunosuppressive therapy [1].
T21 2624-2925 Sentence denotes Patients at the highest risk of invasive aspergillosis (IA) include those undergoing intensive chemotherapy for acute leukemia (AL) or recipients of allogeneic cell transplantation (alloHCT) who develop severe graft-versus-host disease, for whom antifungal prophylaxis is currently recommended [2, 3].
T22 2926-3045 Sentence denotes With changing treatment modalities, new risk groups continue to emerge, such as patients treated with ibrutinib [4, 5].
T23 3046-3308 Sentence denotes Although over the past four decades a link between influenza and IPA has been noted in single cases [6], recent cohort studies provide new insights into the epidemiology and clinical presentation of IPA in intensive care unit (ICU) patients with influenza [7–9].
T24 3309-3675 Sentence denotes Patients presenting with influenza-associated pulmonary aspergillosis (IAPA) may have classic European Organization for Research and Treatment of Cancer (EORTC)/Mycosis Study Group Education and Research Consortium (MSGERC)-defined host factors [10], but a notable proportion of patients was deemed to be at low risk of IPA, including previously healthy individuals.
T25 3676-3841 Sentence denotes In addition, the clinical and radiological presentation was often atypical with radiological features that were not considered suggestive of invasive fungal disease.
T26 3842-4054 Sentence denotes As a consequence, we cannot classify these patients according to existing consensus definitions, i.e., the EORTC/MSGERC definitions and the AspICU algorithm for classification of IPA patients in the ICU [10, 11].
T27 4055-4276 Sentence denotes We therefore set out to discuss current insights into the epidemiology, pathogenesis, diagnosis and management of IAPA and to propose case definitions that can facilitate homogeneity and comparability in clinical studies.
T28 4278-4302 Sentence denotes Participants and methods
T29 4303-4402 Sentence denotes The expert panel is comprised of 29 participants from seven European countries, the USA and Taiwan.
T30 4403-4763 Sentence denotes To ensure heterogenicity, participants were selected from various fields of expertise: medical microbiology (PEV, KL, CL-F, TRR), infectious diseases (BJAR, MB, TC, CJC, OAC, DRG, NAFJ, BJK, OL, MH-N, TFP, FLvdV), intensive care medicine (EA, SB, PD, PW-LL, IM-L, JAS, LV, JW), clinical pharmacology (RJMB, RL, IS), public health (TC) and hematology (OAC, JM).
T31 4764-4931 Sentence denotes Selected participants furthermore had specific expertise in epidemiology, diagnosis and management of invasive fungal diseases or fungal disease guideline development.
T32 4932-4984 Sentence denotes The meeting was prepared by PEV, RJMB, JW and FLvdV.
T33 4985-5057 Sentence denotes Case definitions were developed through a process of informal consensus.
T34 5058-5393 Sentence denotes Although a systematic literature review was not performed, experts in the field presented overviews regarding epidemiology, pathogenesis, diagnosis and treatment of IAPA, which were followed by a group discussion process designed to allow members of the group to voice their opinions and contribute equally to the decision-making [12].
T35 5394-5472 Sentence denotes The goal of the consensus process was to bring the group to general agreement.
T36 5473-5658 Sentence denotes Presentations and initial discussions took place on a single day meeting in April 2019 in Amsterdam and were continued through electronic exchange of views until consensus was achieved.
T37 5659-5846 Sentence denotes The chosen framework included host and risk factors, clinical factors and mycological evidence, similar to the framework in the EORTC/MSGERC definitions and the AspICU algorithm [10, 11].
T38 5847-5940 Sentence denotes A medical writer made notes of the meeting, which were used as input to write the manuscript.
T39 5941-6057 Sentence denotes A first draft manuscript was prepared by PEV, BJAR, RJMB, JW and FLvdV and circulated for comments from all experts.
T40 6058-6111 Sentence denotes The experts reviewed and commented on the manuscript.
T41 6112-6178 Sentence denotes Using these comments, a final version was circulated for approval.
T42 6179-6393 Sentence denotes The logistics of the meeting were handled by a certified Congress organizer (Congress Care, s’Hertogenbosch, the Netherlands) with financial support of Pfizer (Pfizer B.V., Capelle aan den IJssel, the Netherlands).
T43 6394-6564 Sentence denotes Congress Care and Pfizer had no influence on the selection of participants, selected topics, discussions, preparation and final approval of the content of the manuscript.
T44 6566-6579 Sentence denotes Expert review
T45 6581-6622 Sentence denotes Global epidemiology of influenza and IAPA
T46 6623-6828 Sentence denotes Although figures vary depending on geographic region, season and vaccination rates, approximately 0.1% of influenza patients require hospital admission with 5–10% of these requiring ICU admission [13, 14].
T47 6829-6929 Sentence denotes The mortality in patients admitted for influenza is 4% and 20–25% for those admitted to ICU [14–16].
T48 6930-7063 Sentence denotes Bacterial superinfection is common, affecting 10–35% of cases, typically with Streptococcus pneumoniae or Staphylococcus aureus [16].
T49 7064-7306 Sentence denotes However, a recent Dutch–Belgian multicenter study over seven influenza seasons in seven institutes demonstrated influenza as an independent risk factor of IPA (adjusted odds ratio 5.19, 95% confidence interval (CI) 2.63–10.26, p < 0.001) [9].
T50 7307-7505 Sentence denotes Results also showed that the 90-day mortality rate for ICU patients with IAPA was almost double that of ICU influenza patients without IAPA (51% vs. 28%, adjusted odds ratio 1.87, 95% CI 1.05–3.32).
T51 7506-7691 Sentence denotes IAPA was initially thought to be associated with influenza A/H1N1pdm09 only [7, 17], but it became clear that IAPA is also associated with other influenza A and influenza B viruses [9].
T52 7692-7793 Sentence denotes The median time between influenza diagnosis and IAPA was short, often in the first 5 days [7, 8, 18].
T53 7794-8035 Sentence denotes Studies have shown considerable variation in rates of IAPA in different countries, with high rates in the Netherlands, Belgium and Taiwan, but lower rates in other countries [19], and in some we do not know the incidence (e.g., USA) [20–22].
T54 8036-8356 Sentence denotes Potential reasons for these regional differences are related to the underlying conditions, concomitant exposure to corticosteroids, environmental factors, including exposure to Aspergillus, use of non-culture-based diagnostic tests for Aspergillus (e.g., galactomannan (GM)) and differences in awareness of IAPA [23–25].
T55 8357-8455 Sentence denotes Autopsy rates are very low, which results in a considerable underdiagnosis in many countries [26].
T56 8456-8710 Sentence denotes Other factors that might contribute to regional differences in IAPA rates include influenza vaccination rates, with different policies in different countries, and differences in influenza antiviral treatment strategies with oseltamivir or zanamivir [27].
T57 8711-8920 Sentence denotes Annual vaccination reduces influenza-associated complications (hospitalization, ICU admission, severity of illness, superinfection) and improves the outcome in transplant recipients and COPD patients [28, 29].
T58 8922-8942 Sentence denotes Pathogenesis of IAPA
T59 8943-9265 Sentence denotes In pending studies that explore the pathogenesis of IAPA and host immune defects, it is likely that damage to the epithelium by influenza and defective fungal host responses in the lung due to influenza and/or inflammatory conditions predispose to Aspergillus disease, similar as what is seen in bacterial superinfections.
T60 9266-9426 Sentence denotes Furthermore, autopsy studies have shown the presence of sporulating heads of Aspergillus inside the bronchi with invasive growth occurring into the lung tissue.
T61 9427-9600 Sentence denotes Sporulation could contribute to a high fungal burden and spread of the disease within the lung, thus contributing to the rapid disease progression and extensive lung damage.
T62 9601-9745 Sentence denotes Other factors that have been implicated in IAPA include the use of corticosteroids and of neuraminidase inhibitors, such as oseltamivir [7, 30].
T63 9746-9909 Sentence denotes Ultimately, these insights may aid in identifying patients at risk of IAPA and to design effective antifungal and adjunctive immunomodulatory treatment strategies.
T64 9911-9954 Sentence denotes Clinical presentation and diagnosis of IAPA
T65 9955-10105 Sentence denotes A retrospective Belgian study of influenza patients admitted to ICU between September 2009 and March 2011 showed that 9 of 40 (23%) patients had IAPA.
T66 10106-10227 Sentence denotes Four cases (44%) were proven despite not being immunocompromised according to the EORTC/MSGERC consensus definitions [7].
T67 10228-10309 Sentence denotes The median time between influenza diagnosis and IAPA was 2 days (range 0–4 days).
T68 10310-10410 Sentence denotes All IAPA patients had positive BAL GM, and 78% had positive serum GM, despite not being neutropenic.
T69 10411-10652 Sentence denotes Eighty-nine percent of patients had Aspergillus growth in BAL culture (almost exclusively Aspergillus fumigatus), and 55% of patients had endobronchial lesions observed during bronchoscopy, possibly indicating invasive tracheobronchitis [7].
T70 10653-10760 Sentence denotes Similar performance characteristics of BAL GM and culture were reported in two other cohort studies [8, 9].
T71 10761-10901 Sentence denotes BAL sampling is thus an important diagnostic procedure as serum GM can be negative and sputum/tracheal aspirate cultures can remain sterile.
T72 10902-11058 Sentence denotes Lesions that are suggestive of invasive mold disease on imaging in neutropenic patients, such as the halo sign, are often absent in critically ill patients.
T73 11059-11192 Sentence denotes However, in some IAPA patients with autopsy-confirmed Aspergillus tracheobronchitis, chest CT demonstrated peribronchial infiltrates.
T74 11193-11402 Sentence denotes The main diagnostic clue for airway-invasive Aspergillus tracheobronchitis is epithelial plaques, pseudomembranes or ulcers that can be visualized via bronchoscopy, as radiological features may be subtle [31].
T75 11403-11636 Sentence denotes Worsening of radiographic pulmonary infiltrates in patients with influenza is often attributed to progression of ARDS or bacterial infection, leading to a change of antimicrobial therapy without performing diagnostic procedures [32].
T76 11637-11911 Sentence denotes Patients who survived IAPA received antifungal therapy much earlier than those who did not (2 days after diagnosis of influenza among survivors versus 9 days among non-survivors) [8], suggesting that early diagnosis and administration of antifungal therapy may be important.
T77 11912-12120 Sentence denotes Lateral flow tests have recently become available as an alternative for diagnosing IPA (AspLFD, OLM Diagnostics and the sōna Aspergillus GM, IMMY) showing overall good performance in hematology patients [33].
T78 12121-12283 Sentence denotes The very quick assessment, with results available within 30–45 min, makes this type of test very attractive for the management of IAPA and use in clinical trials.
T79 12284-12362 Sentence denotes However, lateral flow tests have not yet been validated in the ICU population.
T80 12363-12554 Sentence denotes IAPA needs to be considered in patients admitted to the ICU with influenza and where indicated these patients should undergo early BAL for Aspergillus antigen testing, culture and microscopy.
T81 12555-12784 Sentence denotes Patients who test positive require anti-Aspergillus therapy, and the BAL fluid sample should be fast-tracked for azole resistance testing by PCR (and culture when positive) in regions with high (> 5%) azole resistance rates [34].
T82 12785-12903 Sentence denotes This would enable diagnostic assessment and initiation of adequate antifungal therapy within 24–48 h of ICU admission.
T83 12904-13083 Sentence denotes Diagnostic workup for IAPA may be repeated in patients deteriorating while on antivirals and/or appropriate antibiotics or when initiating corticosteroid treatment is unavoidable.
T84 13085-13142 Sentence denotes Discussion on clinical presentation and diagnosis of IAPA
T85 13143-13319 Sentence denotes If a patient is admitted to the ICU and has influenza with pulmonary infiltrates, the diagnosis of IAPA should be considered and further investigation performed as appropriate.
T86 13320-13572 Sentence denotes Ideally, this would include in order of invasiveness, serum GM testing, fungal cultures of sputum and/or tracheal aspirate, pulmonary CT, bronchoscopy to visualize the large airways and obtain BAL fluid for GM testing and fungal and bacterial cultures.
T87 13573-13716 Sentence denotes Testing is most appropriate in patients who are on mechanical ventilation, but the diagnostic strategy is less clear in patients not intubated.
T88 13717-13881 Sentence denotes As up to 50% of patients may present with tracheobronchitis, the presence of plaques and ulceration might be considered for inclusion in the definition of IPA [35].
T89 13882-14035 Sentence denotes Policies for taking biopsies of lesions seen on bronchoscopy may vary, mainly because of concerns about the risk of bleeding with biopsy in ICU patients.
T90 14036-14109 Sentence denotes The use of a flexible brush may also be sufficient to make the diagnosis.
T91 14110-14232 Sentence denotes Although a positive serum GM is highly indicative of IA, BAL GM can be positive in patients with Aspergillus colonization.
T92 14233-14321 Sentence denotes It therefore does not absolutely discriminate between colonization and invasive disease.
T93 14322-14404 Sentence denotes However, it clearly makes it more likely that an invasive disease is present [36].
T94 14406-14428 Sentence denotes Use of corticosteroids
T95 14429-14557 Sentence denotes Corticosteroids should not be given to influenza patients as their use may be associated with increased risk of IAPA [7, 37–39].
T96 14558-14707 Sentence denotes A recent Cochrane review on this topic concluded that the use of corticosteroids in patients with influenza was associated with a worse outcome [40].
T97 14708-14767 Sentence denotes However, the evidence was almost exclusively observational.
T98 14768-14955 Sentence denotes Furthermore, patients are often given steroids in the first few days preceding or after ICU admission for a variety of reasons including COPD exacerbation or complications such as sepsis.
T99 14956-15142 Sentence denotes With surveys suggesting that approximately half of the physicians are not aware of IAPA [24], many physicians may additionally not be aware of the potential drawbacks of corticosteroids.
T100 15143-15327 Sentence denotes Whenever the use of corticosteroids is unavoidable, more efforts (bronchoscopy with GM detection in BAL fluid or serum β-D-glucan test) should be made to exclude or diagnose IAPA [41].
T101 15329-15374 Sentence denotes Rationale for antifungal prophylaxis for IAPA
T102 15375-15571 Sentence denotes In settings with high IAPA rates in ICU patients with influenza pneumonia, an antifungal prophylaxis strategy might be appropriate, particularly as IAPA typically occurs early after ICU admission.
T103 15572-15679 Sentence denotes However, there is currently no mold-active antifungal agent licensed for prophylaxis of IA in ICU patients.
T104 15680-15834 Sentence denotes Posaconazole (POS) prophylaxis reduces the prevalence of IA in neutropenic AML patients and those with graft-versus-host disease following alloHCT [2, 3].
T105 15835-15958 Sentence denotes Based on this proof-of-principle, it has been hypothesized that POS prophylaxis can reduce IAPA prevalence in ICU patients.
T106 15959-16134 Sentence denotes Intravenous (IV) administration of POS prophylaxis in the ICU is favored in patients on mechanical ventilation or with a high likelihood of malabsorption of oral formulations.
T107 16135-16237 Sentence denotes POS IV formulation should be administered through a central catheter due to its acidity (pH 3.2) [42].
T108 16239-16291 Sentence denotes Treatment options and challenges for IAPA in the ICU
T109 16292-16377 Sentence denotes First-line treatment options for IPA include voriconazole and isavuconazole [35, 43].
T110 16378-16620 Sentence denotes Other options include echinocandins in combination with anti-mold azoles, and liposomal amphotericin B (L-AmB) in regions with high rates of azole-resistant A. fumigatus, although clinical data with L-AmB in ICU patients are limited [43, 44].
T111 16621-16751 Sentence denotes Achieving adequate drug exposure is challenging in ICU patients with multiple factors contributing to pharmacokinetic variability.
T112 16752-16938 Sentence denotes Unlike L-AmB and the echinocandins, drug interactions are clinically relevant for the azoles and pharmacogenetic factors are important in inter-individual drug exposure variability [45].
T113 16939-17075 Sentence denotes The impact of therapeutic drug monitoring (TDM) for voriconazole shows a clear relation between exposure and both efficacy and toxicity.
T114 17076-17321 Sentence denotes Target plasma trough voriconazole concentrations of ≥ 1.5–2 mg/L are associated with near-maximal clinical response in treatment of IA with a wild-type phenotype [46–51], with higher exposures (> 5.5 mg/L) increasing the risk of (neuro)toxicity.
T115 17322-17449 Sentence denotes Higher trough concentrations (> 2 mg/L) are recommended for treatment of pathogens with elevated MICs (e.g., > 0.25 mg/L) [52].
T116 17450-17641 Sentence denotes For isavuconazole, there is no robust target plasma concentration, and the population average exposure of participants that demonstrated a favorable response (2–4 mg/L) is commonly used [43].
T117 17643-17720 Sentence denotes Discussion on antifungal treatment options and challenges for IAPA in the ICU
T118 17721-18057 Sentence denotes A specific drug–drug interaction is relevant for patients with IAPA given the fact that co-infections with S. aureus are frequently observed; undetectable voriconazole levels have been observed in 11 of 20 patients, who were concomitantly treated with flucloxacillin [53], but the mechanisms of interaction are not yet fully understood.
T119 18058-18116 Sentence denotes Similar interactions have not been seen with other azoles.
T120 18117-18218 Sentence denotes Many other drug interactions with azoles and drugs commonly deployed in the ICU can be expected [45].
T121 18219-18425 Sentence denotes Aerosolized antifungal treatment may be a useful adjunctive therapy to systemic antifungal therapy for patients with confirmed Aspergillus tracheobronchitis, to achieve good endobronchial exposure [35, 54].
T122 18426-18608 Sentence denotes However, dense lipophilic plaques in the trachea may be difficult to penetrate and more research is needed into when and how to use aerosolized antifungals as well as their efficacy.
T123 18609-18842 Sentence denotes The ECCMID/ECMM/ERS Aspergillus guideline reviewed the teratogenic and mutagenic potential of antifungals in early pregnancy and recommends that azoles should be avoided, with polyenes being considered the preferred therapy [43, 55].
T124 18843-18952 Sentence denotes Thus, for pregnant patients at risk of IAPA a diagnostic approach was preferred above antifungal prophylaxis.
T125 18953-19033 Sentence denotes There is little evidence on the impact of ECMO on antifungal drug exposure [56].
T126 19034-19091 Sentence denotes For the echinocandins, an impact of ECMO is not expected.
T127 19092-19217 Sentence denotes Experts felt that, given these uncertainties, TDM of any antifungal used would be advised to ensure sufficient drug exposure.
T128 19219-19253 Sentence denotes Consensus case definition for IAPA
T129 19254-19585 Sentence denotes The expert panel discussed which case definition of IAPA would be appropriate to use in clinical studies, initially considering various aspects regarding four main areas of focus: entry criteria of the consensus definition, host, clinical features and mycological evidence similar to the currently used EORTC/MSGERC classification.
T130 19587-19602 Sentence denotes Entry criterion
T131 19603-19778 Sentence denotes In addition to having a positive diagnostic test for influenza, patients would require to have a clinical syndrome compatible with influenza disease as part of the definition.
T132 19779-19867 Sentence denotes This criterion should be termed the ‘entry criterion’ and not ‘host factor’ for clarity.
T133 19868-20173 Sentence denotes To avoid the risk of missing patients who initially tested negative with a rapid influenza antigen test but subsequently tested positive (by PCR) for influenza when admitted to hospital, a recommendation on a timescale, such as between 1 week before ICU admission and 72–96 h post-admission, was included.
T134 20174-20357 Sentence denotes The consensus on the entry criterion was: a patient requiring ICU admission for respiratory distress with a positive influenza PCR or antigen test temporally related to ICU admission.
T135 20359-20371 Sentence denotes Host factors
T136 20372-20668 Sentence denotes Host factors are considered in the EORTC/MSGERC definition and AspICU algorithm [10, 11], but the system of taking host factors into account was a necessity because the risk of a false-positive Aspergillus test increases substantially when the test is done in patients at low risk of the disease.
T137 20669-20811 Sentence denotes Clinicians had to take into account the type of host in order to increase the pretest probability of an invasive fungal disease being present.
T138 20812-20994 Sentence denotes However, for IAPA the key question is whether the disease is present or not, and not whether the patient group has a higher risk than other patient groups for developing the disease.
T139 20995-21120 Sentence denotes More importantly, the incidence of IAPA in patients admitted to the ICU with influenza may be higher in some centers [9, 21].
T140 21121-21219 Sentence denotes No further host factors are needed to increase the pretest probability in this patient population.
T141 21220-21366 Sentence denotes Although most IAPA cases have at least one underlying condition or steroid use, host factors were not be included in the case definition for IAPA.
T142 21368-21420 Sentence denotes Criteria to define proven and probable cases of IAPA
T143 21421-21598 Sentence denotes The distinction between proven and probable IAPA is important for clinical trials, while in clinical practice, people should not distinguish between proven and probable disease.
T144 21599-21845 Sentence denotes The criteria for proven disease include a patient fulfilling the entry criterion plus histological evidence of invasive fungal elements and mycological evidence for the presence of Aspergillus (obtained by Aspergillus PCR or culture from tissue).
T145 21846-22048 Sentence denotes Tracheobronchitis (tracheal and/or bronchial ulcerations or nodules, pseudomembranes or plaques visualized at bronchoscopy), as also described in the EORTC/MSGERC definitions [10], is a separate entity.
T146 22049-22326 Sentence denotes Although a tissue biopsy would normally be required to prove a case of IAPA, in tracheobronchitis cases hyphal elements suggestive of Aspergillus seen on sloughed-off pseudomembrane, and Aspergillus identified on culture or PCR, can also be considered proven disease (Table 1).
T147 22327-22384 Sentence denotes Table 1 Proposed case definition for IAPA in ICU patients
T148 22385-22485 Sentence denotes Entry criteria: influenza-like illness + positive influenza PCR or antigen + temporally relationship
T149 22486-22581 Sentence denotes Aspergillus tracheobronchitis IAPA in patients without documented Aspergillus tracheobronchitis
T150 22582-22868 Sentence denotes Proven Biopsy or brush specimen of airway plaque, pseudomembrane or ulcer showing hyphal elements and Aspergillus growth on culture or positive Aspergillus PCR in tissue Lung biopsy showing invasive fungal elements and Aspergillus growth on culture or positive Aspergillus PCR in tissue
T151 22869-22916 Sentence denotes Probable Airway plaque, pseudomembrane or ulcer
T152 22917-22951 Sentence denotes and at least one of the following:
T153 22952-22972 Sentence denotes Serum GM index > 0.5
T154 22973-22975 Sentence denotes or
T155 22976-22994 Sentence denotes BAL GM index ≥ 1.0
T156 22995-22997 Sentence denotes or
T157 22998-23018 Sentence denotes Positive BAL culture
T158 23019-23021 Sentence denotes or
T159 23022-23056 Sentence denotes Positive tracheal aspirate culture
T160 23057-23059 Sentence denotes or
T161 23060-23083 Sentence denotes Positive sputum culture
T162 23084-23086 Sentence denotes or
T163 23087-23124 Sentence denotes Hyphae consistent with Aspergillus A:
T164 23125-23145 Sentence denotes Pulmonary infiltrate
T165 23146-23180 Sentence denotes and at least one of the following:
T166 23181-23201 Sentence denotes Serum GM index > 0.5
T167 23202-23204 Sentence denotes or
T168 23205-23223 Sentence denotes BAL GM index ≥ 1.0
T169 23224-23226 Sentence denotes or
T170 23227-23247 Sentence denotes Positive BAL culture
T171 23248-23250 Sentence denotes OR
T172 23251-23253 Sentence denotes B:
T173 23254-23309 Sentence denotes Cavitating infiltrate (not attributed to another cause)
T174 23310-23344 Sentence denotes and at least one of the following:
T175 23345-23368 Sentence denotes Positive sputum culture
T176 23369-23371 Sentence denotes or
T177 23372-23406 Sentence denotes Positive tracheal aspirate culture
T178 23407-23508 Sentence denotes A patient fulfilling the case definition of probable IAPA is required to fulfill the entry criterion.
T179 23509-23732 Sentence denotes A positive serum GM (GM index > 0.5) is important evidence for the diagnosis of IAPA, in patients with pulmonary infiltrates on chest X-ray or other imaging modality or bronchoscopic evidence of tracheobronchitis (Table 1).
T180 23733-23799 Sentence denotes In patients with tracheobronchitis, an infiltrate is not required.
T181 23800-23992 Sentence denotes In patients with endobronchial plaques or pulmonary infiltrates, a positive BAL GM or culture of a tracheal aspirate is considered mycological evidence that supports a probable IAPA diagnosis.
T182 23993-24148 Sentence denotes In patients with bacterial pneumonia where Aspergillus is cultured only from a sputum sample, there may be a risk of overdiagnosis and thus over-treatment.
T183 24149-24353 Sentence denotes For clinical practice, clinicians should take into account that a positive culture of an upper airway sample may indicate IAPA, but that confirmation with serum or BAL GM or BAL culture should be pursued.
T184 24354-24512 Sentence denotes However, one problem is that the background incidence varies in different regions, making it difficult to develop generalized guidelines that apply uniformly.
T185 24513-24619 Sentence denotes The significance of a positive sputum culture thus depends on the background incidence in a specific unit.
T186 24620-24839 Sentence denotes Although any Aspergillus-positive respiratory sample is in itself insufficient to classify patients as probable IAPA, a new pulmonary cavitating infiltrate is indicative of IAPA in patients who meet the entry criterion.
T187 24840-25033 Sentence denotes Therefore, any Aspergillus-positive respiratory sample is sufficient evidence to classify patients as probable IAPA provided that a pulmonary cavitating infiltrate is present (Table 1; Fig. 1).
T188 25034-25280 Sentence denotes Fig. 1 Flowchart of probable IAPA classification. (*)If hyphae consistent with Aspergillus are documented in a biopsy of an airway lesion AND Aspergillus is grown from sputum or a tracheal aspirate, the case fulfills the definition of proven IAPA
T189 25281-25494 Sentence denotes A BAL GM index cutoff of ≥ 1.0 is recommended as this cutoff value ensures high specificity, without decreasing sensitivity significantly, which is also in line with other definitions and recommendations [10, 57].
T190 25495-25656 Sentence denotes Aspergillus PCR is not recommended as a primary diagnostic tool because of concerns about its reliability and positive predictive value for the diagnosis of IPA.
T191 25657-25784 Sentence denotes However, Aspergillus PCR is recommended in the proven category because it enables Aspergillus identification in tissue samples.
T192 25785-25895 Sentence denotes In some patients, discordant results are obtained, for instance a positive sputum culture but negative BAL GM.
T193 25896-26142 Sentence denotes For most situations, IAPA classification relies on a positive GM test, as a positive sputum culture with a negative GM result would be interpreted as a lower probability of IAPA (unless a pulmonary cavity or tracheobronchitis is present)(Fig. 1).
T194 26144-26154 Sentence denotes Conclusion
T195 26155-26357 Sentence denotes IAPA has emerged as a severe complication of influenza, especially in ICU patients, and this secondary infection may occur in any patient, including those considered to be at low risk of developing IPA.
T196 26358-26456 Sentence denotes The global epidemiology of IAPA may be variable, which might be partly due to underdiagnosis [24].
T197 26457-26629 Sentence denotes The clinical presentation of IAPA includes invasive Aspergillus tracheobronchitis, which requires bronchoscopic visualization of plaques in the airways to make a diagnosis.
T198 26630-26767 Sentence denotes Aspergillus culture and BAL GM are positive in > 80% of IAPA cases, and ordering such tests is recommended in influenza cases in the ICU.
T199 26768-26898 Sentence denotes The proposed case definition relies on an entry criterion based on an influenza-like illness and the detection of influenza virus.
T200 26899-27102 Sentence denotes The case definition distinguishes between invasive tracheobronchitis and other pulmonary forms of IAPA, with demonstration of invasive fungal hyphae with positive mycology qualifying as proven infection.
T201 27103-27219 Sentence denotes Detection of GM or positive Aspergillus culture in BAL is the main mycological criteria in probable case definition.
T202 27220-27515 Sentence denotes The expert group acknowledges that to date still limited data exist to support a definitive approach regarding definitions, diagnosis and treatment of IAPA, but the proposed case definition will facilitate clinical research, will enable valid study comparisons and is essential for surveillance.
T203 27516-27672 Sentence denotes Awareness of IAPA and early antifungal therapy based on high clinical suspicion and Aspergillus diagnostics remains critical to improve the outcome of IAPA.
T204 27674-27757 Sentence denotes Can the IAPA definitions be applied to COVID-19-associated pulmonary aspergillosis?
T205 27758-27975 Sentence denotes Recent reports of IPA cases in coronavirus disease 2019 (COVID-19) patients in the ICU raise the question of whether these IAPA definitions can be applied to COVID-19-associated pulmonary aspergillosis (CAPA) [58–60].
T206 27976-28182 Sentence denotes Although the number of CAPA cases that have been reported is still limited, two recent studies reported putative CAPA cases in 9 of 27 (33%) and 5 of 19 (26%) COVID-19 patients admitted to the ICU [59, 60].
T207 28183-28397 Sentence denotes Although the high number of cases suggests a high risk of developing IPA in COVID-19 patients, there are a number of differences regarding the pathogenesis of SARS-CoV-2 infection compared with influenza (Table 2).
T208 28398-28710 Sentence denotes In influenza patients, there are several factors that are thought to contribute to the risk of IAPA, including the local tissue damage caused by influenza, an immune modulatory effect by suppression of the NADPH oxidase complex and possible effect of treatment with neuraminidase inhibitors, such as oseltamivir.
T209 28711-28856 Sentence denotes In SARS-CoV-2 infection, another receptor is used by the virus to enter human cells, which are not commonly found in the large airways (Table 2).
T210 28857-28954 Sentence denotes Thus, the risk of invasive Aspergillus tracheobronchitis may be lower in CAPA compared with IAPA.
T211 28955-29097 Sentence denotes In addition, there is no known direct immune modulatory effect of SARS-CoV-2, which suggests no virus infection-related increased risk of IPA.
T212 29098-29245 Sentence denotes While IAPA is characterized by rapidly fatal infections with high fungal burden, such course of disease progression has not been reported for CAPA.
T213 29246-29419 Sentence denotes On the contrary, eight of nine CAPA cases reported from a French cohort did not receive antifungal therapy, with a mortality rate similar to COVID-19 cases without IPA [59].
T214 29420-29625 Sentence denotes As, in contrast to IAPA cases, virtually all CAPA cases reported to date are serum GM negative, the question remains if COVID-19 patients develop invasive disease or just become colonized with Aspergillus.
T215 29626-29841 Sentence denotes It is possible that COVID-19 is in itself not a risk factor for IPA, but that the risk is associated with other risk factors related to treatment such as administration of corticosteroids or underlying host factors.
T216 29842-30002 Sentence denotes Nevertheless, the high rate of Aspergillus recovered from COVID-19 patients suggests that there might be conditions that favor growth of the fungus in the lung.
T217 30003-30256 Sentence denotes We think that the proposed IAPA case definitions may be considered for classification of CAPA patients, while awaiting further histopathological studies that provide more insight into the interaction between Aspergillus and the SARS-CoV-2-infected lung.
T218 30257-30316 Sentence denotes Table 2 Comparison between characteristics of IAPA and CAPA
T219 30317-30333 Sentence denotes Factor IAPA CAPA
T220 30334-30432 Sentence denotes Host/Risk 57% EORTC/MSGERC host factor negative [9] 85% EORTC/MSGERC host factor negative [59, 60]
T221 30433-30552 Sentence denotes IAPA associated with corticosteroid use [7] IPA developed in SARS-2003-infected patients receiving corticosteroids [61]
T222 30553-30655 Sentence denotes Lymphopenia and chemokine-producing monocyte-derived FCN1 + macrophages causing hyperinflammation [62]
T223 30656-30824 Sentence denotes Virus Cell entry through sialic acids-2,6Gal: epithelial layer in lung including larger airways [63] Cell entry through ACE2: type 2 pneumocytes and ciliated cells [64]
T224 30825-31027 Sentence denotes Immune modulation by suppression of the NADPH oxidase complex [65] No evidence for immunomodulatory effect on known antifungal host defense mechanisms, although this has not been extensively studied yet
T225 31028-31179 Sentence denotes Fungal infection Invasive Aspergillus tracheobronchitis in up to 55% of patients [7–9] Invasive Aspergillus tracheobronchitis not yet reported [59, 60]
T226 31180-31312 Sentence denotes Median time between ICU admission and IAPA diagnosis 2–3 days [7–9] Median time between ICU admission and CAPA diagnosis 6 days [59]
T227 31313-31443 Sentence denotes Aspergillus diagnostics BAL GM positive in > 88% [7–9] BAL GM commonly positive, diagnostic performance currently unknown [59, 60]
T228 31444-31536 Sentence denotes Serum GM positive in 65% [7–9] Serum GM positive in 3 of 14 (21%) COVID-19 patients [59, 60]
T229 31537-31736 Sentence denotes Secondary infections In 80 of 342 (23.4%) ICU patients, most frequent pathogens S. pneumoniae, Pseudomonas aeruginosa and S. aureus [66] In four of 13 (31%) ICU patients, pathogens not specified [67]
T230 31737-32058 Sentence denotes ICU mortality 45% in IAPA compared with 20% in influenza without IAPA (p < 0.0001) [9] 33% in CAPA cases compared with 17% in COVID-19 without CAPA (p = 0.4) [59] (although mortality rates due to COVID-19 without CAPA vary enormous between countries and we have no clear data yet on the true mortality in ICU of COVID-19)
T231 32060-32071 Sentence denotes Disclaimer:
T232 32072-32245 Sentence denotes The findings and conclusions in this report those of the authors do not necessarily represent the official positions of the Centers for Disease Control and Prevention (CDC).
T233 32246-32262 Sentence denotes Publisher's Note
T234 32263-32381 Sentence denotes Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T235 32383-32403 Sentence denotes Author contributions
T236 32404-32503 Sentence denotes An expert meeting was organized by PEV, RJMB, JW and FLvdV and held in Amsterdam on April 16, 2019.
T237 32504-32618 Sentence denotes Present at the expert meeting were PEV, BJAR, RJMB, SB, CJC, OAC, DRG, NAFJ, BJK, KL, JM, MHN, TFP, TRR and FLvdV.
T238 32619-32735 Sentence denotes A first draft manuscript was prepared by PEV, BJAR, RJMB, JW and FLvdV and circulated for comments from all experts.
T239 32736-32789 Sentence denotes All experts reviewed and commented on the manuscript.
T240 32790-32856 Sentence denotes Using these comments, a final version was circulated for approval.
T241 32858-32865 Sentence denotes Funding
T242 32866-32902 Sentence denotes The meeting was supported by Pfizer.
T243 32903-33007 Sentence denotes Pfizer had no role in the topics discussed nor were they involved in drafting of the consensus document.
T244 33009-33042 Sentence denotes Compliance with ethical standards
T245 33044-33065 Sentence denotes Conflicts of interest
T246 33066-33208 Sentence denotes PE Verweij reported grants from Gilead Sciences, MSD, Pfizer and F2G, and non-financial support from OLM and IMMY, outside the submitted work.
T247 33209-33580 Sentence denotes BJA Rijnders was the investigator for studies supported by Gilead Sciences, Janssen-Cilag, MSD, Pfizer, ViiV; has received research grants from Gilead and MSD; was an invited speaker for Gilead, MSD, Pfizer, Jansen-Cilag, BMS; and an advisory board member for BMS, Abbvie, MSD, Gilead, Jansen-Cilag; he received travel support from BMS, Abbvie, MSD, Gilead, Jansen-Cilag.
T248 33581-33858 Sentence denotes RJM Brüggemann served as a consultant to Astellas Pharma, Inc., F2G, Amplyx, Gilead Sciences, Merck Sharp & Dohme Corp., and Pfizer, Inc., and has received unrestricted and research grants from Astellas Pharma, Inc., Gilead Sciences, Merck Sharp & Dohme Corp., and Pfizer, Inc.
T249 33859-33943 Sentence denotes All contracts were through Radboudumc, and all payments were invoiced by Radboudumc.
T250 33944-34030 Sentence denotes E Azoulay has received fees for lectures from Pfizer, Gilead, MSD, Alexion and Baxter.
T251 34031-34117 Sentence denotes His institution received research support from Fisher&Payckle, Jazz pharma and Gilead.
T252 34118-34421 Sentence denotes M Bassetti has received funding for scientific advisory boards, travel and speaker honoraria from Angelini, Astellas, AstraZeneca, Basilea, Bayer, BioMèrieux, Cidara, Correvio, Cubist, Menarini, Molteni, MSD, Nabriva, Paratek, Pfizer, Roche, Shionogi, Tetraphase, Thermo Fisher and The Medicine Company.
T253 34422-34568 Sentence denotes S Blot received research funding from Pfizer and MSD, travel support from Pfizer, MSD and Gilead, and is an invited speaker for Pfizer and Gilead.
T254 34569-34772 Sentence denotes T Calandra reported advisory board membership from Astellas, Basilea, Cidara, MSD, Sobi, ThermoFisher and GE Healthcare and data monitoring board membership from Novartis, all outside the submitted work.
T255 34773-34806 Sentence denotes Fees are paid to its institution.
T256 34807-35152 Sentence denotes CJ Clancy has been awarded investigator-initiated research grants from Astellas, Merck, Melinta and Cidara for projects unrelated to this project, served on advisory boards or consulted for Astellas, Merck, the Medicines Company, Cidara, Scynexis, Shionogi, Qpex and Needham & Company, and spoken at symposia sponsored by Merck and T2Biosystems.
T257 35153-35714 Sentence denotes OA Cornely is supported by the German Federal Ministry of Research and Education and the European Commission, and has received research grants from, is an advisor to, or received lecture honoraria from Actelion, Allecra Therapeutics, Amplyx, Astellas, Basilea, Biosys UK Limited, Cidara, Da Volterra, Entasis, F2G, Gilead, Grupo Biotoscana, Janssen Pharmaceuticals, Matinas, Medicines Company, MedPace, Melinta Therapeutics, Menarini Ricerche, Merck/MSD, Octapharma, Paratek Pharmaceuticals, Pfizer, PSI, Rempex, Scynexis, Seres Therapeutics, Tetraphase, Vical.
T258 35715-35759 Sentence denotes T Chiller reported no conflicts of interest.
T259 35760-35804 Sentence denotes P Depuydt reported no conflicts of interest.
T260 35805-35906 Sentence denotes DR Giacobbe reported honoraria from Stepstone Pharma GmbH and an unconditional grant from MSD Italia.
T261 35907-35953 Sentence denotes NAF Janssen reported no conflicts of interest.
T262 35954-36028 Sentence denotes BJ Kullberg has been a scientific advisor for Amplyx, Cidara and Scynexis.
T263 36029-36196 Sentence denotes K Lagrou received consultancy fees from MSD, SMB Laboratoires Brussels and Gilead, travel support from Pfizer and MSD and speaker fees from Gilead, MSD, FUJIFILM WAKO.
T264 36197-36360 Sentence denotes C Lass-Florl received research funding from Pfizer, Gilead and Egger, travel support from Pfizer, MSD, and Gilead, and is an invited speaker for Pfizer and Gilead.
T265 36361-36467 Sentence denotes RE Lewis has received research support from Merck and has served as an invited speaker for Gilead, Cidara.
T266 36468-36644 Sentence denotes P Wei-Lun Liu has received research grants from MSD, Pfizer, and has served as an invited speaker for Gilead, MSD, Pfizer, Astellas Pharma, and is an advisor to Pfizer, Gilead.
T267 36645-36782 Sentence denotes O Lortholary has served as an invited speaker for Gilead, MSD, Pfizer, Astellas Pharma, and is a consultant for Gilead, Novartis and F2G.
T268 36783-37019 Sentence denotes J Maertens reported personal fees and non-financial support from Basilea Pharmaceuticals, Bio-Rad Laboratories, Cidara, F2G Ltd., Gilead Sciences, Merck, Astellas, Scynexis, and Pfizer Inc. and grants from Gilead Sciences, IMMY and OLM.
T269 37020-37071 Sentence denotes I Martin-Loeches reported no conflicts of interest.
T270 37072-37312 Sentence denotes MH Nguyen has been awarded investigator-initiated research grants from Astellas, Merck, Melinta and Cidara for projects unrelated to this study and served on advisory boards for Astellas, Merck, the Medicines Company, Scynexis and Shionogi.
T271 37313-37509 Sentence denotes TF Patterson reported grants from Cidara to UT Health San Antonio; personal fees from Basilea, Gilead, Mayne, Merck, Pfizer, Scynexis, Sfunga, Toyama and United Medical outside the submitted work.
T272 37510-37683 Sentence denotes TR Rogers has received grants from Gilead Sciences, lecture honoraria from Gilead Sciences and Pfizer Healthcare Ireland, and advisory board membership with Menarini Pharma.
T273 37684-37797 Sentence denotes JA Schouten has received unrestricted educational and research grants from MSD and has been an advisor to Pfizer.
T274 37798-37882 Sentence denotes All contracts were through Radboudumc, and all payments were invoiced by Radboudumc.
T275 37883-38002 Sentence denotes I Spriet has received unrestricted research grants, speaker fees and travel grants from MSD, Pfizer, Gilead and Cidara.
T276 38003-38051 Sentence denotes She has served in the advisory board for Cidara.
T277 38052-38161 Sentence denotes L Vanderbeke is supported by the Flanders Research Foundation (FWO Vlaanderen) through a doctoral fellowship.
T278 38162-38289 Sentence denotes J Wauters reported grants from Gilead Sciences, MSD and Pfizer, and non-financial support from MSD, outside the submitted work.
T279 38290-38353 Sentence denotes FL van de Veerdonk has served as an invited speaker for Gilead.