LitCovid-sentences  

PMC:7306567 / 1920-32058 JSONTXT 13 Projects

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Id Subject Object Predicate Lexical cue
T16 0-17 Sentence denotes Take-home message
T17 18-134 Sentence denotes Invasive pulmonary aspergillosis is an emerging co-infection in patients with influenza who are admitted to the ICU.
T18 135-383 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 385-397 Sentence denotes Introduction
T20 398-703 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 704-1005 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 1006-1125 Sentence denotes With changing treatment modalities, new risk groups continue to emerge, such as patients treated with ibrutinib [4, 5].
T23 1126-1388 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 1389-1755 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 1756-1921 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 1922-2134 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 2135-2356 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 2358-2382 Sentence denotes Participants and methods
T29 2383-2482 Sentence denotes The expert panel is comprised of 29 participants from seven European countries, the USA and Taiwan.
T30 2483-2843 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 2844-3011 Sentence denotes Selected participants furthermore had specific expertise in epidemiology, diagnosis and management of invasive fungal diseases or fungal disease guideline development.
T32 3012-3064 Sentence denotes The meeting was prepared by PEV, RJMB, JW and FLvdV.
T33 3065-3137 Sentence denotes Case definitions were developed through a process of informal consensus.
T34 3138-3473 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 3474-3552 Sentence denotes The goal of the consensus process was to bring the group to general agreement.
T36 3553-3738 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 3739-3926 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 3927-4020 Sentence denotes A medical writer made notes of the meeting, which were used as input to write the manuscript.
T39 4021-4137 Sentence denotes A first draft manuscript was prepared by PEV, BJAR, RJMB, JW and FLvdV and circulated for comments from all experts.
T40 4138-4191 Sentence denotes The experts reviewed and commented on the manuscript.
T41 4192-4258 Sentence denotes Using these comments, a final version was circulated for approval.
T42 4259-4473 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 4474-4644 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 4646-4659 Sentence denotes Expert review
T45 4661-4702 Sentence denotes Global epidemiology of influenza and IAPA
T46 4703-4908 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 4909-5009 Sentence denotes The mortality in patients admitted for influenza is 4% and 20–25% for those admitted to ICU [14–16].
T48 5010-5143 Sentence denotes Bacterial superinfection is common, affecting 10–35% of cases, typically with Streptococcus pneumoniae or Staphylococcus aureus [16].
T49 5144-5386 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 5387-5585 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 5586-5771 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 5772-5873 Sentence denotes The median time between influenza diagnosis and IAPA was short, often in the first 5 days [7, 8, 18].
T53 5874-6115 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 6116-6436 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 6437-6535 Sentence denotes Autopsy rates are very low, which results in a considerable underdiagnosis in many countries [26].
T56 6536-6790 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 6791-7000 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 7002-7022 Sentence denotes Pathogenesis of IAPA
T59 7023-7345 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 7346-7506 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 7507-7680 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 7681-7825 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 7826-7989 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 7991-8034 Sentence denotes Clinical presentation and diagnosis of IAPA
T65 8035-8185 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 8186-8307 Sentence denotes Four cases (44%) were proven despite not being immunocompromised according to the EORTC/MSGERC consensus definitions [7].
T67 8308-8389 Sentence denotes The median time between influenza diagnosis and IAPA was 2 days (range 0–4 days).
T68 8390-8490 Sentence denotes All IAPA patients had positive BAL GM, and 78% had positive serum GM, despite not being neutropenic.
T69 8491-8732 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 8733-8840 Sentence denotes Similar performance characteristics of BAL GM and culture were reported in two other cohort studies [8, 9].
T71 8841-8981 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 8982-9138 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 9139-9272 Sentence denotes However, in some IAPA patients with autopsy-confirmed Aspergillus tracheobronchitis, chest CT demonstrated peribronchial infiltrates.
T74 9273-9482 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 9483-9716 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 9717-9991 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 9992-10200 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 10201-10363 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 10364-10442 Sentence denotes However, lateral flow tests have not yet been validated in the ICU population.
T80 10443-10634 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 10635-10864 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 10865-10983 Sentence denotes This would enable diagnostic assessment and initiation of adequate antifungal therapy within 24–48 h of ICU admission.
T83 10984-11163 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 11165-11222 Sentence denotes Discussion on clinical presentation and diagnosis of IAPA
T85 11223-11399 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 11400-11652 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 11653-11796 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 11797-11961 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 11962-12115 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 12116-12189 Sentence denotes The use of a flexible brush may also be sufficient to make the diagnosis.
T91 12190-12312 Sentence denotes Although a positive serum GM is highly indicative of IA, BAL GM can be positive in patients with Aspergillus colonization.
T92 12313-12401 Sentence denotes It therefore does not absolutely discriminate between colonization and invasive disease.
T93 12402-12484 Sentence denotes However, it clearly makes it more likely that an invasive disease is present [36].
T94 12486-12508 Sentence denotes Use of corticosteroids
T95 12509-12637 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 12638-12787 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 12788-12847 Sentence denotes However, the evidence was almost exclusively observational.
T98 12848-13035 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 13036-13222 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 13223-13407 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 13409-13454 Sentence denotes Rationale for antifungal prophylaxis for IAPA
T102 13455-13651 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 13652-13759 Sentence denotes However, there is currently no mold-active antifungal agent licensed for prophylaxis of IA in ICU patients.
T104 13760-13914 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 13915-14038 Sentence denotes Based on this proof-of-principle, it has been hypothesized that POS prophylaxis can reduce IAPA prevalence in ICU patients.
T106 14039-14214 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 14215-14317 Sentence denotes POS IV formulation should be administered through a central catheter due to its acidity (pH 3.2) [42].
T108 14319-14371 Sentence denotes Treatment options and challenges for IAPA in the ICU
T109 14372-14457 Sentence denotes First-line treatment options for IPA include voriconazole and isavuconazole [35, 43].
T110 14458-14700 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 14701-14831 Sentence denotes Achieving adequate drug exposure is challenging in ICU patients with multiple factors contributing to pharmacokinetic variability.
T112 14832-15018 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 15019-15155 Sentence denotes The impact of therapeutic drug monitoring (TDM) for voriconazole shows a clear relation between exposure and both efficacy and toxicity.
T114 15156-15401 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 15402-15529 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 15530-15721 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 15723-15800 Sentence denotes Discussion on antifungal treatment options and challenges for IAPA in the ICU
T118 15801-16137 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 16138-16196 Sentence denotes Similar interactions have not been seen with other azoles.
T120 16197-16298 Sentence denotes Many other drug interactions with azoles and drugs commonly deployed in the ICU can be expected [45].
T121 16299-16505 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 16506-16688 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 16689-16922 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 16923-17032 Sentence denotes Thus, for pregnant patients at risk of IAPA a diagnostic approach was preferred above antifungal prophylaxis.
T125 17033-17113 Sentence denotes There is little evidence on the impact of ECMO on antifungal drug exposure [56].
T126 17114-17171 Sentence denotes For the echinocandins, an impact of ECMO is not expected.
T127 17172-17297 Sentence denotes Experts felt that, given these uncertainties, TDM of any antifungal used would be advised to ensure sufficient drug exposure.
T128 17299-17333 Sentence denotes Consensus case definition for IAPA
T129 17334-17665 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 17667-17682 Sentence denotes Entry criterion
T131 17683-17858 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 17859-17947 Sentence denotes This criterion should be termed the ‘entry criterion’ and not ‘host factor’ for clarity.
T133 17948-18253 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 18254-18437 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 18439-18451 Sentence denotes Host factors
T136 18452-18748 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 18749-18891 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 18892-19074 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 19075-19200 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 19201-19299 Sentence denotes No further host factors are needed to increase the pretest probability in this patient population.
T141 19300-19446 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 19448-19500 Sentence denotes Criteria to define proven and probable cases of IAPA
T143 19501-19678 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 19679-19925 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 19926-20128 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 20129-20406 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 20407-20464 Sentence denotes Table 1 Proposed case definition for IAPA in ICU patients
T148 20465-20565 Sentence denotes Entry criteria: influenza-like illness + positive influenza PCR or antigen + temporally relationship
T149 20566-20661 Sentence denotes Aspergillus tracheobronchitis IAPA in patients without documented Aspergillus tracheobronchitis
T150 20662-20948 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 20949-20996 Sentence denotes Probable Airway plaque, pseudomembrane or ulcer
T152 20997-21031 Sentence denotes and at least one of the following:
T153 21032-21052 Sentence denotes Serum GM index > 0.5
T154 21053-21055 Sentence denotes or
T155 21056-21074 Sentence denotes BAL GM index ≥ 1.0
T156 21075-21077 Sentence denotes or
T157 21078-21098 Sentence denotes Positive BAL culture
T158 21099-21101 Sentence denotes or
T159 21102-21136 Sentence denotes Positive tracheal aspirate culture
T160 21137-21139 Sentence denotes or
T161 21140-21163 Sentence denotes Positive sputum culture
T162 21164-21166 Sentence denotes or
T163 21167-21204 Sentence denotes Hyphae consistent with Aspergillus A:
T164 21205-21225 Sentence denotes Pulmonary infiltrate
T165 21226-21260 Sentence denotes and at least one of the following:
T166 21261-21281 Sentence denotes Serum GM index > 0.5
T167 21282-21284 Sentence denotes or
T168 21285-21303 Sentence denotes BAL GM index ≥ 1.0
T169 21304-21306 Sentence denotes or
T170 21307-21327 Sentence denotes Positive BAL culture
T171 21328-21330 Sentence denotes OR
T172 21331-21333 Sentence denotes B:
T173 21334-21389 Sentence denotes Cavitating infiltrate (not attributed to another cause)
T174 21390-21424 Sentence denotes and at least one of the following:
T175 21425-21448 Sentence denotes Positive sputum culture
T176 21449-21451 Sentence denotes or
T177 21452-21486 Sentence denotes Positive tracheal aspirate culture
T178 21487-21588 Sentence denotes A patient fulfilling the case definition of probable IAPA is required to fulfill the entry criterion.
T179 21589-21812 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 21813-21879 Sentence denotes In patients with tracheobronchitis, an infiltrate is not required.
T181 21880-22072 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 22073-22228 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 22229-22433 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 22434-22592 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 22593-22699 Sentence denotes The significance of a positive sputum culture thus depends on the background incidence in a specific unit.
T186 22700-22919 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 22920-23113 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 23114-23360 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 23361-23574 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 23575-23736 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 23737-23864 Sentence denotes However, Aspergillus PCR is recommended in the proven category because it enables Aspergillus identification in tissue samples.
T192 23865-23975 Sentence denotes In some patients, discordant results are obtained, for instance a positive sputum culture but negative BAL GM.
T193 23976-24222 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 24224-24234 Sentence denotes Conclusion
T195 24235-24437 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 24438-24536 Sentence denotes The global epidemiology of IAPA may be variable, which might be partly due to underdiagnosis [24].
T197 24537-24709 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 24710-24847 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 24848-24978 Sentence denotes The proposed case definition relies on an entry criterion based on an influenza-like illness and the detection of influenza virus.
T200 24979-25182 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 25183-25299 Sentence denotes Detection of GM or positive Aspergillus culture in BAL is the main mycological criteria in probable case definition.
T202 25300-25595 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 25596-25752 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 25754-25837 Sentence denotes Can the IAPA definitions be applied to COVID-19-associated pulmonary aspergillosis?
T205 25838-26055 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 26056-26262 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 26263-26477 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 26478-26790 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 26791-26936 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 26937-27034 Sentence denotes Thus, the risk of invasive Aspergillus tracheobronchitis may be lower in CAPA compared with IAPA.
T211 27035-27177 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 27178-27325 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 27326-27499 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 27500-27705 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 27706-27921 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 27922-28082 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 28083-28336 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 28337-28396 Sentence denotes Table 2 Comparison between characteristics of IAPA and CAPA
T219 28397-28413 Sentence denotes Factor IAPA CAPA
T220 28414-28512 Sentence denotes Host/Risk 57% EORTC/MSGERC host factor negative [9] 85% EORTC/MSGERC host factor negative [59, 60]
T221 28513-28632 Sentence denotes IAPA associated with corticosteroid use [7] IPA developed in SARS-2003-infected patients receiving corticosteroids [61]
T222 28633-28735 Sentence denotes Lymphopenia and chemokine-producing monocyte-derived FCN1 + macrophages causing hyperinflammation [62]
T223 28736-28904 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 28905-29107 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 29108-29259 Sentence denotes Fungal infection Invasive Aspergillus tracheobronchitis in up to 55% of patients [7–9] Invasive Aspergillus tracheobronchitis not yet reported [59, 60]
T226 29260-29392 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 29393-29523 Sentence denotes Aspergillus diagnostics BAL GM positive in > 88% [7–9] BAL GM commonly positive, diagnostic performance currently unknown [59, 60]
T228 29524-29616 Sentence denotes Serum GM positive in 65% [7–9] Serum GM positive in 3 of 14 (21%) COVID-19 patients [59, 60]
T229 29617-29816 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 29817-30138 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)