Next Article in Journal
Influenza Vaccination and Non-Pharmaceutical Measure Effectiveness for Preventing Influenza Outbreaks in Schools: A Surveillance-Based Evaluation in Beijing
Next Article in Special Issue
BCG Provides Short-Term Protection from Experimental Cerebral Malaria in Mice
Previous Article in Journal
Degradomics-Based Analysis of Tetanus Toxoids as a Quality Control Assay
Previous Article in Special Issue
Immune System Modulations by Products of the Gut Microbiota
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Covid-19-Associated Pulmonary Aspergillosis: The Other Side of the Coin

Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy
Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Author to whom correspondence should be addressed.
Vaccines 2020, 8(4), 713;
Submission received: 19 October 2020 / Revised: 19 November 2020 / Accepted: 27 November 2020 / Published: 1 December 2020


The immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a critical factor in the clinical presentation of COVID-19, which may range from asymptomatic to a fatal, multi-organ disease. A dysregulated immune response not only compromises the ability of the host to resolve the viral infection, but may also predispose the individual to secondary bacterial and fungal infections, a risk to which the current therapeutic immunomodulatory approaches significantly contribute. Among the secondary infections that may occur in COVID-19 patients, coronavirus-associated pulmonary aspergillosis (CAPA) is emerging as a potential cause of morbidity and mortality, although many aspects of the disease still remain unresolved. With this opinion, we present the current view of CAPA and discuss how the same mechanisms that underlie the dysregulated immune response in COVID-19 increase susceptibility to Aspergillus infection. Likewise, resorting to endogenous pathways of immunomodulation may not only restore immune homeostasis in COVID-19 patients, but also reduce the risk for aspergillosis. Therefore, CAPA represents the other side of the coin in COVID-19 and our advances in the understanding and treatment of the immune response in COVID-19 should represent the framework for the study of CAPA.

1. Introduction

The coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which interacts with heparan sulfate and angiotensin-converting enzyme 2 (ACE2) [1] to penetrate susceptible tissues. The nose shows the highest expression of ACE2 along the respiratory tract [2] and represents a permissive entry site to the virus that subsequently translocates to the lungs, likely by aspiration, to ignite pathogenesis [2]. However, viral tropism is not restricted to the respiratory tract and the virus can be detected in multiple organs, such as the liver, brain, and kidneys [3]. The clinical presentation of COVID-19 is variable, ranging from asymptomatic to a fatal, multi-organ disease, and multiple risk factors determine an individual’s prognosis. Such risk factors include both demographic characteristics, i.e., age ([4] and refs therein) and gender [5], and clinical aspects, i.e., the presence of co-morbidities, such as diabetes [6], chronic obstructive pulmonary disease [7], cardiovascular disease [8], and cancer [9]. An increasing risk for COVID-19 patients is represented by the occurrence of co-infections and superinfections, which may deteriorate the clinical picture [10,11]. Indeed, bacterial, fungal, and viral infections have been detected in COVID-19 patients, although at a low incidence [12]. Among the superinfections that may occur in COVID-19 patients, fungal pathogens are increasingly being recognized as an emergent threat [13], although many aspects still remain unclear from a diagnostic, clinical, therapeutic, and mechanistic point of view.
With this, we will present current evidence of invasive fungal infections in COVID-19 patients and existing debate on clinical features of the disease. We will then provide possible mechanistic explanations, linking the dysregulation of the immune response in COVID-19 patients with the increased susceptibility to infection. Finally, we will discuss potential therapeutic approaches that by re-establishing a homeostatic response of the immune system, would reduce the risk of invasive fungal infections.

2. Coronavirus-Associated Pulmonary Aspergillosis (CAPA)

Since the first indications of the presence of Aspergillus in specimens from COVID-19 patients in the early descriptions of Chinese patients [14,15,16,17], reports on coronavirus-associated pulmonary aspergillosis (CAPA) have appeared in the literature [18,19,20,21,22] and increased steadily, such that more than 100 cases have now been described worldwide in intensive care units (ICU) treating COVID-19 patients [13]. However, defining the incidence of CAPA remains an open question, which is hampered by diagnostic difficulties, which are widely discussed in the literature, such as in [13,23,24]. These issues include the general absence of host factors, as defined by the European Organization for Research and Treatment of Cancer and the Mycoses Study Group [25], in COVID-19 patients, the challenges in performing bronchoscopy and autopsy for the risk of generating potentially infective aerosol, and the low sensitivity of galactomannan testing in non-neutropenic patients. Alternative methods, such as endotracheal aspirates, may provide confounding results for the inability to distinguish between colonization and invasive aspergillosis. Similarly, β-D-glucan testing is not specific for Aspergillus infection and may require further confirmation. Recent extensive diagnosic testing has been performed in 719 critically ill COVID-19 patients. In a subset of 61 patients for whom both serum and respiratory samples were available, rates of 5% (3/61) and 15% (10/61) of proven/probable and possible CAPA, respectively, were reported [26].
Notwithstanding these complications, the presence of Aspergillus in COVID-19 patients has parallels with the aspergillosis observed in patients admitted to the ICU with severe influenza or influenza-associated pulmonary aspergillosis (IAPA) [27]. Indeed, a study comparing IAPA and CAPA identified a similar incidence of invasive aspergillosis in influenza and COVID-19 patients, the overall absence of host risk factors, a similar timing of diagnosis, and a poor prognosis [28]. Accordingly, it has been proposed that the same IAPA definitions may apply to CAPA [27], although a more specific definition has recently been suggested [29]. In any case, the pathogenesis of IAPA and CAPA seems to differ for the distinct viral ability to induce tissue damage and immunomodulatory effects [27]. For instance, influenza and SARS-CoV-2 viruses bind to different receptors with distinct distribution along the respiratory tract. The human influenza virus binds sialic acids attached to galactose by an alpha(2,6) linkage commonly also present in large airways as opposed to SARS-CoV-2 receptors, which may correlate with an increased risk of invasive Aspergillus tracheobronchitis in IAPA compared to CAPA [27]. Second, influenza virus has a direct effect of antifungal host defence mechanisms by inhibiting the NADPH oxidase, while to date, such activities have not been described for SARS-CoV-2 [27]. These differences make CAPA a distinct clinical entity, at least in the etiology of aspergillosis, and it is debated whether COVID-19 actually represents a risk factor for aspergillosis. Indeed, a major role may be played by the therapy of COVID-19. For instance, the use of tocilizumab, a monoclonal antibody against the interleukin-6 receptor, may prevent Th17 responses and favor aspergillosis. Similarly, chronic steroid treatment may impair host defenses, including LC3-associated phagocytosis [30]. Additional risk factors, such as lung damage [31] or structural defects [22] or broad-spectrum antibiotics usage [32], may play a role in the development of aspergillosis. However, it cannot be excluded that SARS-CoV-2 infection and the dysregulated immune response may favor the creation of conditions permissive for the growth of Aspergillus [27].
All in all, available evidence suggest that CAPA, among the potential secondary infections, may represent a cause of mortality and morbidity in critically ill COVID-19 patients and identifying risk factors that depend on both the disease and treatment is crucial for therapeutic purposes.

3. Immune Response in COVID-19

Following penetration in susceptible tissues, SARS-CoV-2 elicits an immune response that may develop along different trajectories, leading to a wide spectrum of clinical presentations. In mild COVID-19, there is a strong activation of the innate immune compartment, with a prominent role for HLA-DRhiCD11chi inflammatory monocytes, with high expression of interferon (IFN)-stimulated genes, while severe patients are marked by the presence of dysfunctional monocytes and neutrophils [33]. The reduced antiviral type I and III IFNs response is opposed by the abundant production of inflammatory cytokines [34] and a cytokine storm may contribute to the deterioration of severe COVID-19 patients [35,36,37]. The defective IFN response may result from multiple causes, including the presence of autoantibodies [38] or inborn errors [39,40]. The adaptive immune system is also compromised in severe patients with insurgence of lymphopenia, caused by unbalanced differentiation from hematopoietic precursors in the presence of emergency myelopoiesis, impaired recruitment and activation, along with the presence of an exhausted phenotype [41]. In addition, lymphopenia may impair immunological memory [41]. In contrast, patients with asymptomatic or mild COVID-19 develop a strong T cell immunity [42]. Humoral immunity has also been linked with the outcome of COVID-19 infection. Indeed, moderate and severe COVID-19 patients develop IgG and IgM responses, but survivors and non-survivors differ in their development of humoral responses, with the latter showing defective development and impaired IgG responses [43].
The advances in the definition of the immune response in COVID-19 patients allows one to discuss whether the dysregulation observed in severe patients may result in permissive conditions for the development of secondary infections, such as invasive fungal infections. The discussion on the host antifungal mechanisms potentially subverted by the dysregulated immune response can be taken at multiple levels, including soluble mediators and immune cells. A defective type I IFN response may impair the protection against Aspergillus, as supported by multiple lines of evidence. For instance, the expression of type III IFNs, primed by type I IFNs, activate the antifungal response of neutrophils [44] and mice with chronic granulomatous disease (CGD), characterized by impaired phagocytic oxidase activity, and who are susceptible to invasive aspergillosis, are protected by stimulation of type I IFN [45]. In addition, plasmacytoid DCs, known to produce high amounts of type I IFNs upon viral infection, participate in the defense against A. fumigatus and IFN-α/βR−/− mice were more susceptible to invasive aspergillosis than wild-type mice [46]. Similarly, an overproduction of inflammatory cytokines may damage the lung and promote aspergillosis [47,48,49]. With regards to immune cells, the neutrophils observed in severe patients are characterized by impaired oxidative burst [33], which may reflect in a reduced ability to protect from Aspergillus, similar to the condition observed in CGD. In addition, an excessive Th17 response in COVID-19 patients [50,51] may change the protective antifungal role of Th17 cells into a detrimental role [52].
In conclusion, severe COVID-19 is associated with a dysregulated immune response that may not only impact the clinical deterioration of patients, but also modulate the susceptibility to secondary infections, for instance by impairing host antifungal defences and increasing the risk of Aspergillus infection.

4. Restoring Immune Homeostasis in COVID-19 to Prevent CAPA

Current therapeutic strategies to limit the pathology associated with an increased inflammatory response are associated with side effects, including an impaired ability to respond to concomitant infections that are consequent to immune suppression. For instance, tocilizumab is associated with a higher prevalence of infection [53] and the same applies to chronic steroid treatment. An alternative strategy would be to re-equilibrate the immune response by resorting to endogenous pathways of immunomodulation ([54] and Di Stadio et al., submitted). For instance, one of the features of COVID-19 is represented by the production of the inflammatory cytokine IL-1. Epithelial damage causes the release of IL-1α, which induces the recruitment of neutrophils and monocytes and the production of IL-1β [55]. In addition, innate sensing will result in additional production of IL-1β by the NLRP3 inflammasome, creating an amplification loop and a cytokine cascade, with production of IL-6, which may turn detrimental [55]. Targeting the NLRP3/IL-1 pathway by administering anakinra, the recombinant version of IL-1 receptor antagonist might block this noxious circuit and has proved beneficial in COVID-19 patients with a favorable safety profile [54,56,57,58,59]. It is arguable that while restoring a homeostatic immune response in severe COVID-19 patients, anakinra could also reduce susceptibility to secondary infections, including aspergillosis. In this regard, we have previously shown that anakinra protected against aspergillosis in cystic fibrosis [60] and CGD [61], both characterized by unbalanced inflammasome activation and susceptibility to Aspergillus infection. As another example, the activation of the aryl hydrocarbon receptor (AhR), a xenobiotic receptor, was involved in the modulation of the immune response [62]. AhR activation has been linked to mucosal protection by stimulating the production of IL-22 and potentiating the barrier functons in the gut [63]. A similar activity in the respiratory tract would be beneficial to protect from mucosal damage and re-establish protection against infection [64]. Although a recent report has associated AhR activation with lung pathogenesis in COVID-19 [65], the multiplicity of ligands and the different effects upon AhR binding do not allow definitive conclusions on the role of AhR and further studies will be required to determine whether activation is protective against COVID-19 and potential secondary infections, such as with Aspergillus.
Another example is represented by thymosin α1, an endogenous thymic peptide with a wide range of immunomodulatory activities [66] and the capacity to balance a dysregulated immune response in a context-dependent manner. Indeed, thymosin α1 could either be immunostimulatory, such as in cancer and immune deficiency, or promote tolerance in inflammatory conditions, for instance by inducing the indoleamine 2,3-dioxygenase 1 pathway [67,68,69] or promoting autophagy [68]. The latter process is increasingly being recognized as a regulator of lung health and protection against microbial infection, with potential relevance for a variety of lung diseases, including COVID-19 [70]. Of interest, thymosin α1 has already proven to be beneficial in the protection against viral [71] and fungal [72] infections, by promoting an IFN response and a protective Th1 resistance, respectively. Its potential efficacy in critical and severe COVID-19 patients, along with an excellent safety profile, has been assessed [54,73,74] and a reversal of lymphopenia and T cell exhaustion suggested a therapeutic effect. It appears that normalization of the adaptive immune response may also be protective against secondary infections, such as aspergillosis [72]. Interestingly, thymosin α1 was not protective against COVID-19 when used in prophylaxis [75], suggesting that thymosin α1 directly works on the suppressed adaptive immune system once the disease has developed. However, thymosin α1 could still be effective in non-exposed individuals if used in combination with a vaccine [76]. The development of a vaccine is recognized as a priority to halt the pandemic and a huge effort is devoted to this purpose [77]. It is known that thymosin α1 is able to enhance the immune response to vaccination, including specific immune suppressed populations, such as elderly people [76], thus representing a potential adjuvant in the use of a SARS-CoV-2 vaccine. In addition, vaccines are also expected to reduce the COVID-19-associated complications, including secondary infections. Therefore, thymosin α1 represents an endogenous immunomodulatory molecule with multiple applications in COVID-19, ranging from its ability to restore immune homeostasis in critical and severe COVID-19 patients to the boosting of the immune response to vaccination before infection.
In summary, selective targeting of endogenous immune pathways dysregulated in COVID-19 patients may prove beneficial not only to revert the alterations of the immune response in severe cases, but also to reduce the susceptibility to superinfection, including CAPA. However, the timing of this intervention is crucial since it should be initiated in the early stages of COVID-19 with clear immune dysregulation. A serum cytokine profile along with the measurements of selected metabolites and clinical parameters would be instrumental to detect early derailment of the immune response and indicate a proper window of intervention [78].

5. Conclusions

COVID-19 still represents an important threat for human health. A huge effort has helped to tackle the variable presentation of the disease from a mechanistic perspective and the differential engagement of the immune system emerges as a key factor underlying this complexity. At the same time, a dysregulated immune system and the available treatments may open the door for additional threats and the increased susceptibility to secondary infections is increasingly being recognized. Among the superinfections, CAPA plays a critical role and the dissection of mechanistic events resulting in increased susceptibility to Aspergillus infection are just beginning to be unraveled. The possibility to resort to endogenous pathways of immune regulation, as discussed in this paper, may provide the ability to restore the immune alterations resulting from SARS-CoV-2 invasion with protection against subsequent infection, thus opening up novel opportunities for intervention.

Author Contributions

Conceptualization, C.C. and L.R.; writing—original draft preparation, C.C. and L.R.; writing—review and editing, C.C., F.L.v.d.V., and L.R.; funding acquisition, F.L.v.d.V. and L.R. All authors have read and agreed to the published version of the manuscript.


This project was funded by the European Union’s Horizon 2020 research and innovation program under grant agreement no. 847507 to F.L.v.d.V. and L.R.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.


  1. Clausen, T.M.; Sandoval, D.R.; Spliid, C.B.; Pihl, J.; Perrett, H.R.; Painter, C.D.; Narayanan, A.; Majowicz, S.A.; Kwong, E.M.; McVicar, R.N.; et al. SARS-CoV-2 infection depends on cellular heparan sulfate and ACE2. Cell 2020, 183, 1043–1057.e15. [Google Scholar] [CrossRef] [PubMed]
  2. Hou, Y.J.; Okuda, K.; Edwards, C.E.; Martinez, D.R.; Asakura, T.; Dinnon, K.H., 3rd; Kato, T.; Lee, R.E.; Yount, B.L.; Mascenik, T.M.; et al. SARS-CoV-2 reverse genetics reveals a variable infection gradient in the respiratory tract. Cell 2020, 182, 429–446.e14. [Google Scholar] [CrossRef]
  3. Puelles, V.G.; Lutgehetmann, M.; Lindenmeyer, M.T.; Sperhake, J.P.; Wong, M.N.; Allweiss, L.; Chilla, S.; Heinemann, A.; Wanner, N.; Liu, S.; et al. Multiorgan and renal tropism of SARS-CoV-2. N. Engl. J. Med. 2020, 383, 590–592. [Google Scholar] [CrossRef] [PubMed]
  4. Mallapaty, S. The coronavirus is most deadly if you are older and male—New data reveal the risks. Nature 2020, 585, 16–17. [Google Scholar] [CrossRef] [PubMed]
  5. Scully, E.P.; Haverfield, J.; Ursin, R.L.; Tannenbaum, C.; Klein, S.L. Considering how biological sex impacts immune responses and COVID-19 outcomes. Nat. Rev. Immunol. 2020, 20, 442–447. [Google Scholar] [CrossRef] [PubMed]
  6. Holman, N.; Knighton, P.; Kar, P.; O’Keefe, J.; Curley, M.; Weaver, A.; Barron, E.; Bakhai, C.; Khunti, K.; Wareham, N.J.; et al. Risk factors for COVID-19-related mortality in people with type 1 and type 2 diabetes in England: A population-based cohort study. Lancet Diabetes Endocrinol. 2020, 8, 823–833. [Google Scholar] [CrossRef]
  7. Leung, J.M.; Niikura, M.; Yang, C.W.T.; Sin, D.D. COVID-19 and COPD. Eur. Respir. J. 2020, 56, 2002108. [Google Scholar] [CrossRef]
  8. Nishiga, M.; Wang, D.W.; Han, Y.; Lewis, D.B.; Wu, J.C. COVID-19 and cardiovascular disease: From basic mechanisms to clinical perspectives. Nat. Rev. Cardiol. 2020, 17, 543–558. [Google Scholar] [CrossRef]
  9. Lee, L.Y.W.; Cazier, J.B.; Starkey, T.; Briggs, S.E.W.; Arnold, R.; Bisht, V.; Booth, S.; Campton, N.A.; Cheng, V.W.T.; Collins, G.; et al. COVID-19 prevalence and mortality in patients with cancer and the effect of primary tumour subtype and patient demographics: A prospective cohort study. Lancet Oncol. 2020, 21, 1309–1316. [Google Scholar] [CrossRef]
  10. Clancy, C.J.; Nguyen, M.H. COVID-19, superinfections and antimicrobial development: What can we expect? Clin. Infect. Dis. 2020. [Google Scholar] [CrossRef]
  11. Bengoechea, J.A.; Bamford, C.G. SARS-CoV-2, bacterial co-infections, and AMR: The deadly trio in COVID-19? EMBO Mol. Med. 2020, 12, e12560. [Google Scholar] [CrossRef] [PubMed]
  12. Garcia-Vidal, C.; Sanjuan, G.; Moreno-Garcia, E.; Puerta-Alcalde, P.; Garcia-Pouton, N.; Chumbita, M.; Fernandez-Pittol, M.; Pitart, C.; Inciarte, A.; Bodro, M.; et al. Incidence of co-infections and superinfections in hospitalized patients with COVID-19: A retrospective cohort study. Clin. Microbiol. Infect. 2020. [Google Scholar] [CrossRef] [PubMed]
  13. Hoenigl, M. Invasive Fungal Disease complicating COVID-19: When it rains it pours. Clin. Infect. Dis. 2020. [Google Scholar] [CrossRef]
  14. Chen, N.; Zhou, M.; Dong, X.; Qu, J.; Gong, F.; Han, Y.; Qiu, Y.; Wang, J.; Liu, Y.; Wei, Y.; et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet 2020, 395, 507–513. [Google Scholar] [CrossRef] [Green Version]
  15. Yang, X.; Yu, Y.; Xu, J.; Shu, H.; Xia, J.; Liu, H.; Wu, Y.; Zhang, L.; Yu, Z.; Fang, M.; et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study. Lancet Respir. Med. 2020, 8, 475–481. [Google Scholar] [CrossRef] [Green Version]
  16. Du, Y.; Tu, L.; Zhu, P.; Mu, M.; Wang, R.; Yang, P.; Wang, X.; Hu, C.; Ping, R.; Hu, P.; et al. Clinical features of 85 fatal cases of COVID-19 from Wuhan. A retrospective observational study. Am. J. Respir. Crit. Care Med. 2020, 201, 1372–1379. [Google Scholar] [CrossRef] [Green Version]
  17. Chen, X.; Zhao, B.; Qu, Y.; Chen, Y.; Xiong, J.; Feng, Y.; Men, D.; Huang, Q.; Liu, Y.; Yang, B.; et al. Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely correlated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients. Clin. Infect. Dis. 2020. [Google Scholar] [CrossRef]
  18. Lescure, F.X.; Bouadma, L.; Nguyen, D.; Parisey, M.; Wicky, P.H.; Behillil, S.; Gaymard, A.; Bouscambert-Duchamp, M.; Donati, F.; Le Hingrat, Q.; et al. Clinical and virological data of the first cases of COVID-19 in Europe: A case series. Lancet Infect. Dis. 2020, 20, 697–706. [Google Scholar] [CrossRef] [Green Version]
  19. Alanio, A.; Delliere, S.; Fodil, S.; Bretagne, S.; Megarbane, B. Prevalence of putative invasive pulmonary aspergillosis in critically ill patients with COVID-19. Lancet Respir. Med. 2020, 8, e48–e49. [Google Scholar] [CrossRef]
  20. Koehler, P.; Cornely, O.A.; Bottiger, B.W.; Dusse, F.; Eichenauer, D.A.; Fuchs, F.; Hallek, M.; Jung, N.; Klein, F.; Persigehl, T.; et al. COVID-19 associated pulmonary aspergillosis. Mycoses 2020, 63, 528–534. [Google Scholar] [CrossRef]
  21. Blaize, M.; Mayaux, J.; Nabet, C.; Lampros, A.; Marcelin, A.G.; Thellier, M.; Piarroux, R.; Demoule, A.; Fekkar, A. Fatal invasive aspergillosis and coronavirus disease in an immunocompetent patient. Emerg. Infect. Dis. 2020, 26, 1636–1637. [Google Scholar] [CrossRef] [PubMed]
  22. van Arkel, A.L.E.; Rijpstra, T.A.; Belderbos, H.N.A.; van Wijngaarden, P.; Verweij, P.E.; Bentvelsen, R.G. COVID-19-associated pulmonary aspergillosis. Am. J. Respir. Crit. Care Med. 2020, 202, 132–135. [Google Scholar] [CrossRef] [PubMed]
  23. Verweij, P.E.; Gangneux, J.P.; Bassetti, M.; Bruggemann, R.J.M.; Cornely, O.A.; Koehler, P.; Lass-Florl, C.; van de Veerdonk, F.L.; Chakrabarti, A.; Hoenigl, M.; et al. Diagnosing COVID-19-associated pulmonary aspergillosis. Lancet Microbe 2020, 1, e53–e55. [Google Scholar] [CrossRef]
  24. Mohamed, A.; Rogers, T.R.; Talento, A.F. COVID-19 associated invasive pulmonary aspergillosis: Diagnostic and therapeutic challenges. J. Fungi 2020, 6, 115. [Google Scholar] [CrossRef]
  25. Donnelly, J.P.; Chen, S.C.; Kauffman, C.A.; Steinbach, W.J.; Baddley, J.W.; Verweij, P.E.; Clancy, C.J.; Wingard, J.R.; Lockhart, S.R.; Groll, A.H.; et al. Revision and update of the consensus definitions of invasive fungal disease from the european organization for research and treatment of cancer and the mycoses study group education and research consortium. Clin. Infect. Dis. 2020, 71, 1367–1376. [Google Scholar] [CrossRef] [Green Version]
  26. Borman, A.M.; Palmer, M.D.; Fraser, M.; Patterson, Z.; Mann, C.; Oliver, D.; Linton, C.J.; Gough, M.; Brown, P.; Dzietczyk, A.; et al. COVID-19 associated invasive aspergillosis: Data from the UK National Mycology Reference Laboratory. J. Clin. Microbiol. 2020. [Google Scholar] [CrossRef]
  27. Verweij, P.E.; Rijnders, B.J.A.; Bruggemann, R.J.M.; Azoulay, E.; Bassetti, M.; Blot, S.; Calandra, T.; Clancy, C.J.; Cornely, O.A.; Chiller, T.; et al. Review of influenza-associated pulmonary aspergillosis in ICU patients and proposal for a case definition: An expert opinion. Intensive Care Med. 2020, 46, 1524–1535. [Google Scholar] [CrossRef]
  28. Sarrazyn, C.; Dhaese, S.; Demey, B.; Vandecasteele, S.; Reynders, M.; Van Praet, J.T. Incidence, risk factors, timing and outcome of influenza versus Covid-19 associated putative invasive aspergillosis. Infect. Control Hosp. Epidemiol. 2020, 1–7. [Google Scholar] [CrossRef]
  29. White, P.L.; Dhillon, R.; Cordey, A.; Hughes, H.; Faggian, F.; Soni, S.; Pandey, M.; Whitaker, H.; May, A.; Morgan, M.; et al. A national strategy to diagnose COVID-19 associated invasive fungal disease in the ICU. Clin. Infect. Dis. 2020. [Google Scholar] [CrossRef]
  30. Bruggemann, R.J.; van de Veerdonk, F.L.; Verweij, P.E. The challenge of managing COVID-19 associated pulmonary aspergillosis. Clin. Infect. Dis. 2020. [Google Scholar] [CrossRef]
  31. Russell, F.M.; Wang, A.; Ehrman, R.R.; Jacobs, J.; Croft, A.; Larsen, C. Risk factors associated with hospital admission in COVID-19 patients initially admitted to an observation unit. Am. J. Emerg. Med. 2020. [Google Scholar] [CrossRef]
  32. Morace, G.; Borghi, E. Fungal infections in ICU patients: Epidemiology and the role of diagnostics. Minerva Anestesiol. 2010, 76, 950–956. [Google Scholar] [PubMed]
  33. Schulte-Schrepping, J.; Reusch, N.; Paclik, D.; Bassler, K.; Schlickeiser, S.; Zhang, B.; Kramer, B.; Krammer, T.; Brumhard, S.; Bonaguro, L.; et al. Severe COVID-19 is marked by a dysregulated myeloid cell compartment. Cell 2020, 182, 1419–1440.e23. [Google Scholar] [CrossRef]
  34. Blanco-Melo, D.; Nilsson-Payant, B.E.; Liu, W.C.; Uhl, S.; Hoagland, D.; Moller, R.; Jordan, T.X.; Oishi, K.; Panis, M.; Sachs, D.; et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell 2020, 181, 1036–1045.e39. [Google Scholar] [CrossRef]
  35. Tay, M.Z.; Poh, C.M.; Renia, L.; MacAry, P.A.; Ng, L.F.P. The trinity of COVID-19: Immunity, inflammation and intervention. Nat. Rev. Immunol. 2020, 20, 363–374. [Google Scholar] [CrossRef] [PubMed]
  36. Jose, R.J.; Manuel, A. COVID-19 cytokine storm: The interplay between inflammation and coagulation. Lancet Respir. Med. 2020, 8, e46–e47. [Google Scholar] [CrossRef]
  37. Mangalmurti, N.; Hunter, C.A. Cytokine storms: Understanding COVID-19. Immunity 2020, 53, 19–25. [Google Scholar] [CrossRef] [PubMed]
  38. Bastard, P.; Rosen, L.B.; Zhang, Q.; Michailidis, E.; Hoffmann, H.H.; Zhang, Y.; Dorgham, K.; Philippot, Q.; Rosain, J.; Beziat, V.; et al. Auto-antibodies against type I IFNs in patients with life-threatening COVID-19. Science 2020, 370, eabd4585. [Google Scholar] [CrossRef]
  39. Zhang, Q.; Bastard, P.; Liu, Z.; Le Pen, J.; Moncada-Velez, M.; Chen, J.; Ogishi, M.; Sabli, I.K.D.; Hodeib, S.; Korol, C.; et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science 2020, 370, eabd4570. [Google Scholar] [CrossRef]
  40. Van der Made, C.I.; Simons, A.; Schuurs-Hoeijmakers, J.; van den Heuvel, G.; Mantere, T.; Kersten, S.; van Deuren, R.C.; Steehouwer, M.; van Reijmersdal, S.V.; Jaeger, M.; et al. Presence of genetic variants among young men with severe COVID-19. JAMA 2020, 324, 663. [Google Scholar] [CrossRef]
  41. Zhou, T.; Su, T.T.; Mudianto, T.; Wang, J. Immune asynchrony in COVID-19 pathogenesis and potential immunotherapies. J. Exp. Med. 2020, 217, 217. [Google Scholar] [CrossRef] [PubMed]
  42. Sekine, T.; Perez-Potti, A.; Rivera-Ballesteros, O.; Stralin, K.; Gorin, J.B.; Olsson, A.; Llewellyn-Lacey, S.; Kamal, H.; Bogdanovic, G.; Muschiol, S.; et al. Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19. Cell 2020, 183, 158–168.e14. [Google Scholar] [CrossRef] [PubMed]
  43. Zohar, T.; Loos, C.; Fischinger, S.; Atyeo, C.; Wang, C.; Slein, M.D.; Burke, J.; Yu, J.; Feldman, J.; Hauser, B.M.; et al. Compromised humoral functional evolution tracks with SARS-CoV-2 mortality. Cell 2020. [Google Scholar] [CrossRef] [PubMed]
  44. Espinosa, V.; Dutta, O.; McElrath, C.; Du, P.; Chang, Y.J.; Cicciarelli, B.; Pitler, A.; Whitehead, I.; Obar, J.J.; Durbin, J.E.; et al. Type III interferon is a critical regulator of innate antifungal immunity. Sci. Immunol. 2017, 2, eaan5357. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Seyedmousavi, S.; Davis, M.J.; Sugui, J.A.; Pinkhasov, T.; Moyer, S.; Salazar, A.M.; Chang, Y.C.; Kwon-Chung, K.J. Exogenous stimulation of type I interferon protects mice with chronic granulomatous disease from aspergillosis through early recruitment of host-protective neutrophils into the lung. mBio 2018, 9, e00422-18. [Google Scholar] [CrossRef] [Green Version]
  46. Ramirez-Ortiz, Z.G.; Lee, C.K.; Wang, J.P.; Boon, L.; Specht, C.A.; Levitz, S.M. A nonredundant role for plasmacytoid dendritic cells in host defense against the human fungal pathogen Aspergillus fumigatus. Cell Host Microbe 2011, 9, 415–424. [Google Scholar] [CrossRef] [Green Version]
  47. Romani, L. Immunity to fungal infections. Nat. Rev. Immunol. 2011, 11, 275–288. [Google Scholar] [CrossRef]
  48. Romani, L.; Puccetti, P. Protective tolerance to fungi: The role of IL-10 and tryptophan catabolism. Trends Microbiol. 2006, 14, 183–189. [Google Scholar] [CrossRef]
  49. Arastehfar, A.; Carvalho, A.; van de Veerdonk, F.L.; Jenks, J.D.; Koehler, P.; Krause, R.; Cornely, O.A.; David, S.P.; Lass-Florl, C.; Hoenigl, M. COVID-19 Associated Pulmonary Aspergillosis (CAPA)-from immunology to treatment. J. Fungi 2020, 6, 91. [Google Scholar] [CrossRef]
  50. De Biasi, S.; Meschiari, M.; Gibellini, L.; Bellinazzi, C.; Borella, R.; Fidanza, L.; Gozzi, L.; Iannone, A.; Lo Tartaro, D.; Mattioli, M.; et al. Marked T cell activation, senescence, exhaustion and skewing towards TH17 in patients with COVID-19 pneumonia. Nat. Commun. 2020, 11, 3434. [Google Scholar] [CrossRef]
  51. Xu, Z.; Shi, L.; Wang, Y.; Zhang, J.; Huang, L.; Zhang, C.; Liu, S.; Zhao, P.; Liu, H.; Zhu, L.; et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir. Med. 2020, 8, 420–422. [Google Scholar] [CrossRef]
  52. Dewi, I.M.W.; van de Veerdonk, F.L.; Gresnigt, M.S. The multifaceted role of t-helper responses in host defense against aspergillus fumigatus. J. Fungi 2017, 3, 55. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Guaraldi, G.; Meschiari, M.; Cozzi-Lepri, A.; Milic, J.; Tonelli, R.; Menozzi, M.; Franceschini, E.; Cuomo, G.; Orlando, G.; Borghi, V.; et al. Tocilizumab in patients with severe COVID-19: A retrospective cohort study. Lancet Rheumatol. 2020, 2, e474–e484. [Google Scholar] [CrossRef]
  54. Romani, L.; Tomino, C.; Puccetti, P.; Garaci, E. Off-label therapy targeting pathogenic inflammation in COVID-19. Cell Death Discov. 2020, 6, 49. [Google Scholar] [CrossRef]
  55. Van de Veerdonk, F.L.; Netea, M.G. Blocking IL-1 to prevent respiratory failure in COVID-19. Crit. Care 2020, 24, 445. [Google Scholar] [CrossRef]
  56. Aouba, A.; Baldolli, A.; Geffray, L.; Verdon, R.; Bergot, E.; Martin-Silva, N.; Justet, A. Targeting the inflammatory cascade with anakinra in moderate to severe COVID-19 pneumonia: Case series. Ann. Rheum. Dis. 2020, 79, 1381–1382. [Google Scholar] [CrossRef]
  57. Cavalli, G.; De Luca, G.; Campochiaro, C.; Della-Torre, E.; Ripa, M.; Canetti, D.; Oltolini, C.; Castiglioni, B.; Tassan Din, C.; Boffini, N.; et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: A retrospective cohort study. Lancet Rheumatol. 2020, 2, e325–e331. [Google Scholar] [CrossRef]
  58. Huet, T.; Beaussier, H.; Voisin, O.; Jouveshomme, S.; Dauriat, G.; Lazareth, I.; Sacco, E.; Naccache, J.M.; Bezie, Y.; Laplanche, S.; et al. Anakinra for severe forms of COVID-19: A cohort study. Lancet Rheumatol. 2020, 2, e393–e400. [Google Scholar] [CrossRef]
  59. Calabrese, L.H.; Calabrese, C. Cytokine release syndrome and the prospects for immunotherapy with COVID-19. Part 2: The role of interleukin 1. Cleve. Clin. J. Med. 2020. [Google Scholar] [CrossRef]
  60. Iannitti, R.G.; Napolioni, V.; Oikonomou, V.; De Luca, A.; Galosi, C.; Pariano, M.; Massi-Benedetti, C.; Borghi, M.; Puccetti, M.; Lucidi, V.; et al. IL-1 receptor antagonist ameliorates inflammasome-dependent inflammation in murine and human cystic fibrosis. Nat. Commun. 2016, 7, 10791. [Google Scholar] [CrossRef]
  61. de Luca, A.; Smeekens, S.P.; Casagrande, A.; Iannitti, R.; Conway, K.L.; Gresnigt, M.S.; Begun, J.; Plantinga, T.S.; Joosten, L.A.; van der Meer, J.W.; et al. IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans. Proc. Natl. Acad. Sci. USA 2014, 111, 3526–3531. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Stockinger, B.; Di Meglio, P.; Gialitakis, M.; Duarte, J.H. The aryl hydrocarbon receptor: Multitasking in the immune system. Annu. Rev. Immunol. 2014, 32, 403–432. [Google Scholar] [CrossRef] [PubMed]
  63. Zelante, T.; Iannitti, R.G.; Cunha, C.; De Luca, A.; Giovannini, G.; Pieraccini, G.; Zecchi, R.; D’Angelo, C.; Massi-Benedetti, C.; Fallarino, F.; et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 2013, 39, 372–385. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Puccetti, M.; Paolicelli, G.; Oikonomou, V.; De Luca, A.; Renga, G.; Borghi, M.; Pariano, M.; Stincardini, C.; Scaringi, L.; Giovagnoli, S.; et al. Towards targeting the aryl hydrocarbon receptor in cystic fibrosis. Mediat. Inflamm. 2018, 2018, 1601486. [Google Scholar] [CrossRef]
  65. Federico, G.; Zhaorong, L.; Cybele, C.G.; Francisco, J.Q. A potential role for AHR in SARS-CoV-2 pathology. Res. Sq. 2020. [Google Scholar] [CrossRef]
  66. King, R.; Tuthill, C. Immune modulation with thymosin alpha 1 treatment. Vitam Horm 2016, 102, 151–178. [Google Scholar] [CrossRef]
  67. Romani, L.; Bistoni, F.; Perruccio, K.; Montagnoli, C.; Gaziano, R.; Bozza, S.; Bonifazi, P.; Bistoni, G.; Rasi, G.; Velardi, A.; et al. Thymosin alpha1 activates dendritic cell tryptophan catabolism and establishes a regulatory environment for balance of inflammation and tolerance. Blood 2006, 108, 2265–2274. [Google Scholar] [CrossRef] [Green Version]
  68. Romani, L.; Oikonomou, V.; Moretti, S.; Iannitti, R.G.; D’Adamo, M.C.; Villella, V.R.; Pariano, M.; Sforna, L.; Borghi, M.; Bellet, M.M.; et al. Thymosin alpha1 represents a potential potent single-molecule-based therapy for cystic fibrosis. Nat. Med. 2017, 23, 590–600. [Google Scholar] [CrossRef] [Green Version]
  69. Renga, G.; Bellet, M.M.; Pariano, M.; Gargaro, M.; Stincardini, C.; D’Onofrio, F.; Mosci, P.; Brancorsini, S.; Bartoli, A.; Goldstein, A.L.; et al. Thymosin alpha1 protects from CTLA-4 intestinal immunopathology. Life Sci. Alliance 2020, 3, e202000662. [Google Scholar] [CrossRef]
  70. Pehote, G.; Vij, N. Autophagy augmentation to alleviate immune response dysfunction, and resolve respiratory and COVID-19 exacerbations. Cells 2020, 9, 1952. [Google Scholar] [CrossRef]
  71. Bozza, S.; Gaziano, R.; Bonifazi, P.; Zelante, T.; Pitzurra, L.; Montagnoli, C.; Moretti, S.; Castronari, R.; Sinibaldi, P.; Rasi, G.; et al. Thymosin alpha1 activates the TLR9/MyD88/IRF7-dependent murine cytomegalovirus sensing for induction of anti-viral responses in vivo. Int. Immunol. 2007, 19, 1261–1270. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Romani, L.; Bistoni, F.; Gaziano, R.; Bozza, S.; Montagnoli, C.; Perruccio, K.; Pitzurra, L.; Bellocchio, S.; Velardi, A.; Rasi, G.; et al. Thymosin alpha 1 activates dendritic cells for antifungal Th1 resistance through toll-like receptor signaling. Blood 2004, 103, 4232–4239. [Google Scholar] [CrossRef] [PubMed]
  73. Yu, K.; He, J.; Wu, Y.; Xie, B.; Liu, X.; Wei, B.; Zhou, H.; Lin, B.; Zuo, Z.; Wen, W.; et al. Dysregulated adaptive immune response contributes to severe COVID-19. Cell Res. 2020, 30, 814–816. [Google Scholar] [CrossRef] [PubMed]
  74. Liu, Y.; Pang, Y.; Hu, Z.; Wu, M.; Wang, C.; Feng, Z.; Mao, C.; Tan, Y.; Liu, Y.; Chen, L.; et al. Thymosin alpha 1 (Talpha1) reduces the mortality of severe COVID-19 by restoration of lymphocytopenia and reversion of exhausted T cells. Clin. Infect. Dis. 2020, 71, 2150–2157. [Google Scholar] [CrossRef]
  75. Liu, X.; Liu, Y.; Wang, L.; Hu, L.; Liu, D.; Li, J. Analysis of the prophylactic effect of thymosin drugs on COVID-19 for 435 medical staff: A hospital-based retrospective study. J. Med. Virol. 2020. [Google Scholar] [CrossRef]
  76. Tuthill, C.; Rios, I.; De Rosa, A.; Camerini, R. Thymosin alpha1 continues to show promise as an enhancer for vaccine response. Ann. N. Y. Acad. Sci. 2012, 1270, 21–27. [Google Scholar] [CrossRef]
  77. Le, T.T.; Cramer, J.P.; Chen, R.; Mayhew, S. Evolution of the COVID-19 vaccine development landscape. Nat. Rev. Drug Discov. 2020, 19, 667–668. [Google Scholar] [CrossRef]
  78. Su, Y.; Chen, D.; Yuan, D.; Lausted, C.; Choi, J.; Dai, C.L.; Voillet, V.; Duvvuri, V.R.; Scherler, K.; Troisch, P.; et al. Multi-omics resolves a sharp disease-state shift between mild and moderate COVID-19. Cell 2020. [Google Scholar] [CrossRef]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Costantini, C.; van de Veerdonk, F.L.; Romani, L. Covid-19-Associated Pulmonary Aspergillosis: The Other Side of the Coin. Vaccines 2020, 8, 713.

AMA Style

Costantini C, van de Veerdonk FL, Romani L. Covid-19-Associated Pulmonary Aspergillosis: The Other Side of the Coin. Vaccines. 2020; 8(4):713.

Chicago/Turabian Style

Costantini, Claudio, Frank L. van de Veerdonk, and Luigina Romani. 2020. "Covid-19-Associated Pulmonary Aspergillosis: The Other Side of the Coin" Vaccines 8, no. 4: 713.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop