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LitCovid-PD-GO-BP

{"project":"LitCovid-PD-GO-BP","denotations":[{"id":"T4","span":{"begin":2356,"end":2368},"obj":"http://purl.obolibrary.org/obo/GO_0009405"},{"id":"T5","span":{"begin":2413,"end":2425},"obj":"http://purl.obolibrary.org/obo/GO_0009405"},{"id":"T6","span":{"begin":2813,"end":2828},"obj":"http://purl.obolibrary.org/obo/GO_0044409"},{"id":"T7","span":{"begin":2813,"end":2828},"obj":"http://purl.obolibrary.org/obo/GO_0036267"},{"id":"T8","span":{"begin":2822,"end":2828},"obj":"http://purl.obolibrary.org/obo/GO_0040007"},{"id":"T9","span":{"begin":2861,"end":2872},"obj":"http://purl.obolibrary.org/obo/GO_0043934"},{"id":"T10","span":{"begin":2861,"end":2872},"obj":"http://purl.obolibrary.org/obo/GO_0030437"},{"id":"T11","span":{"begin":3893,"end":3899},"obj":"http://purl.obolibrary.org/obo/GO_0040007"}],"text":"Expert review\n\nGlobal epidemiology of influenza and IAPA\nAlthough 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]. The mortality in patients admitted for influenza is 4% and 20–25% for those admitted to ICU [14–16]. Bacterial superinfection is common, affecting 10–35% of cases, typically with Streptococcus pneumoniae or Staphylococcus aureus [16]. 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 \u003c 0.001) [9]. 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). 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]. The median time between influenza diagnosis and IAPA was short, often in the first 5 days [7, 8, 18]. 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]. 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]. Autopsy rates are very low, which results in a considerable underdiagnosis in many countries [26]. 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]. 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].\n\nPathogenesis of IAPA\nIn 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. Furthermore, autopsy studies have shown the presence of sporulating heads of Aspergillus inside the bronchi with invasive growth occurring into the lung tissue. 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. Other factors that have been implicated in IAPA include the use of corticosteroids and of neuraminidase inhibitors, such as oseltamivir [7, 30]. Ultimately, these insights may aid in identifying patients at risk of IAPA and to design effective antifungal and adjunctive immunomodulatory treatment strategies.\n\nClinical presentation and diagnosis of IAPA\nA retrospective Belgian study of influenza patients admitted to ICU between September 2009 and March 2011 showed that 9 of 40 (23%) patients had IAPA. Four cases (44%) were proven despite not being immunocompromised according to the EORTC/MSGERC consensus definitions [7]. The median time between influenza diagnosis and IAPA was 2 days (range 0–4 days). All IAPA patients had positive BAL GM, and 78% had positive serum GM, despite not being neutropenic. 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]. Similar performance characteristics of BAL GM and culture were reported in two other cohort studies [8, 9]. BAL sampling is thus an important diagnostic procedure as serum GM can be negative and sputum/tracheal aspirate cultures can remain sterile.\nLesions that are suggestive of invasive mold disease on imaging in neutropenic patients, such as the halo sign, are often absent in critically ill patients. However, in some IAPA patients with autopsy-confirmed Aspergillus tracheobronchitis, chest CT demonstrated peribronchial infiltrates. 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]. 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]. 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. 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]. 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. However, lateral flow tests have not yet been validated in the ICU population.\nIAPA 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. 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 (\u003e 5%) azole resistance rates [34]. This would enable diagnostic assessment and initiation of adequate antifungal therapy within 24–48 h of ICU admission. Diagnostic workup for IAPA may be repeated in patients deteriorating while on antivirals and/or appropriate antibiotics or when initiating corticosteroid treatment is unavoidable.\n\nDiscussion on clinical presentation and diagnosis of IAPA\nIf 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. 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. Testing is most appropriate in patients who are on mechanical ventilation, but the diagnostic strategy is less clear in patients not intubated. 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]. 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. The use of a flexible brush may also be sufficient to make the diagnosis.\nAlthough a positive serum GM is highly indicative of IA, BAL GM can be positive in patients with Aspergillus colonization. It therefore does not absolutely discriminate between colonization and invasive disease. However, it clearly makes it more likely that an invasive disease is present [36].\n\nUse of corticosteroids\nCorticosteroids should not be given to influenza patients as their use may be associated with increased risk of IAPA [7, 37–39]. A recent Cochrane review on this topic concluded that the use of corticosteroids in patients with influenza was associated with a worse outcome [40]. However, the evidence was almost exclusively observational. 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. 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. 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].\n\nRationale for antifungal prophylaxis for IAPA\nIn 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. However, there is currently no mold-active antifungal agent licensed for prophylaxis of IA in ICU patients. Posaconazole (POS) prophylaxis reduces the prevalence of IA in neutropenic AML patients and those with graft-versus-host disease following alloHCT [2, 3]. Based on this proof-of-principle, it has been hypothesized that POS prophylaxis can reduce IAPA prevalence in ICU patients. 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. POS IV formulation should be administered through a central catheter due to its acidity (pH 3.2) [42].\n\nTreatment options and challenges for IAPA in the ICU\nFirst-line treatment options for IPA include voriconazole and isavuconazole [35, 43]. 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]. Achieving adequate drug exposure is challenging in ICU patients with multiple factors contributing to pharmacokinetic variability. 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]. The impact of therapeutic drug monitoring (TDM) for voriconazole shows a clear relation between exposure and both efficacy and toxicity. 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 (\u003e 5.5 mg/L) increasing the risk of (neuro)toxicity. Higher trough concentrations (\u003e 2 mg/L) are recommended for treatment of pathogens with elevated MICs (e.g., \u003e 0.25 mg/L) [52]. 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].\n\nDiscussion on antifungal treatment options and challenges for IAPA in the ICU\nA 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. Similar interactions have not been seen with other azoles. Many other drug interactions with azoles and drugs commonly deployed in the ICU can be expected [45].\nAerosolized 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]. 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. 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]. Thus, for pregnant patients at risk of IAPA a diagnostic approach was preferred above antifungal prophylaxis.\nThere is little evidence on the impact of ECMO on antifungal drug exposure [56]. For the echinocandins, an impact of ECMO is not expected. Experts felt that, given these uncertainties, TDM of any antifungal used would be advised to ensure sufficient drug exposure."}

LitCovid-PD-GlycoEpitope

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