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T1 0-62 Sentence denotes Fungal Co-infections Associated with Global COVID-19 Pandemic:
T2 63-111 Sentence denotes A Clinical and Diagnostic Perspective from China
T3 113-121 Sentence denotes Abstract
T4 122-266 Sentence denotes Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been sweeping across the globe.
T5 267-459 Sentence denotes Based on a retrospective analysis of SARS and influenza data from China and worldwide, we surmise that the fungal co-infections associated with global COVID-19 might be missed or misdiagnosed.
T6 460-623 Sentence denotes Although there are few publications, COVID-19 patients, especially severely ill or immunocompromised, have a higher probability of suffering from invasive mycoses.
T7 624-896 Sentence denotes Aspergillus and Candida infections in COVID-19 patients will require early detection by a comprehensive diagnostic intervention (histopathology, direct microscopic examination, culture, (1,3)-β-d-glucan, galactomannan, and PCR-based assays) to ensure effective treatments.
T8 897-1128 Sentence denotes We suggest it is prudent to assess the risk factors, the types of invasive mycosis, the strengths and limitations of diagnostic methods, clinical settings, and the need for standard or individualized treatment in COVID-19 patients.
T9 1129-1332 Sentence denotes We provide a clinical flow diagram to assist the clinicians and laboratory experts in the management of aspergillosis, candidiasis, mucormycosis, or cryptococcosis as co-morbidities in COVID-19 patients.
T10 1334-1411 Sentence denotes The Global Popularity of COVID-19 and the Possibility of Fungal Co-infections
T11 1412-1621 Sentence denotes As the human-to-human transmitted disease, coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been an emergency global public health events [1, 2].
T12 1622-1785 Sentence denotes Till May 18th, 2020, the COVID-19 has rapidly spread to 212 countries and caused nearly 5 million laboratory-confirmed cases and more than 310,000 deaths globally.
T13 1786-1981 Sentence denotes Like SARS-CoV and Middle East Respiratory Syndrome Coronavirus (MERS-CoV), SARS-CoV-2 is responsible for lower respiratory infection and can cause Acute Respiratory Distress Syndromes (ARDS) [3].
T14 1982-2152 Sentence denotes Besides, the diffuse alveolar damage with severe inflammatory exudation, COVID-19 patients always have immunosuppression with a decrease in CD4 + T and CD8 + T cells [4].
T15 2153-2412 Sentence denotes Critically ill patients, especially the patients who were admitted to the intensive care unit (ICU) and required mechanical ventilation, or had a longer duration of hospital stays, even as long as 50 days, were more likely to develop fungal co-infections [5].
T16 2413-2593 Sentence denotes Hence, it is important to notice that COVID-19 patients can develop further fungal infections during the middle and latter stages of this disease, especially severely ill ones [6].
T17 2595-2652 Sentence denotes Epidemiology of Fungal Co-infections in COVID-19 Patients
T18 2653-3030 Sentence denotes To analyze the incidence of fungal co-infections in COVID-19 patients, we searched PubMed, Scopus, Embase, and Web of Science, using the keywords “fungi” OR “fungus” OR “fungal infection” OR “invasive fungal diseases” OR “secondary infection” AND “COVID-19” OR “SARS-CoV-2” OR “2019-nCoV” OR “2019 novel coronavirus” without date (up to May 18, 2020) and language restrictions.
T19 3031-3129 Sentence denotes We also searched CNKI and Wanfang Data using the same terms in Chinese, with no time restrictions.
T20 3130-3270 Sentence denotes The title, abstract, and full text of related articles determined according to these search criteria were carefully reviewed by the authors.
T21 3271-3428 Sentence denotes Unfortunately, we have found very few articles reporting on fungal co-infections, not only that, some studies have not provided the details of the pathogens.
T22 3429-3571 Sentence denotes Even so, we found COVID-19 patients, especially severely ill ones or accompanied with immunocompromised state, had co-infections of fungi [7].
T23 3572-3819 Sentence denotes In China, Chen et al. performed fungal culture on all 99 COVID-19 patients at admission and found five (5%, 5/99) cases of fungal infection, including one case of Aspergillus flavus, one case of Candida glabrata and three cases of C. albicans [8].
T24 3820-3975 Sentence denotes Yang et al. found there (3/52, 5.8%) patients had fungal co-infection in 52 critically ill patients, including A. flavus, A. fumigatus and C. albicans [5].
T25 3976-4153 Sentence denotes Other China studies have found a higher percentage of secondary infections (8–15%) in COVID-19 patients, but it is not clear whether it is bacterial or fungal infection [9, 10].
T26 4154-4400 Sentence denotes In addition, one study mentioned that 2.8% (31/1099) patients were treated with antifungal medicine, including 1.9% (18/926) non-severe patients and 7.5% (13/173) severe patients, but there was no etiological evidence of fungal co-infection [11].
T27 4401-4496 Sentence denotes Another study mentioned there was no patient treated with antifungal medicine in 149 cases [4].
T28 4497-4679 Sentence denotes A German study found COVID-19 associated invasive pulmonary aspergillosis (IPA) was found in five (26.3%) of 19 consecutive critically ill patients with moderate to severe ARDS [12].
T29 4680-4809 Sentence denotes In Netherlands, there were six patients (19.4%) presumed IPA in 31 ICU patients, of which five were identified A. fumigatus [13].
T30 4810-4968 Sentence denotes Besides, among the 5 first well-described French COVID-19 patients, an old severely ill man was co-infected with A. flavus by tracheal aspirates culture [14].
T31 4970-5064 Sentence denotes Neglected Fungal Co-infection in COVID-19 Patients by Suggestive Ideas from SARS and Influenza
T32 5065-5218 Sentence denotes Studies have shown that SARS-CoV and SARS-CoV-2 belong to the same species and have the similar prevalence, biological and clinical characteristics [15].
T33 5219-5519 Sentence denotes Looking back on SARS in 2003, we found the incidence of fungal infection in SARS patients was 14.8–27%, which was even higher in severely ill ones, up to 21.9–33% [16, 17], meanwhile, fungal infection was the main cause of death for SARS patients, accounting for 25–73.7% in all causes of death [18].
T34 5520-5668 Sentence denotes Besides, in the past decade, increasing reports of severe influenza pneumonia resulting in ARDS complicated by fungal infection were published [19].
T35 5669-5886 Sentence denotes One research found IPA was diagnosed in 83 (19%) of 432 patients admitted with influenza, which was higher in immunocompromised patients (32%), and in the event of IPA, the mortality will increase from 28 to 51% [20].
T36 5887-6010 Sentence denotes However, as for fungal co-infection in COVID-19 patients, only few studies have reported it, which may have been neglected.
T37 6011-6189 Sentence denotes Clinically, many COVID-19 patients did not undergo sputum fungal assessment at the beginning, moreover, it is difficult to detect fungus with a single sputum fungal culture [11].
T38 6190-6498 Sentence denotes With the disease aggravating, it is easy to attribute the severe respiratory symptoms to COVID-19, at the most considering of the co-infection with bacterium or even mycoplasma [21] which usually leads to the in-time use of antibiotics, while the diagnosis of fungal infection is always delayed or neglected.
T39 6499-6719 Sentence denotes Based on the experience of SARS in 2003 and the cases of invasive aspergillosis combined with severe influenza, it is critically important to pay attention to the probability of COVID-19 accompanied by fungal infections.
T40 6721-6805 Sentence denotes Clinical and Diagnostic Perspective of COVID-19 Associated with Fungal Co-infections
T41 6806-6896 Sentence denotes As the ongoing COVID-19 pandemic, more and more experts are aware of fungal co-infections.
T42 6897-7022 Sentence denotes The French High Council for Public Health recommended to systematically screen for fungal pathogens in COVID-19 patients [6].
T43 7023-7249 Sentence denotes Lanjuan Li academician and her colleagues who have accumulated experience with severe COVID-19 treatment, reminded clinicians should focus on patients’ fungal infections, especially severely ill or immunocompromised ones [22].
T44 7250-7369 Sentence denotes At the early phase of the disease or with extrapulmonary fungal infections, it may present with atypical chest imaging.
T45 7370-7976 Sentence denotes Hence, it is necessary for severely ill patients to receive fungal pathogens surveillance, including (i) etiological examination: direct microscopy and culture; (ii) histopathology; (iii) serology: antigen and antibody, (1,3)-β-d-glucan (BDG) [23] and galactomannan (GM) detection by serum are also need to be tested for suspicious patients, while bronchoalveolar lavage fluid (BALF) and tracheal aspirate (TA) sampling for culture and biomarker testing should be performed under well-protected conditions due to the risk of aerosol spreading and health care worker infections [24]; (iv) PCR-based methods:
T46 7977-8116 Sentence denotes Real-time polymerase chain reaction (PCR) techniques and molecular identification can be performed to identify pathogens if necessary [25].
T47 8117-8247 Sentence denotes After identifying the pathogen, the antifungal susceptibility testing (AST) can be performed to select sensitive antifungal drugs.
T48 8248-8315 Sentence denotes If the AST cannot be carried out, it should be treated empirically.
T49 8316-8423 Sentence denotes The main fungal pathogens for fungal co-infections in severe COVID-19 patients are Aspergillus and Candida.
T50 8424-8555 Sentence denotes Other infrequent opportunistic pathogenic fungus caused lung infections also need to be considered, such as Mucor and Cryptococcus.
T51 8557-8584 Sentence denotes Invasive Aspergillosis (IA)
T52 8585-8728 Sentence denotes Aspergillus species could be an important cause of life-threatening infection in COVID-19 patients, especially in those with high risk factors.
T53 8729-9047 Sentence denotes The potential risk factors for the patients include GC use, prolonged neutropenia, chronic obstructive pulmonary disease (COPD), allogeneic hematopoietic stem cell transplant (allo-HSCT) [26], solid organ transplant (SOT) [27], inherited immunodeficiencies, hemopoietic malignancy (HM), cystic fibrosis (CF) [28], etc.
T54 9048-9307 Sentence denotes The diagnosis of IA requires a microbiologic and/or histopathologic evidence, although specimen acquisition is challenging in many patients because lung biopsy might be contraindicated in patients with coagulation disorders or severe respiratory failure [13].
T55 9308-9786 Sentence denotes Histopathologic examination mainly rely on finding special fungal stains on lung fluid or tissue when a fungal infection is suspected and may reveal the characteristic acute angle branching septate hyphae of Aspergillus spp., and Grocott-Gomori’s methenamine-silver stain (GMS) and periodic acid-Schiff (PAS) stains of fixed tissue will helpful, while it is difficult to distinguish Aspergillus spp. from other filamentous fungi such as Fusarium spp. and Scedosporium spp. [29].
T56 9787-11136 Sentence denotes Therefore, it is necessary to have a definitive confirmation by culture or nonculture technique, including (i) direct microscopic examination with the optical brightener methods, Calcofluor or Blankophor, which may increase the sensitivity and specificity for detecting Aspergillus-like features; (ii) culture on fungal-specific media at 37 °C for 2–5 days, if positive, morphological features of Aspergillus can be identified under the microscope or the DNA sequencing may be used in reference laboratories to identify the species accurately, but usually culture yield is low and a negative result does not exclude the diagnosis of IA; (iii) molecular assays targeting ribosomal DNA (rDNA) sequences can also be used for detection of Aspergillus in tissues or BALF, especially PCR-based assays can be used to detect Aspergillus spp. and CYP51A resistance mutations in A. fumigatus, although these methods have not been standardized or limited by laboratory conditions or proven commercial reagents in some countries [30]; (iv) serum and BALF GM testing are also recommended as an early and accurate marker using less invasive techniques for the diagnosis, especially in neutropenic patients, with advantages of less injury and time-efficient, though sometimes this test in blood samples are less sensitive than cultures of respiratory samples [25].
T57 11137-11420 Sentence denotes The treatment recommendations can be supported by the 2016 Update guideline by the Infectious Diseases Society of America that the prophylaxis, therapeutic medication, combined, and alternative medication of aspergillus infection have been given more detailed guidance opinions [30].
T58 11421-11645 Sentence denotes Generally, drugs recommended for the treatment and prophylaxis of IA include triazoles (itraconazole, voriconazole, posaconazole, esaconazole), Amphotericin B and its liposomes and echinococcins (micafungin or carpofenjing).
T59 11646-11835 Sentence denotes Most patients can choose triazole drugs to treat IA, however, therapeutic drug monitoring (TDM) is recommended and the interaction between azoles and other drugs should be fully considered.
T60 11837-11862 Sentence denotes Invasive Candidiasis (IC)
T61 11863-12192 Sentence denotes For the severe COVID-19 patients who have more opportunities to be treat with broad-spectrum antibacterial drugs, parenteral nutrition and invasive examinations, or the patients accompanied with prolonged neutropenia and other immune impairment factors, the risk of infection with Candida species may significantly increase [31].
T62 12193-12581 Sentence denotes Diagnosis of IC depends on culture methods including culture of blood or other samples collected under sterile conditions which are usually considered as gold standards for IC, and nonculture diagnostic tests including mannan and antimannan IgG tests, C. albicans germ tube antibody (CAGTA), BDG and PCR-based assays, which are now entering clinical practice as adjuncts to cultures [32].
T63 12582-13109 Sentence denotes There are mainly two disadvantages about blood culture, on the one hand, the blood culture time is long, because the average positive alarm time is 2–3 days (range 1 to ≥ 7 days), plus identification and susceptibility test duration 4 to 6 days, on the other hand, it is not sensitive than PCR with much lower detection limit when Candida concentration is ≤ 1 CFU/mL and easy to have failure to detect in extremely low concentrations of candidiasis, intermittent candidiasis or deep Candida infection has not entered the blood.
T64 13110-13257 Sentence denotes Hence, several nonculture diagnostic tests are recommended, but also there is widespread uncertainty about their utility in clinical practice [31].
T65 13258-13535 Sentence denotes BDG is a major cell wall constituent of Candida and most pathogenic fungi, excluding Cryptococcus species, Blastomyces species, and Mucorales, which is widely used in clinical and well recommended by detecting serum, but cannot distinguish between Candida and other fungi [25].
T66 13536-13726 Sentence denotes Besides, mannan and antimannan IgG tests, CAGTA are employed at many European centers, and higher sensitivity and specificity by a combination with mannan/antimannan assay are observed [33].
T67 13727-14004 Sentence denotes There are promising PCR tests, including multiplex-PCR platforms, at the same time, it exists some limitations for a lack of multicenter validation of assay performance, so there are no FDA-cleared PCR assays for Candida, but commercial and in-house tests are widely available.
T68 14005-14166 Sentence denotes Further, T2 magnetic resonance is also can be used by amplifying and detecting Candida DNA, but its feasibility in early diagnosis of candidemia remains unclear.
T69 14167-14505 Sentence denotes MALDI-TOF technology is available in more hospitals with the biggest advantage of its promptness taking no more than 5 min to identify a microorganism from isolated colonies, even researchers have developed protocols to identify yeasts directly from positive blood culture bottles within half an hour without performing a subculture [32].
T70 14506-14795 Sentence denotes Overall, not only it is necessary to fully realize the benefits of combining culture and nonculture methods, but also, clinicians must take the types of IC, the strengths and limitations of each assay and the context of the clinical setting into account to have a judicious interpretation.
T71 14796-14955 Sentence denotes Besides, susceptibility test is recommended for all blood-stream and other clinically relevant Candida isolates, especially for C. glabrata or C. parapsilosis.
T72 14956-15204 Sentence denotes The treatment recommendations can be supported by the 2016 Update guideline by the Infectious Diseases Society of America that the therapeutic and alternative medication of candidiasis infection have been given more detailed guidance opinions [34].
T73 15205-15517 Sentence denotes Generally, patients who are suspected or confirmed with IC should be treated with echinocandin (caspofungin, micafungin, and anidulafungin), azoles (fluconazole, voriconazole, itraconazole), and Amphotericin B and its liposomes, what’s more, TDM for azoles should be used to optimize efficacy and limit toxicity.
T74 15519-15540 Sentence denotes Invasive Mucormycosis
T75 15541-15686 Sentence denotes COVID-19 patients with trauma, diabetes mellitus, GC use, HM, prolonged neutropenia, allo-HSCT, SOT are more likely to develop mucormycosis [35].
T76 15687-15945 Sentence denotes Mucormycosis is usually suspected based on results of direct microscopy or plus fluorescent brighteners from clinical specimens such as sputum, BALF, and skin lesions that Mucorales hyphae are non-septate or pauci-septatethe with a variable width of 6–16 μm.
T77 15946-16106 Sentence denotes To confirm the diagnosis, non-pigmented hyphae showing tissue invasion should be shown in tissue sections stained with hematoxylin–eosin (HE), PAS, or GMS [36].
T78 16107-16202 Sentence denotes Culture of specimens is strongly recommended for identification of genus and species, also AST.
T79 16203-16476 Sentence denotes What’s more, it is suggested to be cultured at 30 °C and 37 °C separately that typically cottony white or grayish black colony usually will be found, afterward morphological identification of fungi or DNA sequencing based on bar code genes, such as 18S, ITS, 28 s, or rDNA.
T80 16477-16633 Sentence denotes MALDI-TOF identification is just moderately supported because it depends mainly on in-house databases, and many laboratories do not have this capacity [37].
T81 16634-16844 Sentence denotes Further, it is promising to detect fungi DNA, in serum as well as in other body fluids, even in paraffin-embedded tissue, however, because of lack of standardization supported it is only with moderate strength.
T82 16845-17201 Sentence denotes The treatment recommendations can be supported by the global guideline for the diagnosis and management of mucormycosis in 2019 by European Confederation of Medical Mycology (ECMM) and Mycoses Study Group Education and Research Consortium that the therapeutic and alternative medication of mucormycosis have been given more detailed guidance opinions [35].
T83 17202-17352 Sentence denotes Generally, it strongly supports an early complete surgical treatment for mucormycosis whenever possible, in addition to systemic antifungal treatment.
T84 17353-17493 Sentence denotes In neutropenic patients, those with graft-versus-host disease or high risk factor, primary prophylaxis with posaconazole may be recommended.
T85 17494-17699 Sentence denotes Amphotericin B lipid complex, liposomal Amphotericin B and posaconazole oral suspension are treated as the first-line antifungal monotherapy, while isavuconazole is strongly supported as salvage treatment.
T86 17700-17834 Sentence denotes There are no convincing data to guide the use of antifungal combination therapy of polyenes and azoles or polyenes plus echinocandins.
T87 17836-17859 Sentence denotes Invasive Cryptococcosis
T88 17860-18115 Sentence denotes COVID-19 patients with human immunodeficiency virus (HIV) infection accompanied by CD4 + T-lymphocyte count < 200 cells/μL, allo-HSCT, SOT, or other immune impaired are susceptible to cryptococcosis which predominantly present as meningoencephalitis [38].
T89 18116-18379 Sentence denotes Given the complexities surrounding the diagnosis of cryptococcosis and identification of Cryptococcus species including C. neoformans and C. gattii species, the diagnosis of cryptococcosis is usually based on a combination of clinical and laboratory confirmation.
T90 18380-18504 Sentence denotes The methods used to confirm the infection are culture, direct microscopy, histopathology, serology, and molecular detection.
T91 18505-18747 Sentence denotes To diagnose cryptococcosis, specimen from cerebrospinal fluid (CSF) can be mixed with India ink and observed under a microscope that the distinctive structure for Cryptococcus spp. with narrow budding encapsulated yeasts usually can be found.
T92 18748-18875 Sentence denotes Samples for culture should be placed on Sabouraud dextrose agar at 30 °C for 7 days, in aerobic conditions, and observed daily.
T93 18876-18973 Sentence denotes Moreover, cultures from patients receiving systemic antifungal therapy might need longer to grow.
T94 18974-19021 Sentence denotes Cryptococcus appears as mucoid creamy colonies.
T95 19022-19159 Sentence denotes Capsular polysaccharides of Cryptococcus can be detected and quantified from body fluids such as serum, CSF, BAL, or pathological tissue.
T96 19160-19358 Sentence denotes Three formats of cryptococcal antigen (CrAg) detection tests are currently available: the latex agglutination test (LAT), the enzyme-linked immunoassay (EIA), and the lateral flow immunoassay (LFA).
T97 19359-19509 Sentence denotes These methods are rapid, sensitive, and specific, but have not been standardized for respiratory specimens such as BAL, pleural fluid, or sputum [32].
T98 19510-19663 Sentence denotes Molecular detection of Cryptococcus is required in specific situations where other diagnostic tools have failed to confirm a diagnosis of cryptococcosis.
T99 19664-19823 Sentence denotes These molecular methods include pan-fungal PCR, DNA sequencing for identification, multiplex PCR, isothermal amplification method, and probe-based microarrays.
T100 19824-19982 Sentence denotes Once a diagnosis cryptococcosis is made, a lumbar puncture and cerebrospinal fluid (CSF) examination (including antigen) are recommended in all patients [39].
T101 19983-20076 Sentence denotes Cryptococcus can disseminate into the central nervous system causing cryptococcal meningitis.
T102 20077-20367 Sentence denotes The treatment recommendations can be supported by guidelines for the diagnosis, prevention, and management of cryptococcal disease in HIV-infected adults, adolescents, and children in 2018 by World Health Organization (from: https://www.who.int/hiv/pub/guidelines/cryptococcal-disease/en/).
T103 20368-20735 Sentence denotes Generally, the following is recommended as the preferred regimen: (i) Induction phase for amphotericin B deoxycholate and + flucytosine, followed by fluconazole; alternative options for fluconazole + flucytosine or amphotericin B deoxycholate + fluconazole. (ii) Consolidation phase for fluconazole. (iii) Maintenance (or secondary prophylaxis) phase for fluconazole.
T104 20737-20744 Sentence denotes Summary
T105 20745-20939 Sentence denotes By analyzing retrospective analysis of SARS and influenza data from China and worldwide, we surmise that the fungal co-infections associated with global COVID-19 might be missed or misdiagnosed.
T106 20940-21202 Sentence denotes Further, as a life-threatening infectious disease, COVID-19 patients showed overexpression of inflammatory cytokines, and impaired cell-mediated immune response with decreased CD4 + T and CD8 + T cell counts, indicating its susceptibility to fungal co-infection.
T107 21203-21422 Sentence denotes Moreover, COVID-19 patients accompanied with immunocompromised state, such as prolonged neutropenia, HSCT, GC use, SOT, inherited or acquired immunodeficiencies, and tumor are more likely to develop fungal co-infection.
T108 21423-21661 Sentence denotes Here, we summarized updated diagnostic information (histopathology, direct microscopic examination, culture, (1,3)-β-d-glucan, galactomannan, PCR-based assays, MALDI-TOF technology, etc.) and treatment recommendations of invasive mycosis.
T109 21662-21893 Sentence denotes We suggest it is prudent to assess the risk factors, the types of invasive mycosis, the strengths and limitations of diagnostic methods, clinical settings, and the need for standard or individualized treatment in COVID-19 patients.
T110 21894-22111 Sentence denotes Finally, provide a clinical flow diagram (Fig. 1) to assist the clinicians and laboratory experts in the management of aspergillosis, candidiasis, mucormycosis, or cryptococcosis as comorbidities in COVID-19 patients.
T111 22112-22186 Sentence denotes Fig. 1 Diagnostic and therapeutic pathway for invasive fungal co-infection
T112 22188-22204 Sentence denotes Publisher's Note
T113 22205-22323 Sentence denotes Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T114 22324-22389 Sentence denotes Ge Song and Guanzhao Liang have contributed equally to this work.
T115 22391-22398 Sentence denotes Funding
T116 22399-22527 Sentence denotes This work was supported by The subitem of the Important and Special Project of the Science and Technology Ministry of China (No.
T117 22528-22582 Sentence denotes 2018ZX10734404) and National Pathogen Resource Center.
T118 22584-22617 Sentence denotes Compliance with Ethical Standards
T119 22619-22639 Sentence denotes Conflict of interest
T120 22640-22699 Sentence denotes The authors declare that they have no conflict of interest.