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T1 0-79 Sentence denotes COVID-19 Associated Pulmonary Aspergillosis (CAPA)—From Immunology to Treatment
T2 81-89 Sentence denotes Abstract
T3 90-397 Sentence denotes Like severe influenza, coronavirus disease-19 (COVID-19) resulting in acute respiratory distress syndrome (ARDS) has emerged as an important disease that predisposes patients to secondary pulmonary aspergillosis, with 35 cases of COVID-19 associated pulmonary aspergillosis (CAPA) published until June 2020.
T4 398-607 Sentence denotes The release of danger-associated molecular patterns during severe COVID-19 results in both pulmonary epithelial damage and inflammatory disease, which are predisposing risk factors for pulmonary aspergillosis.
T5 608-827 Sentence denotes Moreover, collateral effects of host recognition pathways required for the activation of antiviral immunity may, paradoxically, contribute to a highly permissive inflammatory environment that favors fungal pathogenesis.
T6 828-1155 Sentence denotes Diagnosis of CAPA remains challenging, mainly because bronchoalveolar lavage fluid galactomannan testing and culture, which represent the most sensitive diagnostic tests for aspergillosis in the ICU, are hindered by the fact that bronchoscopies are rarely performed in COVID-19 patients due to the risk of disease transmission.
T7 1156-1264 Sentence denotes Similarly, autopsies are rarely performed, which may result in an underestimation of the prevalence of CAPA.
T8 1265-1525 Sentence denotes Finally, the treatment of CAPA is complicated by drug–drug interactions associated with broad spectrum azoles, renal tropism and damage caused by SARS-CoV-2, which may challenge the use of liposomal amphotericin B, as well as the emergence of azole-resistance.
T9 1526-1700 Sentence denotes This clinical reality creates an urgency for new antifungal drugs currently in advanced clinical development with more promising pharmacokinetic and pharmacodynamic profiles.
T10 1702-1704 Sentence denotes 1.
T11 1705-1717 Sentence denotes Introduction
T12 1718-1871 Sentence denotes Invasive fungal infections caused by various fungal genera, including Aspergillus, complicate and endanger lives of millions of individuals annually [1].
T13 1872-2222 Sentence denotes Aspergillus genera, most frequently Aspergillus fumigatus, are ubiquitous in the environment and cause a wide range of infections in humans, including invasive pulmonary aspergillosis (IPA), chronic pulmonary aspergillosis (CPA), allergic bronchopulmonary aspergillosis (ABPA), chronic rhinosinusitis, fungal asthma, and Aspergillus bronchitis [2,3].
T14 2223-2646 Sentence denotes IPA, the most severe manifestation of disease from Aspergillus, is associated with high mortality rates and is a prominent complication among those with profound immunosuppression, such as those undergoing hematopoietic transplantation, as well as those with structural lung damage who receive systemic corticosteroids for their underlying condition, such as patients with chronic obstructive pulmonary diseases (COPD) [2].
T15 2647-2905 Sentence denotes Recently, it has been reported that a relatively high number of influenza patients presenting with severe acute respiratory distress syndrome (ARDS) also rapidly develop IPA, which is associated with increased duration of hospitalization and mortality [4,5].
T16 2906-3036 Sentence denotes Corticosteroid use and pulmonary epithelial damages caused by severe influenza are the main risk factors for developing IPA [4,5].
T17 3037-3193 Sentence denotes The recent global pandemic of coronavirus disease-19, also known as COVID-19, has infected over 6 million patients worldwide, with more than 360,000 deaths.
T18 3194-3540 Sentence denotes It has been shown that up to 40% of COVID-19 hospitalized patients can develop ARDS [6], and thereby become susceptible to acquire co-infections caused by bacteria and also Aspergillus spp. [7,8], although frequency of co-infections seems to vary between centers and overall co-infections may occur less frequently than with severe influenza [9].
T19 3541-3670 Sentence denotes Once they occur, these superinfections are associated with high mortality rates and may prolong the acute phase of COVID-19 [10].
T20 3671-3891 Sentence denotes In this comprehensive review, we discuss various aspects of COVID-19 associated pulmonary aspergillosis (CAPA), focusing specifically on immunology, risk factors, prevalence, diagnosis, treatment, and current challenges.
T21 3893-3895 Sentence denotes 2.
T22 3896-3906 Sentence denotes Immunology
T23 3907-4083 Sentence denotes Dissecting the complex pathogenesis of CAPA requires a molecular understanding of the physiological processes whereby infection with SARS-CoV-2 facilitates fungal pathogenesis.
T24 4084-4296 Sentence denotes Similar to other SARS coronaviruses, SARS-CoV-2 targets and invades epithelial cells and type II pneumocytes through binding of the SARS spike protein to the angiotensin-converting enzyme 2 (ACE2) receptors [11].
T25 4297-4485 Sentence denotes Cleavage of the S1/S2 domain by the type 2 transmembrane protease TMPRSS2 leads to the activation of the spike protein [12], thereby facilitating viral entry into the target cell via ACE2.
T26 4486-4629 Sentence denotes Besides its role as a SARS virus receptor, ACE2 was also demonstrated to be required for protection from severe acute lung injury in ARDS [13].
T27 4630-4768 Sentence denotes In support of this, an insertion/deletion polymorphism that affects ACE activity was associated with ARDS susceptibility and outcome [14].
T28 4769-4984 Sentence denotes Whether the preceding interaction of SARS-CoV-2 with host cells, by disrupting the regulation of the renin-angiotensin system and or the kallikrein-kinin system, contributes to the development of CAPA, is not known.
T29 4985-5128 Sentence denotes Viral entry and infection elicit an immune response, which is initiated by the establishment of an inflammatory cascade by innate immune cells.
T30 5129-5407 Sentence denotes Although the receptor(s) and signaling pathways involved in the immune recognition of Aspergillus and the downstream production of inflammatory mediators are relatively well characterized [15], not much is known regarding how the immune system senses and responds to SARS-CoV-2.
T31 5408-5597 Sentence denotes Based on the available knowledge for infections with other coronaviruses, two possible mechanisms can be anticipated and are likely to explain the development of ARDS and consequently CAPA.
T32 5598-5859 Sentence denotes The first involves the release of danger-associated molecular patterns (DAMPs), signal molecules released by dying or damaged cells that act as endogenous danger signals to promote and exacerbate the immune and inflammatory response leading to lung injury [16].
T33 5860-5958 Sentence denotes It is noteworthy that DAMPs have also been shown to regulate inflammation in fungal diseases [17].
T34 5959-6158 Sentence denotes The DAMP/receptor for advanced glycation end-products axis was found to integrate with Toll-like receptors (TLRs) to generate and amplify the inflammatory response in experimental aspergillosis [18].
T35 6159-6372 Sentence denotes Moreover, recipients of allogeneic stem-cell transplantation harboring genetic variants underlying a hyperactivation of danger signaling in response to infection displayed an increased risk of developing IPA [19].
T36 6373-6594 Sentence denotes This emerging concept could help explain fungal pathogenesis in conditions of exuberant inflammation such as that observed in COVID-19 patients and highlights DAMP targeting as potential immunomodulatory strategy in CAPA.
T37 6595-6822 Sentence denotes A second possibility involves the collateral effects of recognition pathways required for the activation of antiviral immunity that may, paradoxically, contribute to an inflammatory environment that favors secondary infections.
T38 6823-6997 Sentence denotes ACE2 is not well expressed on immune cells and SARS-CoV are recognized by TLR4 and TLR3, leading to the activation of MyD88- or TRIF-mediated signaling, respectively [20,21].
T39 6998-7138 Sentence denotes Of note, this may be potentiated in the presence of Aspergillus spp. which activate TLR4/MyD88/TRIF through the cleavage of fibrinogen [22].
T40 7139-7279 Sentence denotes It is likely that SARS-CoV-2 may elicit, to a large extent, overlapping signaling pathways towards the production of inflammatory cytokines.
T41 7280-7455 Sentence denotes In addition, the activation of the inflammasome by SARS-CoV and the consequent production of IL-1β is an event that contributes further to the hyperinflammatory response [23].
T42 7456-7639 Sentence denotes A transcriptome analysis of COVID-19 patients revealed an early immune response characterized by a marked upregulation of the IL-1 pathway, even after respiratory function nadir [24].
T43 7640-7926 Sentence denotes The possibility that IL-1 and related pro-inflammatory pathways could serve as therapeutic targets was demonstrated by the favorable responses in severe COVID-19 patients with secondary hemophagocytic lymphohistiocytosis treated with the interleukin-1 receptor antagonist anakinra [25].
T44 7927-8010 Sentence denotes Similar findings were also disclosed in acute leukemia patients with COVID-19 [26].
T45 8011-8256 Sentence denotes Likewise, IL-1 blockade with anakinra has also been found to ameliorate inflammation in both chronic granulomatous disease [27] and cystic fibrosis [28], and in either case, to restrain susceptibility to infection or colonization by Aspergillus.
T46 8257-8462 Sentence denotes Therefore, the early hyperactivation of the IL-1 pathway induced by the SARS-CoV-2 infection may be a major factor establishing a highly permissive inflammatory environment that favors fungal pathogenesis.
T47 8463-8666 Sentence denotes Besides IL-1, increased levels of IL-6 have also been consistently reported in severe cases of COVID-19 [29,30], with an impact on immune cell function and the anti-viral mechanisms of immune cells [31].
T48 8667-8924 Sentence denotes An enhanced production of IL-6 is also observed in epithelial cells following infection with A. fumigatus, suggesting that, at least in some patients, the co-infection may contribute to the increased levels of this cytokine in severe COVID-19 patients [32].
T49 8925-9152 Sentence denotes In a large patient series of COVID-19 patients with ARDS, the use of the IL-6 receptor antagonist tocilizumab was recently reported to promote rapid and sustained responses associated with significant clinical improvement [33].
T50 9153-9330 Sentence denotes However, such clinical approach could paradoxically enhance the predisposition to CAPA, similar to animal models of IL-6 deficiency subjected to experimental aspergillosis [34].
T51 9331-9470 Sentence denotes For this reason, ongoing trials are addressing the combined use of IL-6 antagonists and antifungal prophylaxis in severe COVID-19 patients.
T52 9471-9644 Sentence denotes An emerging body of evidence supports therefore an increased systemic inflammatory reaction in patients with severe SARS-CoV-2 infection who are more likely to develop CAPA.
T53 9645-9831 Sentence denotes In this regard, increased levels of circulating proinflammatory cytokines, such as TNF, were observed in patients requiring intensive care, compared to those with milder infections [35].
T54 9832-10023 Sentence denotes Other studies, however, have also unveiled marked defects in immune cell populations, namely T-lymphocytes, as another factor explaining the immune dysfunction in patients with COVID-19 [36].
T55 10024-10179 Sentence denotes This suggests that while sustained innate immune function leads to hyperinflammation [37], lymphocyte numbers decline, and their function may be defective.
T56 10180-10367 Sentence denotes In this regard, severe lymphocytopenia was among the factors in a risk score model that predicted the development of invasive mold disease in patients with hematological malignances [38].
T57 10368-10723 Sentence denotes It is thus reasonable to speculate that in elderly individuals or with co-morbidities, defective immune responses to SARS-CoV-2 may allow unrestricted viral replication which, in turn, elicits hyperinflammation and severe complications such as ARDS [39], besides establishing favorable conditions for the acquisition of secondary infections, such as CAPA.
T58 10724-11059 Sentence denotes While there is much to be learned about CAPA, our current understanding of the pathophysiology of other coinfections with respiratory viruses such as influenza [40] provides an important framework towards the effective design of immunotherapeutic approaches and the identification of the patients that could benefit the most from them.
T59 11061-11063 Sentence denotes 3.
T60 11064-11107 Sentence denotes Risk Factors Implicated in CAPA Development
T61 11108-11352 Sentence denotes Importantly, the pathogenesis of IPA differs between neutropenic and non-neutropenic patients, including those with COVID-19, impacting clinical presentation, radiological findings and diagnostic test results in the mycology laboratory [41,42].
T62 11353-11931 Sentence denotes Despite these important differences, revised European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) definitions [43] focus primarily on neutropenic patients with underlying hematological malignancies and “typical” presentation of IPA and have been shown to have limited applicability and inferior performance in non-neutropenic patients who frequently do not fulfil radiological and host criteria, including patients with COVID-19 [41,44].
T63 11932-12272 Sentence denotes This has resulted in the creation of an alternative clinical algorithm for diagnosing IPA in the ICU setting in 2012 [41], which defines putative IPA and is now the standard of care for defining IPA in the ICU [4,45], where highly reliable definitions of IA are still missing (work on improved definitions is currently in progress [45,46]).
T64 12273-12423 Sentence denotes Rapid development of CAPA few days following ICU admission [47] resembles the observation made for influenza-associated pulmonary aspergillosis [4,5].
T65 12424-12585 Sentence denotes Risk factors predisposing COVID-19 patients to develop secondary pulmonary aspergillosis are similar to those identified for influenza-IPA superinfections [4,5].
T66 12586-12887 Sentence denotes The most important risk factors include severe lung damage during the course of COVID-19 [48], the use of corticosteroids in those with ARDS, the widespread use of broad-spectrum antibiotics in intensive care units [49], and the presence of comorbidities such as structural lung defects [47,50,51,52].
T67 12888-13142 Sentence denotes There are some reports revealing that pulmonary fibrosis can be triggered by the cytokine storm activated by the viral antigens, toxicity posed by drugs, high airway pressure and hypoxia-induced acute lung injury secondary to mechanical ventilation [53].
T68 13143-13407 Sentence denotes While interstitial pulmonary fibrosis per se does not predispose to development of IPA, a small subset of these COVID-19 survivors may require long term corticosteroid treatment, which may predispose them to CAPA years after the acute phase of the viral infection.
T69 13408-13513 Sentence denotes Overall, 29% of the CAPA cases published to date (10/35) had received systemic corticosteroids (Table 1).
T70 13514-13733 Sentence denotes In those with ARDS, systemic corticosteroids are used to alleviate the immune responses and prevent cytokine storm [6,54,55,56], but may at the same time increase vulnerability for developing secondary infections [4,5].
T71 13734-13916 Sentence denotes Although detailed case series have not reported on antibiotic use among patients, broad-spectrum antibiotics are presumed to be used in 75% of COVID-19 patients admitted to ICU [49].
T72 13917-14292 Sentence denotes Since the human gut microbiome is a highly complicated structure of bacteria and fungi, although bacteria are the most diverse constituents, the administration of antibiotics results in perturbation of microbiome steady-state composition, which allows fungi to thrive, and may predispose the host to invasive fungal infections once the immune system becomes impaired [65,66].
T73 14293-14377 Sentence denotes Underlying medical conditions may also predispose COVID-19 patients to develop CAPA.
T74 14378-14656 Sentence denotes Among the 35 CAPA cases published to date (Table 1), hypertension (17/35; 49%), diabetes (9/35; 26%), obesity (8/35; 23%), COPD (5/35; 14%), heart diseases (5/35; 14%), hypercholesterinemia (4/35; 11%), and asthma (3/35; 9%) were among the most prevalent comorbidities observed.
T75 14657-14871 Sentence denotes While hypertension, coronary heart diseases, and diabetes increase the risk of infection overall [67,68,69], structural lung damage caused by COPD or asthma may particularly predispose patients to develop IPA [70].
T76 14873-14875 Sentence denotes 4.
T77 14876-14891 Sentence denotes CAPA Prevalence
T78 14892-14989 Sentence denotes Several studies from China reported high rates of Aspergillus infections among COVID-19 patients.
T79 14990-15189 Sentence denotes In one study from the Jiangsu province in China, 60/257 COVID-19 (23.3%) patients had throat swab samples that tested positive for Aspergillus spp. and were reported as Aspergillus co-infections [8].
T80 15190-15502 Sentence denotes In another Chinese study from the Zhejiang province 8 of the 104 patients with COVID-19 (7.7%) patients were reported to have IPA although questions remain regarding criteria used for diagnosing IPA in this study (authors state EORTC/MSG criteria were used but all 8 patients seemingly lacked host factors) [71].
T81 15503-15638 Sentence denotes Another study from China reported that 27% of the COVID-19 patients (13/48) developed fungal infections but lacked further details [7].
T82 15639-15749 Sentence denotes In other reports from China, lower rates of fungal infections were reported ranging between 3.2–5% [54,55,72].
T83 15750-15870 Sentence denotes None of those studies have used specific definitions and standardized diagnostic algorithms to identify and define CAPA.
T84 15871-16071 Sentence denotes In fact, diagnosis of pulmonary aspergillosis is challenging with culture exhibiting limited sensitivity [73,74], and galactomannan testing—the current gold standard—is rarely available in China [75].
T85 16072-16378 Sentence denotes As a result, some of these reported rates are likely an underestimate of the real burden of IPA in patients with COVID-19 requiring ICU admission, while other rates may be an overestimation due to potentially misinterpreting Aspergillus colonization in the upper respiratory tract as Aspergillus infection.
T86 16379-16595 Sentence denotes More recently, several studies and case-series from Europe (France, Germany, Belgium, and the Netherlands) have reported high rates of CAPA among COVID-19 cases with ARDS, ranging from 20–35% (Table 1) [47,50,51,52].
T87 16596-16713 Sentence denotes The development of CAPA was fairly rapid, with a median of 6 days and range of 3–28 days after ICU admission [47,52].
T88 16714-16926 Sentence denotes Moreover, two additional CAPA cases have been reported from Germany [61] and single cases have also been reported from the Netherlands [62], Austria [60], Italy [59], Australia [63], and France [57,58] (Table 1).
T89 16927-17010 Sentence denotes Among 35 CAPA cases reported to date, there were a total of 5 proven cases [52,59].
T90 17011-17121 Sentence denotes The overall mortality rate was 63% (22/35), among whom 4 were female (4/8; 50%) and 14 were male (18/27; 67%).
T91 17122-17246 Sentence denotes The mortality in case series reported from France, Germany, Belgium and Netherlands ranged between 44.5–66.7% [47,50,51,52].
T92 17247-17436 Sentence denotes Of particular importance was the 100% fatality rate of those with underlying diseases reported from the Netherlands, while the two patients without underlying conditions both survived [47].
T93 17437-17662 Sentence denotes Noteworthy is the fact that COVID-19 patients presented with ARDS typically fall into the elderly category [6], whereas ARDS in those infected with influenza involves both children <5 years old and elderly >65 years old [76].
T94 17663-17819 Sentence denotes The difficulties in diagnosing CAPA, which are outlined in more detail in the next section of this review, may also contribute to increased mortality rates.
T95 17820-18019 Sentence denotes The most notable example is a study from France [57], where both culture and serology assays were negative for the initial respiratory samples and became only positive after the patient expired [57].
T96 18020-18209 Sentence denotes In a case from Italy, initial BALF culture was positive for A. fumigatus but the treatment was delayed for two days and only started after the serum galactomannan test became positive [59].
T97 18210-18263 Sentence denotes CAPA was later confirmed by autopsy examination [59].
T98 18264-18471 Sentence denotes As a result, authors encouraged prompt initiation of systemic antifungal therapy immediately after obtaining positive results even if Aspergillus is detected in samples from the upper respiratory tract [59].
T99 18472-18789 Sentence denotes Since azole resistance can be associated with a higher mortality rate when compared to patients infected with azole susceptible A. fumigatus isolates, it is of paramount importance to use antifungal susceptibility testing to inform targeted antifungal treatment, especially in regions with high azole resistance [77].
T100 18790-19005 Sentence denotes Azole-resistant A. fumigatus isolates were also persistently recovered from tracheal aspirates during the course of azole treatment in the most recent study from the Netherlands implicated a CAPA case for whom [62].
T101 19006-19244 Sentence denotes The azole-resistant A. fumigatus isolate (itraconazole, voriconazole, and posaconazole MICs were 16, 2, and 0.5 µg/mL, respectively) harbored a well-known mutation, TR34/L98H [62], presumed to have been acquired from the environment [77].
T102 19245-19508 Sentence denotes The in vitro MIC value of the isolate obtained at day 19 (2 mg/L) was higher than the voriconazole serum trough concentration measured on day 17 (1.43 mg/L) and despite switching voriconazole to l-AmB, the patient died due to deteriorating health conditions [62].
T103 19509-19686 Sentence denotes Overall, A. fumigatus appeared to be the most prevalent Aspergillus spp. isolated among respiratory samples with positive culture (26/29; 90%), followed by A. flavus (2/29; 7%).
T104 19688-19690 Sentence denotes 5.
T105 19691-19744 Sentence denotes Diagnostic Workup for Accurate Identification of CAPA
T106 19745-19989 Sentence denotes The optimal diagnostic algorithm for diagnosing CAPA is currently unknown, and this question is actively being investigated in an ongoing multinational explorative trial in conjunction with the European Confederation of Medical Mycology (ECMM).
T107 19990-20284 Sentence denotes The most common methods to date include attempting to recover Aspergillus spp. on culture media of bronchoalveolar fluid (BALF) and tracheal aspirate, as well as utilizing serologic biomarker testing such as the conventional Galactomannan (GM) from BALF, tracheal aspirate, and serum specimens.
T108 20285-20579 Sentence denotes Other diagnostic tests that may prove useful also include Aspergillus PCR, serum (1→3)-β-d-glucan (BDG), the Aspergillus galactomannan lateral flow assay (LFA) (IMMY, Norman, Oklahoma, USA), and the Aspergillus-specific lateral-flow device (LFD) test (OLM Diagnostics, Newcastle Upon Tyne, UK).
T109 20580-20912 Sentence denotes In published cases and case series from Germany [50,61], France [51,57,58], Italy [59], Austria [60], Belgium [52], Australia [63], and the Netherlands [47], CAPA was most commonly mycologically diagnosed by either culture from BALF or tracheal aspirate and/or based on a positive GM or LFD from BALF or tracheal aspirate (Table 1).
T110 20913-21171 Sentence denotes Across published cases, Aspergillus culture was positive in 29/35 (83%) of patients; of those with a positive culture and a reported source, 16/29 (55%) were recovered from—often undirected—BALF, 12/29 (41%) from tracheal aspirate, and 1/29 (3%) from sputum.
T111 21172-21354 Sentence denotes In those where a BALF GM test was performed, 14/23 (61%) had a titer ≥1.5 ODI and 16/23 (70%) a titer ≥0.5 ODI, while 6/28 (21%) of those with serum GM results had a titer > 0.5 ODI.
T112 21355-21484 Sentence denotes PCR from respiratory specimens or tissue was positive in 10/14 (71%) and LFD from tracheal secretion positive in 1/1 of patients.
T113 21485-21618 Sentence denotes Thus, BALF and tracheal aspirate culture and conventional GM testing from BALF appear to be the most promising diagnostic modalities.
T114 21619-21781 Sentence denotes Still, bronchoscopy can potentially aerosolize virus [78] in patients with COVID-19 infection, thus posing a risk to patients and personnel from SARS-CoV-2 virus.
T115 21782-22157 Sentence denotes In many centers, the role of bronchoscopy is limited and testing from blood samples may be safer and more optimal and allow also for twice weekly screening which has been implemented in many centers [52], although the low levels of GM positivity from serum in these reports is discouraging, and the sensitivity of serum BDG, which is less specific for IA, was only 44% (4/9).
T116 22159-22161 Sentence denotes 6.
T117 22162-22193 Sentence denotes CAPA Treatment—Current Paradigm
T118 22194-22382 Sentence denotes While it is currently unknown whether antifungal treatment of COVID-19 associated IPA translates into a survival benefit, diagnosis should in most cases trigger early antifungal treatment.
T119 22383-22501 Sentence denotes Outside the hematologic malignancy setting, voriconazole remains the recommended first-line treatment for IPA [79,80].
T120 22502-22757 Sentence denotes However, besides its narrow therapeutic window and the requirement for therapeutic drug monitoring to ensure efficacy and prevent neuro and hepatotoxicity [81], drug–drug interactions may particularly limit the use of voriconazole in the ICU setting [82].
T121 22758-22918 Sentence denotes Being metabolized via CYP2C19, CYP2C9, and CYP3A4, voriconazole is among the drugs most frequently associated with major drug–drug interactions in the ICU [83].
T122 22919-23224 Sentence denotes Furthermore, it may show interactions with experimental COVID-19 therapies, including hydroxychloroquine, atazanavir, lopinavir/ritonavir and last but not least—although weaker—with remdesivir, which is also a substrate for CYP3A4, although its metabolism is primarily mediated by hydrolase activity [84].
T123 23225-23341 Sentence denotes Isavuconazole and liposomal amphotericin B are the primary alternative options for treatment of IPA in the ICU [79].
T124 23342-23470 Sentence denotes Compared to voriconazole, isavuconazole shows a more favorable pharmacokinetic profile, and is associated with fewer toxicities.
T125 23471-23661 Sentence denotes However, it is also metabolized via CYP3A4 and could therefore be problematic, although drug–drug interactions are generally less a problem with isavuconazole than with voriconazole [85,86].
T126 23662-23862 Sentence denotes Liposomal amphotericin B is a broadly effective alternative treatment option, however, in the ICU renal insufficiency often complicates initiation or requires discontinuation of this antifungal agent.
T127 23863-24028 Sentence denotes This concern is particularly relevant for patients infected by SARS-CoV-2 which has shown renal tropism and been described as a frequent cause of kidney injury [87].
T128 24029-24258 Sentence denotes While itraconazole is now rarely used to treat invasive aspergillosis, it has been shown to exhibit some antiviral activity, specifically as a cholesterol transport inhibitor, and was effective in a feline coronavirus model [88].
T129 24259-24508 Sentence denotes In addition, its novel oral SUBA formulation has great bioavailability [89], and itraconazole may therefore be an alternative option for treating COVID-19 associated IPA, although it shares the problem of drug–drug interactions with other triazoles.
T130 24509-24832 Sentence denotes While currently available echinocandins are not considered first-line treatment options for invasive aspergillosis due to their limited antifungal activity against Aspergillus spp., they are generally well tolerated with limited drug–drug interactions and show at least fungistatic activity against Aspergillus hyphae [90].
T131 24833-24977 Sentence denotes Furthermore, they synergistic interactions with some other antifungals, making them an excellent choice for combination antifungal therapy [90].
T132 24978-25297 Sentence denotes New antifungal classes currently under development, namely fosmanogepix and olorofim [91], may have equal efficacy without the same burden of drug–drug interactions and toxicity, and may therefore overcome the limitations of currently available antifungals and become the preferred treatment options in the near future.
T133 25298-25709 Sentence denotes If the reported high incidence of COVID-19 associated IPA in ICU patients is confirmed in larger studies, there may be justification for prophylaxis trials, for which not only triazoles and nebulized liposomal amphotericin B [52], but also another novel antifungal currently under development, rezafungin (i.e., once weekly echinocandin with improved activity against Aspergillus spp.), may be a candidate [92].
T134 25711-25713 Sentence denotes 7.
T135 25714-25759 Sentence denotes The Current Challenges and How to Tackle Them
T136 25760-25843 Sentence denotes Bacterial, fungal and viral secondary infections or co-infections affect mortality.
T137 25844-25985 Sentence denotes Acinetobacter baumanii, Klebsiella pneumonia and Aspergillus species are important nosocomial pathogens [93] complicating the disease course.
T138 25986-26093 Sentence denotes Studies from France [51], Germany [50], Belgium [52], and the Netherlands [47], underline the role of CAPA.
T139 26094-26192 Sentence denotes Diagnosing co-infections is complex and rapid diagnosis plays a crucial role in this setting [49].
T140 26193-26361 Sentence denotes Close monitoring for infection development is needed, as well as longitudinal sampling throughout the disease course using culture dependent and independent techniques.
T141 26362-26532 Sentence denotes Aspergillus antigen and PCR testing of respiratory fluids should be a routine procedure for critically ill patients [94], specifically for those suffering from ARDS [50].
T142 26533-26643 Sentence denotes Co-infection with human metapneumovirus has been reported in two of five cases in the German CAPA series [50].
T143 26644-26832 Sentence denotes It is unknown whether hospitals caring for COVID-19 test comprehensive respiratory pathogen panels, and to date no analysis of mixed viral infection in COVID-19 patients has been reported.
T144 26833-26970 Sentence denotes In the context of COVID-19, mixed viral infection may be misinterpreted as presence of innocent bystanders and thus remain underreported.
T145 26971-27084 Sentence denotes With bronchoalveolar lavage and autopsy regarded as high-risk procedures, key diagnostic instruments are lacking.
T146 27085-27243 Sentence denotes Autopsy studies are key to understanding pathophysiology of COVID-19 [95] and are critically enlighten interaction between SARS-CoV-2 and different pathogens.
T147 27244-27400 Sentence denotes With availability of lower respiratory samples, normally obtained by BALF, the quality of microbiological and virological work up would be greatly improved.
T148 27401-27529 Sentence denotes Inspection of trachea and bronchi is achieved by bronchoscopy, which is critical to find possible Aspergillus tracheobronchitis.
T149 27530-27751 Sentence denotes Thus, physicians face the dilemma of taking the hazard of aerosolization of SARS-CoV-2, risking transmission versus the endeavor of facilitating the optimal diagnosis and treatment to the patients entrusted to their care.
T150 27752-27861 Sentence denotes To this day, our understanding of the true impact of Aspergillus co-infections remains frustratingly limited.
T151 27862-28001 Sentence denotes Therefore, guidance on proper management of these high-risk procedures to prevent transmission and super spreading of SARS-CoV-2 is needed.
T152 28002-28221 Sentence denotes The European Confederation of Medical Mycology initiated national multicenter studies aiming to explore the risk of fungal infections during COVID-19 [94] and is currently working on diagnostic and treatment algorithms.
T153 28222-28345 Sentence denotes Key goals are to improve the outcome by avoiding misdiagnosis and by initiation of early and targeted antifungal treatment.
T154 28347-28349 Sentence denotes 8.
T155 28350-28369 Sentence denotes Future Perspectives
T156 28370-28489 Sentence denotes We anticipate that autopsies of COVID-19 fatalities will increase and likely prove the clinical relevance of CAPA [96].
T157 28490-28647 Sentence denotes Immune dysregulation together with epithelial lung damage stemming from COVID-19 immunopathology is a likely mechanism predisposing for IPA development [97].
T158 28648-28793 Sentence denotes IPA will be recognized as important co-infection in patients with severe COVID-19, but incidence will likely vary between different ICU settings.
T159 28794-29036 Sentence denotes In settings where COVID-19 associated IPA occurs most commonly, screening for IPA in blood and true BALF samples (i.e., obtained via bronchoscopy) will be implemented followed by preemptive treatment in those with mycological evidence of IPA.
T160 29037-29265 Sentence denotes In other high-incidence settings, clinical antifungal prophylaxis trials will be conducted among COVID-19 patients admitted to the ICU aiming to show a decrease in putative [4] and proven IPA cases, as well as overall mortality.
T161 29266-29443 Sentence denotes Treatment trials will compare efficacy and safety of new antifungal drugs currently under development with established antifungals, initiating a new era of antifungal treatment.
T162 29445-29465 Sentence denotes Author Contributions
T163 29466-29719 Sentence denotes Conceptualization, M.H., A.A., and A.C.; writing—original draft preparation, A.A., A.C., M.H., F.L.v.d.V., J.D.J., C.L.-F., P.K., O.A.C., D.S.P., R.K.; writing—review and editing, M.H., A.A., A.C., F.L.v.d.V., J.D.J., C.L.-F., P.K., O.A.C., D.S.P., R.K.
T164 29720-29796 Sentence denotes All authors have read and agreed to the published version of the manuscript.
T165 29798-29805 Sentence denotes Funding
T166 29806-30166 Sentence denotes AC was supported by the Fundação para a Ciência e a Tecnologia (FCT) (CEECIND/03628/2017, UIDB/50026/2020 and UIDP/50026/2020), and the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) (NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023).
T167 30167-30216 Sentence denotes This research received no other external funding.
T168 30218-30239 Sentence denotes Conflicts of Interest
T169 30240-30292 Sentence denotes M.H. received research funding by Gilead and Pfizer.
T170 30293-30430 Sentence denotes D.S.P. receives research support and/or serves on advisory boards for Amplyx, Cidara, Scynexis, N8 Medical, Merck, Regeneron, and Pfizer.
T171 30431-30932 Sentence denotes P.K. has received non-financial scientific grants from Miltenyi Biotec GmbH, Bergisch Gladbach, Germany, and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany, and is an adivisor to, or received lecture honoraria from Akademie für Infektionsmedizin e.V., Astellas Pharma, Gilead Sciences, GPR Academy Ruesselsheim, MSD Sharp & Dohme GmbH, NOXXON Pharma NV., and University Hospital, LMU Munich outside the submitted work.
T172 30933-31786 Sentence denotes O.A.C. is supported by the German Federal Ministry of Research and Education; is funded by the Deutsche Forschungsgemeinschaft (German Research Foundation) under Germany’s Excellence Strategy (CECAD, EXC 2030 - 390661388); has received research grants from Actelion, Amplyx, Astellas, Basilea, Cidara, Da Volterra, F2G, Gilead, Janssen Pharmaceuticals, Medicines Company, MedPace, Melinta Therapeutics, MSD, Pfizer, and Scynexis; is a consultant to Actelion, Allecra Therapeutics, Amplyx, Astellas, Basilea, Biosys UK, Cidara, Da Volterra, Entasis, F2G, Gilead, Matinas, MedPace, Menarini Ricerche, Roche Diagnostics, MSD, Nabriva Therapeutics, Octapharma, Paratek Pharmaceuticals, Pfizer, PSI, Rempex, Scynexis, Seres Therapeutics, Tetraphase, and Vical; and received lecture honoraria from Astellas, Basilea, Gilead, Grupo Biotoscana, MSD, and Pfizer.
T173 31788-31902 Sentence denotes Table 1 Clinical characteristics of COVID-19 patients with pulmonary aspergillosis published before 10 June 2020.
T174 31903-32126 Sentence denotes Country (Prevalence) COHORT [Ref] Age/Sex Underlying Conditions CAPA Classification Local/Systemic Corticosteroid Use GM (ODI)/Serum BDG (pg/mL)/qPCR Species (Voriconazole Susceptibility Pattern) Treatment # Outcome
T175 32127-32441 Sentence denotes Germany (5/19; 26.3%)ARDS [50] 62/F Cholecystectomy for cholecystitis, arterial hypertension, obesity with sleep apnea, hypercholesterolemia, ex-smoker, COPD (GOLD 2) Putative Inhaled steroids for COPD GM Serum negative GM BALF> 2.5 qPCR BALF = Positive Aspergillus fumigatus (S) culture from BALF VCZ Died
T176 32442-32633 Sentence denotes 70/M Vertebral disc prolapse left L4/5, flavectomy and nucleotomy, Ex-smoker Putative No GM Serum = 0.7 GM BALF> 2.5 qPCR BALF = Positive A. fumigatus by PCR; negative culture ISA Died
T177 32634-32917 Sentence denotes 54/M Arterial hypertension, diabetes mellitus, aneurysm coiling right A. vertebralis Putative Intravenous corticosteroid therapy 0.4 mg/kg/d, total of 13 days) GM Serum negative GM BALF> 2.5 qPCR BALF = Positive A. fumigatus (S) culture from tracheal aspirate CASPO→ VCZ Alive
T178 32918-33160 Sentence denotes 73/M Arterial hypertension, bullous emphysema, smoker, COPD (GOLD 3), Previous Hepatitis B Putative Inhaled steroids for COPD GM Serum negative qPCR tracheal secretion = Positive A. fumigatus (S) culture from tracheal aspirate VCZ Died
T179 33161-33281 Sentence denotes 54/F None Putative No GM Serum = 1.3 and 2.7 qPCR tracheal secretion = Negative Negative culture CASPO→ VCZ Alive
T180 33282-33571 Sentence denotes France (9/27; 33.3%)ARDS * [51] 53/M Hypertension, obesity, ischemic heart disease Putative Dexamethasone iv 20 mg once daily from day 1 to day 5, followed by 10 mg once daily from day 6 to day 10 GM Serum = 0.13 GM BALF = 0.89 BDG = 523 qPCR = Negative Negative culture None Alive
T181 33572-33717 Sentence denotes 59/F Hypertension, obesity, diabetes Putative No GM Serum = 0.04 GM BALF = 0.03 qPCR = Negative A. fumigatus, culture from BALF None Alive
T182 33718-33965 Sentence denotes 69/F Hypertension, obesity Putative Dexamethasone iv 20 mg once daily from day 1 to day 5, followed by 10 mg once daily from day 6 to day 10 GM Serum = 0.04 BDG = 7.8 qPCR BALF = 23.9 A. fumigatus, culture from tracheal secretion None Alive
T183 33966-34204 Sentence denotes 63/F Hypertension, diabetes, ischemic heart disease Putative Dexamethasone iv 20 mg once daily from day 1 to day 5, followed by 10 mg once daily from day 6 to day 10 GM Serum = 0.51GM BALF = 0.15 BDG = 63 Negative culture None Died
T184 34205-34358 Sentence denotes 43/M Asthma with steroid use history Putative No GM Serum = 0.04 GM BALF = 0.12 BDG = 7 qPCR = Negative A. fumigatus, culture from BALF None Alive
T185 34359-34597 Sentence denotes 79/M Hypertension Putative Dexamethasone iv 20 mg once daily from day 1 to day 5, followed by 10 mg once daily from day 6 to day 10 GM Serum = 0.02 GM BALF = 0.05 BDG = 23 qPCR BALF = 34.5 A. fumigatus, culture from BALF None Alive
T186 34598-34841 Sentence denotes 77/M Hypertension, asthma Putative Dexamethasone iv 20 mg once daily from day 1 to day 5, followed by 10 mg once daily from day 6 to day 10 GM Serum = 0.37 GM BALF = 3.91 BDG = 135 qPCR BALF = 29 A. fumigatus, culture from BALF VCZ Died
T187 34842-35091 Sentence denotes 75/F Hypertension, diabetes Putative Dexamethasone iv 20 mg once daily from day 1 to day 5, followed by 10 mg once daily from day 6 to day 10 GM Serum = 0.37 GM BALF = 0.36 BDG = 450 qPCR BALF = 31.7 A. fumigatus, culture from BALF CASPO Died
T188 35092-35234 Sentence denotes 47/M Multiple myeloma with steroid therapy Probable No GM Serum = 0.09 BDG = 14 A. fumigatus, culture from tracheal secretion None Died
T189 35235-35452 Sentence denotes Netherlands (6/31; 19.4%)ARDS [47] 83/M Cardiomyopathy Possible Prednisolone 0ꞏ13mg/kg/day for 28 dayspre-admission GM Serum = 0.4 A. fumigatus, culture from tracheal aspirate VCZ + ANID (5/6) L-AmB (1/6) Died
T190 35453-35611 Sentence denotes 67/M COPD (GOLD 3), Post RTx NSCLC 2014 Possible Prednisolone 0ꞏ37mg/kg/day for 2 dayspre-admission NA A. fumigatus, culture from tracheal aspirate Died
T191 35612-35700 Sentence denotes 75/M COPD (GOLD 2a) Probable No GM BALF = 4.0 A. fumigatus, culture from BALF Died
T192 35701-35766 Sentence denotes 43/M None Probable No GM Serum = 0.1 GM BALF = 3.8 NA Alive
T193 35767-35923 Sentence denotes 57/M Bronchial asthma Probable Fluticasone 1ꞏ94 mcg/kg/day for 1 month pre-admission GM Serum = 0.1 GM BALF = 1.6 A. fumigatus. culture from BALF Died
T194 35924-36002 Sentence denotes 58/M None Possible No NA Aspergillus spp. (S), culture from sputum Alive
T195 36003-36137 Sentence denotes Belgium (7/20; 35%)ARDS [52] 86/M Hypercholesterinemia NA No GM serum = 0.1 A. flavus culture from tracheal aspirate None Died
T196 36138-36264 Sentence denotes 38/M Obesity, hypercholesterinemia Proven No GM serum = 0.3 GM BALF > 2.8 A. fumigatus culture from BALF VCZ, ISA Alive
T197 36265-36362 Sentence denotes 62/M Diabetes Proven No GM serum = 0.2 GM BALF = 2 A. fumigatus culture from BALF VCZ Died
T198 36363-36507 Sentence denotes 73/M Diabetes, obesity, hypertension, hypercholesterinemia Proven No GM serum= 0.1 GM BALF > 2.8 A. fumigatus culture from BALF VCZ Alive
T199 36508-36673 Sentence denotes 77/M Diabetes, chronic kidney disease, hypertension, pemphigus foliaceus Proven Yes, ND GM serum = 0.1 GM BALF = 2.79 A. fumigatus culture from BALF VCZ Alive
T200 36674-36793 Sentence denotes 55/M HIV, hypertension, hypercholesterinemia NA No GM serum = 0.80 GM BALF = 0.69 Negative culture VCZ, ISA Died
T201 36794-36889 Sentence denotes 75/M Acute myeloid leukemia NA No GM BALF = 2.63 A. fumigatus culture from BALF VCZ Died
T202 36890-37302 Sentence denotes France (1)ARDS [57] 74/M Myelodysplastic syndrome, CD8 + T-cell lymphocytosis, Hashimoto’s thyroiditis, hypertension, benign prostatic hypertrophy Putative No First GM on tracheal secretion = Negative First qPCR = Positive Second GM tracheal secretion = NA Second qPCR = Positive Direct smear of the second sample = branched septate hyphae A. fumigatus, culture of the second tracheal secretion None Died
T203 37303-37464 Sentence denotes France (1/5; 20%)Mixed ICU [58] 80/M Thyroid cancer (patient presented with ARDS) Putative NA No A. flavus, culture from tracheal secretion VCZ→ ISA Died
T204 37465-37683 Sentence denotes Italy (1)ARDS [59] 73/M Diabetes, hypertension, obesity, hyperthyroidism, atrial fibrillation Proven No GM Serum = 8.6 qPCR from paraffin block tissue = Positive A. fumigatus, culture from BALF L-AmB → ISA Died
T205 37684-38064 Sentence denotes Austria (1)ARDS [60] 70/M COPD (GOLD 2), obstructive sleep apnea syndrome, insulin-dependent type 2 diabetes with end organ damage, arterial hypertension, coronary heart disease, and obesity Putative Inhaled Budesonide (400 mg per day) GM Serum = Negative BDG = Negative LFD Positive from endotracheal aspiration A. fumigatus, culture from endotracheal aspiration VCZ Died
T206 38065-38205 Sentence denotes Germany (2)ARDS [61] 80/M Suspected pulmonary fibrosis ND No GM Serum = 1.5 GM BALF = 6.3 A. fumigatus, culture from BALF L-AmB Died
T207 38206-38305 Sentence denotes 70/M None ND No GM Serum = Negative GM BALF = 6.1 A. fumigatus, culture from BALF L-AmB Died
T208 38306-38620 Sentence denotes Netherlands (1)ARDS [62] 74/F Polyarthritis, reflux, stopped smoking 20 years ago Putative No GM serum = Persistently < 0.5 GM tracheal aspirate = >3 BDG serum = 1590 A. fumigatus, culture from tracheal aspirate (R)TR34/L98HICZ = 16µg/mL, VCZ = 2µg/mL, and POSA = 0.5µg/ml VCZ + CASPO→ Oral VCZ→ L-AmB Died
T209 38621-38814 Sentence denotes Australia (1) ARDS [63] 66/F Hypertension, osteopenia, ex-smoker (20 pack years) Putative No N/A A. fumigatus culture from tracheal aspirate (3x) VCZ + Therapeutic Drug monitoring Alive
T210 38815-38953 Sentence denotes * All serum qPCR remained negative. # All dosages are standard dosages (e.g., VCZ 6 mg/kg bid Day 1, and 4 mg/kg bid starting Day 2) [64].
T211 38954-39514 Sentence denotes ARDS: acute respiratory distress syndrome; NA: not applicable; ND: not determined; BALF: bronchoalveolar lavage fluid; BDG: beta-D-Glucan; COPD: chronic obstructive pulmonary disease; GM; galactomannan; GOLD: global initiative for chronic obstructive lung disease; NSCLC: non-small-cell lung cancer; ODI: optical density index; RTx: radio therapy; LFD: lateral flow device; qPCR: quantitative real-time PCR; VCZ: voriconazole; ISA: isavuconazole; CASPO: caspofungin; ANID: anidulafungin; L-AmB: liposomal amphotericin B; ICZ: itraconazole; POSA = posaconazole.