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COVID-19 AND ASPERGILLUS CO-INFECTIONS

In addition to a high number of personal observations shared by clinicians who have been taking care of patients with invasive pulmonary aspergillosis as a complication of severe Covid-19 disease in intensive care units across the world, papers are now being published with proven cases, and studies are planned to assess COVID-19 associated pulmonary aspergillosis (CAPA). Key developments are highlighted below. 

Update 15th May 2021

The headlines are shocking. ‘Deadly black fungus threatening India’s COVID-19 patients’. New emerging clinical observations show that the COVID-19 pandemic has resulted in an increased number of patients being highly susceptible to mucormycosis, referred to as COVID-19 associated mucormycosis (CAM). Mucormycosis is caused by a group of fungi called Mucorales species. Mucorales species do not belong to the so-called black fungi, but mucormycosis is a disease associated with excessive tissue death (necrosis) resulting in body tissues turning black (hence the name).   While CAPA (see rest of Blog) has been the main focus of fungal coinfections in COVID-19 patients, we need to pay attention to this emerging threat with an even higher case-fatality rate. 

A publication in the Lancet Infectious Diseases journal this week describes 80 COVID-19 patients who developed mucormycosis.¹ The majority of patients were reported by colleagues in India. 49% of the patients died and of those surviving, a significant proportion suffered life-changing morbidities with loss of vision occurring in 46% of patients. A well-known risk factor for developing mucormycosis is diabetes, especially poorly controlled diabetes that results in hyperglycemia and ketoacidosis. During periods of acidosis, serum levels of free iron will increase, which will favour the growth of Mucorales species.

 n addition, these patients suffer from aberrant immune responses characterised by persistent inflammation making them at risk for fungal infections. Further inflammation evoked by the response of the immune system to Sars-CoV-2, potentiates this aberrant inflammatory profile and enhances the development of fungal coinfections. Of the 80 patients reported with CAM, 82.5% had diabetes. In comparison, only 34% of patients with CAPA had diabetes.² India suffers from a high prevalence of diabetes, which has most likely resulted in the large number of patients suffering from CAM.

Diagnosis and treatment of mucormycosis is extremely challenging with few diagnostic tools and a restricted number of effective antifungals drugs. We need better diagnostics, more effective antifungals, and an improved understanding of the underlying pathogenesis, to improve the outcome of these fungal coinfections.  In this regard, there is promising work by Prof Ashraf Ibrahim and his team, who are developing new immunotherapies to reduce the burden of mucormycosis and which show promise for improving patient outcomes.³

References

1. Hoenigl et al. The emergence of COVID-19 associated mucormycosis: Analysis of cases from 18 countries. Lancet Infect Dis 2021, May 12. DOI: https://dx.doi.org/10.2139/ssrn.3844587
2. Salmanton-Garcia et al. COVID-19-associated pulmonary aspergillosis, March – August 2020. Emerg Infect Dis 2021; 27: 1077-1086. DOI: https://doi.org/10.3201/eid2704.204895
3. Gebremarium et al. Anit-CotH3 antibodies protect mice from mucormycosis by prevention of invasion and augmenting opsonophagocytosis. Sci Adv 2019; 5:eaaw1327. DOI: https://doi.org/10.1126/sciadv.aaw1327.

 Update 2^nd March 2021

The Medical Mycology Case Reports journal has published a special issue compiling early clinical experiences with COVID-19 associated pulmonary aspergillosis (CAPA). The journal is edited by the MRC Centre for Medical Mycology’s Adilia Warris, who has been at the forefront of research into the emerging threat of CAPA. These reports case highlight the challenges encountered in diagnosing and treating CAPA, and aim create awareness for early recognition of this co-infection in critically ill COVID-19 patients.  Click on the link to access the individual papers in this special issue.

Update 29^th January 2021:

The COVID-19 pandemic has resulted in the identification of a new clinical Aspergillus disease phenotype, COVID-19 associated pulmonary aspergillosis (or CAPA), for which a precise definition, diagnostic criteria and treatment guidelines are lacking.  This has led to an additional layer of complexity and huge challenges in the management of these critically ill patients. 

Therefore, the European Confederation for Medical Mycology (ECMM) and the International Society for Human and Animal Mycology (ISHAM) have joined together to provide (1) consensus criteria to better define CAPA, and (2) clinical management guidance.¹

In line with the existing consensus criteria for the definition of invasive fungal diseases in immunocompromised patients², the authors propose a classification system based on the degree of certainty of the diagnosis, e.g. possible, probable or proven. This classification system is primarily of value for research purposes (including clinical trials) and registries. Also, clear clinical guidance is provided in terms of (a) which patients to test for the presence of CAPA, (b) the usefulness of fungal diagnostic tests and imaging, (c) the interpretation of the test results, (d) and how to treat those affected.

Clinicians and clinical researchers will  warmly welcome this guidance, especially at a time when we are still learning about this new disease, whilst simultaneously trying to prevent or at least minimize the harm being caused by this fungus to critically ill COVID-19 patients.  

References

1. Koehler et al, Lancet Infect Dis 2020. DOI: 10.1016/S1473-3099(20)30847-1
2. Donnelly et al, Clin Infect Dis 2020. DOI: 10.1093/cid/ciz1008.

Update 25th November 2020:

Diagnosing Covid-19 associated pulmonary Aspergillosis (CAPA)is a tricky business, made more complex by difficulties obtaining respiratory samples to confirm or refute the diagnosis. Concerns over aerosolisation of respiratory secretions and the SARS-CoV2 virus have limited the number of invasive procedures performed, and instead, putative diagnoses of pulmonary Aspergillus have relied on serum samples or samples taken from the upper airway tract, for which diagnostic tests have not been validated¹. In a recent paper Koehler et al¹ use a Resusci-Anne and fluorescent solution to mimic bronchoscopy of an intubated patient and assess healthcare worker exposure worker to aerosolised droplets during the procedure. By adjusting the system slightly, they were able to reduce healthcare worker exposure significantly and suggest that this might be an alternative set-up to ensure optimal diagnostic sampling and healthcare worker safety.

Whether physicians will be sufficiently reassured to perform invasive procedures on Covid-19 positive patients in light of these suggestions remains another matter, although it is worth highlighting that the degree of droplet aerosolisation during bronchoscopy is an extremely understudied area. Two studies performed prior to the Covid-19 outbreak found that bronchoscopy was not associated with significant aerosol generation at the level of healthcare provider head height² and that healthcare workers performing bronchoscopies were not at higher risk of contracting SARS disease compared to other healthcare workers who weren’t conducting bronchoscopies³, although the authors acknowledge the paucity of data and the weak nature of data that is available. A convincingly safe method of obtaining respiratory samples during this pandemic remains elusive; the paper published by Koehler et al¹ may offer some hope in this regard.

References

1. Koehler et al, Mycoses 2020. DOI: 10.1111/myc.13183
2. O’Neill et al, Clin Infect Dis 2017. DOI: 10.1093/cid/cix535
3. Tran et al, PLoS One 2012. DOI: 10.1371/journal.pone.0035797

 

Update 4th November 2020:

Our colleagues in the UK National Mycology Reference Laboratory and honorary members of our MRC Centre for Medical Mycology, Andy Borman and Liz Johnson, have just published their unique experiences of the requests they have received for fungal diagnostic tests to enable clinicians to diagnose COVID-19 associated pulmonary aspergillosis. 

During the period March to July 2020, over 1,000 serum and respiratory samples from 719 critically ill patients with COVID-19 were received. Serum samples were analysed for the presence of the fungal antigens β–D-glucan (1000 tests; panfungal marker) and galactomannan (516 tests; Aspergillus antigen). Extended diagnostic work-up (microscopy, culture, Aspergillus-PCR and galactomannan) was done on respiratory specimens from 61 patients.

Using the modified AspICU diagnostic algorithm proposed by Gangneux et al (2020), an incidence of 5% probable and 15% possible cases of CAPA were diagnosed. Positive β-D-glucan results were obtained in 18.2% of the tests performed, with only 1.6% being positive for galactomannan. Serum β-D-glucan was positive in 12 out of 15 patients with suspected CAPA. The galactomannan test was less sensitive, with 5 out of the 15 patients being positive. For only 5 of those patients a bronchoalveolar lavage sample was received, but these showed markedly higher yields for the detection of Aspergillus and/or galactomannan.

The authors conclude that measurement of serum β-D-glucan levels might be a promising screening tool to detect CAPA, and that a multi-facetted approach is needed as no single biomarker, or even a combination of 2 biomarkers, is capable of detecting all CAPA cases.  

References:

Borman et al,  J Clin Microbiol 2020. https://jcm.asm.org/content/jcm/early/2020/10/16/JCM.02136-20.full.pdf

Gangneux et al, J Fungi 2020. https://www.mdpi.com/2309-608X/6/3/105 

 

Update 15th September 2020:

COVID-19 associated pulmonary aspergillosis (CAPA) 

The number of COVID-19 patients suffering from Aspergillus co-infection continue to rise. Over 100 patients with COVID-19 associated pulmonary aspergillosis (CAPA) have been reported from many countries in Europe, Asia, Australia and South America. When looking at incidences of CAPA in critically ill patients (e.g. patients on ICUs), rates vary substantially from 4% to as high as 35%. The challenges in diagnosing fungal infections, and in particular CAPA, are thought to explain this variety in incidence rates. Clinical symptoms and abnormalities on chest imaging are non-specific, positive sputum samples or tracheal aspirates do not differentiate between colonisation and infection, and to perform invasive diagnostic procedures (e.g. bronchoscopy and bronchoalveolar lavage or lung biopsy) is often not feasible due to the clinical condition of the patients. In addition, those procedures are risky due to the possible transmission of Sars-CoV-2 as a result of aerosol formation. Nevertheless, an early diagnosis of Aspergillus co-infection is of huge importance to start effective treatment in a timely manner.

Colleagues in Wales have evaluated an enhanced testing strategy to diagnose fungal co-infections in critically ill COVID-19 patients. Every patient with refractory severe lung disease or deterioration of the lung function admitted to the ICU underwent screening for fungal co-infection. In total, 135 adult patients were screened either by blood cultures and beta-D-glucan in serum (n=123), non-directed bronchial lavage for cultures, galactomannan and fungal PCR (n=60), or both (n=48).

Seventeen (13%) had evidence of an invasive yeast infection, while thirty (22%) had Aspergillus positive results. In half of the patients with multiple Aspergillus positive results, typical abnormalities for invasive pulmonary aspergillosis were seen on the CT-chest images. Mortality was significantly higher in patients with fungal co-infection compared to those without (51% vs 31% respectively, p=0.04), but even higher in patients with CAPA (58%) and close to 100% in those not receiving appropriate antifungal therapy. The use of corticosteroids was associated with increased rates of CAPA.  

Given the high burden of fungal co-infection and improved outcomes with prompt anti-fungal treatment, a standardised diagnostic approach to identify the presence of a fungal co-infection has the potential to improve the dismal outcome of CAPA. This study shows that with the current available fungal diagnostic tools, a screening strategy to diagnose fungal co-infections timely in critically ill COVID-19 patients, is feasible and beneficial.

Reference: White et al. Clin Infect Dis 2020. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1298/5899192

Reference: Hoenigl et al Clin Infect Dis 2020. https://doi.org/10.1093/cid/ciaa1342

 

Update 2nd July 2020:

COVID-19, COVID-19 associated pulmonary aspergillosis (CAPA), and Corticosteroids.

Last week a review was published in the Journal of Fungi¹ which provides a summary of the 35 cases of COVID-19 associated pulmonary aspergillosis (CAPA) reported so far during this pandemic. Risk factors predisposing COVID-19 patients to developing CAPA resemble those observed for influenza-associated pulmonary aspergillosis (IAPA). These include severe lung damage, the use of corticosteroids, and the presence of chronic lung disease. Age ranges (43 – 86 years) for CAPA patients are higher than those observed for IAPA, reflecting the vulnerability of elderly people to severe COVID-19 disease. One-third of the CAPA patients summarized in this review received corticosteroids. Although corticosteroids alleviate harmful inflammation, they render the patient more susceptible to secondary fungal disease. No difference in mortality rates were observed between CAPA patients who received corticosteroids and those who did not (63% and 64%, respectively). Interestingly, the preliminary results of a large randomised clinical trial to test dexamethasone as a potential treatment for COVID-19 were made public last week. This trial showed that dexamethasone reduced mortality by one-third in patients with severe COVID-19.  However, the details of this trail are not yet available, and it is not clear whether the dexamethasone treatment has affected co-infection rates, including CAPA. 

Reference: J. Fungi 2020, 6, 91; doi:10.3390/jof6020091 : https://www.mdpi.com/2309-608X/6/2/91 

 

Update 15th June 2020:

First case of azole-resistant COVID-19 associated pulmonary aspergillosis

While not unexpected in the era of emerging antifungal resistance, this adds another layer of complexity to the management of Aspergillus co-infections in patients with severe COVID-19.

Colleagues from the Center of Expertise in Mycology in Nijmegen describe a case in which azole-resistant Aspergillus fumigatus was detected through close monitoring of a patient with repeated cultures of respiratory samples. The initial isolate, recovered from tracheal aspirate at ICU admission, showed infection with a susceptible strain of A. fumigatus, and treatment with voriconazole was initiated. A repeat culture 12 days later was still positive and now showed azole-resistant A. fumigatus. Antifungal treatment was changed to liposomal amphotericin B. Cultures remained positive for A. fumigatus and the patient died 18 days after ICU admission. 

This case report illustrates the value of repeated sampling and, significantly, repeated susceptibility testing to monitor for the presence of azole-resistant A. fumigatus. The patient may have been infected with different strains of A. fumigatus, but the resistant strain was not picked up during the first cultures due to an abundance of azole-susceptible A. fumigatus. However, under pressure of voriconazole therapy, the azole-resistant strain was able to outgrow the susceptible strain. Unfortunately, at the time of death, A. fumigatus was still recovered from tracheal aspirate indicating that the fungal infection had not been resolved.

Reference: Meijer et al, Journal of Fungi 2020, 6, 79; doi:10.3390/jof6020079: https://www.mdpi.com/2309-608X/6/2/79 

COVID-19-associated invasive pulmonary aspergillosis

Rutsaert and co-workers reported last week that, over a 6 week period, of the 20 patients admitted to their ICU with severe COVID-19 and requiring invasive mechanical ventilation, 7 (35%) were suspected to have pulmonary aspergillosis (median age 66 yrs, range 38-86 yrs). Although most patients had underlying conditions that made them vulnerable to severe COVID-19, only 3 were immunocompromised.  Rapid growth of A. fumigatus bronchial aspirates led to the suspicion of pulmonary aspergillosis. Four patients were proven to have pulmonary aspergillosis, based on histopathological evidence, and four of these seven patients died. Based on their experience in the first weeks of the COVID-19 pandemic, a management protocol was developed in which all mechanically ventilated COVID-19 patients are systematically screened for Aspergillus infection using serum galactomannan twice weekly, opportunistic sampling is performed when a bronchoscopy is required, and prophylactic nebulization with liposomal amphotericin B is provided 

Reference: Rutsaert et al, Ann Intensive Care 2020; 10: 71 : https://annalsofintensivecare.springeropen.com/articles/10.1186/s13613-020-00686-4 

 

Update 2nd June 2020:

First case of proven invasive pulmonary aspergillosis complicating SARC-CoV-2 pneumonia

Earlier reports describing COVID-19 associated pulmonary aspergillosis CAPA have clearly illustrated the diagnostic challenges in diagnosing pulmonary aspergillosis in patients with severe COVID-19 disease. In these patients, Aspergillus was picked up in BAL-fluid their suggesting, rather than confirming, pulmonary aspergillosis. The authors of this new case report demonstrate the value of a tissue diagnosis, albeit at autopsy. Invasive growth of Aspergillus in lung tissue was detected, with an earlier culture of BAL-fluid being positive for A. fumigatus. Both the performance of a BAL as well as performing an autopsy are under pressure due to concerns about the formation of aerosols while collecting samples from a patient, and the consequential risk of transmission of SARS-CoV-2.  The urge to avoid taking patient samples may result in under-diagnosis of this fatal complication.

Reference: Antinori et al. Invasive pulmonary aspergillosis complication SARS-CoV-2 pneumonia: A diagnostic challenge. Travel Med Infect Dis 2020; article in press https://doi.org/10.1016/j.tmaid.2020.101752

 

Update 19th May 2020:

Covid-19 Associated Pulmonary Aspergillosis (CAPA)

Until now, 23 cases of COVID-19 associated pulmonary aspergillosis (CAPA) have been reported in the literature. The most recent case series (6 patients aged between 43 and 85 years) from a centre in the Netherlands shows an alarming increase in mortality rates among patients with severe COVID-19 disease and Aspergillus infection. Mortality rates were 67% in this group, compared to 32% in patients with severe COVID-19 disease without signs of Aspergillus infection. 

Reference: van Arkel et al. 2020, COVID-19 Associated Pulmonary Aspergillosis: https://www.atsjournals.org/doi/pdf/10.1164/rccm.202004-1038LE

CAPA in a 70 year-old patient reported in Austria

Another fatal case of CAPA in a 70-year-old patient has been reported by a centre in Austria. 

Reference: Prattes et al. 2020, Invasive pulmonary aspergillosis complicating COVID-19 in the ICU - A case report:  https://www.sciencedirect.com/science/article/pii/S2211753920300300?via%3Dihub

Challenges in recognising and diagnosing CAPA summarised in the Lancet

The challenges in recognising and diagnosing CAPA have been summarized in an editorial by Verweij and colleagues published in Lancet Microbe last week. The authors recommend a number of areas for future research to understand the interactions between the host, COVID-19, and Aspergillus; how to diagnose CAPA; and how to prevent and treat CAPA.

Reference: Verweij et al., 2020, Diagnosing COVID-19-associated pulmonary aspergillosis:https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(20)30027-6/fulltext

 

Update 5th May 2020: 

Last week, two new publications reported the severity of, and increased risk of, COVID-19 associated pulmonary aspergillosis. Those reports also illustrate the challenges associated with diagnosing pulmonary aspergillosis in patients with severe COVID-19 admitted to the intensive care unit, as no standard definitions currently exist to diagnose invasive aspergillosis in critically ill patients.

Fatal Invasive Aspergillosis and Coronavirus Disease in an Immunocompetent Patient

A case report published in Emerging Infectious Diseases by our French colleagues shows a rapid deterioration of COVID-19 associated pulmonary aspergillosis in an immunocompetent man of 74 years of age who died within 9 days of presenting with severe COVID-19. Aspergillus was grown repeatedly from tracheal aspirates, and PCR tests for Aspergillus fumigatus were positive as well. Clearly, the patient was infected with Aspergillus, and yet the fungal biomarkers in the serum were negative. This reflects the challenges associated with diagnosing the disease. 

Reference: Blaize M, Mayaux J, Nabet C, Lampros A, Marcelin A-G, Thellier M, et al. Fatal invasive aspergillosis and coronavirus disease in an immunocompetent patient. Emerg Infect Dis. 2020 Jul. https://doi.org/10.3201/eid2607.201603 

COVID‐19 Associated Pulmonary Aspergillosis

A retrospective review of patients admitted with acute respiratory distress syndrome caused by COVID-19 to an intensive care unit in Germany, has shown that 5 out of 19 patients were co-infected with Aspergillus. Despite antifungal therapy, 3 out of 5 patients died. Aspergillus fumigatus was grown from bronchoalveolar lavage fluid of 4 patients, 3 patients tested positive for galactomannan in bronchoalveolar lavage fluid, and one patient tested repeated positive for galactomannan in serum.  The paper provides important details about the abnormalities observed on imaging by CT-scanning of the chest, which revealed ground glass opacities and nodular consolidations in all 5 of the patients.

Reference: Phillip Koehler et al. 2020, COVID-19 Associated Pulmonary Aspergillosis. https://doi.org/10.1111/myc.13096

 

Update 28th April 2020:

Study led by Dr Tihana Bicanic (St Georges Hospital London) to assess COVID-19 associated pulmonary aspergillosis.

Dr Bicanic’s study assessing the incidence and pathogenesis of invasive aspergillosis in adult intensive care patients with severe influenza (AspiFLu) has extended its inclusion criteria to include patients with severe COVID-19. This will allow a comparison of those two groups with respect to the occurrence of co-infection with invasive aspergillosis. The study is taking place across four hospitals trusts; Guy’s and St Thomas’, King’s College Hospital, St George’s University Hospitals, Manchester University.

Reference: https://doi.org/10.1186/ISRCTN51287266

Correspondence in The Lancet Microbe by Cox and colleagues

Published on April 24, the correspondence urges that rapid characterisation of co-infection is essential in the management and treatment of the most severe COVID-19 cases, as this could save lives. Although this correspondence is focussed on bacterial co-infections, characterisation of fungal co-infections is especially urgent due to an even higher case-fatality rate.

Reference: Cox el at. 2020. Co-infections: potentially lethal and unexplored in COVID-19. https://doi.org/10.1016/S2666-5247(20)30009-4

Journal of Mycologie Médicale

Our colleagues in France published an editorial of the Journal of Mycologie Médicale last week to highlighting the need to actively search for and recognize fungal co-infections as a severe complication in patients admitted to intensive care units with COVID-19. Local implementation of fungal diagnostic tools and multicentre studies assessing the occurrence of fungal co-infections in this pandemic is essential to improve management and patient outcome. 

Reference: Gangneux et al. 2020. Invasive fungal diseases during COVID-19: We should be prepared. Journal de Mycologie Médicale https://doi.org/10.1016/j.mycmed.2020.100971 

A new finding on how our immune system behaves when dealing with a fungus and a virus simultaneously

An interesting new finding about how our immune system behaves when it has to deal with a fungus and a virus at the same time, comes from Professor Robin May’s lab (University of Birmingham). They found that macrophages eject the fungal cells more quickly when a virus is present at the same time (so-called ‘vomocytosis’). The escaping fungal cell will then be able to spread more easily throughout the body and cause infection.

Reference: Seoane et al. 2020. Viral infection triggers interferon-induced expulsion of live Cryptococcus neoformans by macrophages. PLoS Pathog 16(2): e1008240. https://doi.org/10.1371/journal.ppat.1008240

Covid-19 associated invasive aspergillosis (CAPA)

Alanio and colleagues (2020) reported that, of 27 patients being ventilated on the ICU, 33% showed signs of Aspergillus co-infection. These rates are comparable to those for Influenza (H1N1) associated invasive aspergillosis (IAPA) and, from those experiences, we know that mortality rates are significantly higher for those influenza patients who are co-infected with Aspergillus.

Based on the data available and previous experiences with IAPA, screening patients admitted to the ICU with severe Covid-19 disease for Aspergillus co-infectionshould be given strong consideration to allow for early diagnosis and timely treatment to prevent a worsening of outcomes. There are a number of valuable fungal diagnostic tools, which were also used to diagnose IAPA, as reported recently by Alanio and colleagues (2020). These include examining fungal cultures from sputum and/or BAL-fluid, galactomannan and β-D-glucan in BAL-fluid and/or serum, lateral flow device for testing BAL-fluid, and fungal PCR testing.

A number of antifungal treatment modalities are available for CAPA,  individual choices for a specific antifungal depend on the prevalence of azole-resistance, expected drug-drug interactions, tolerability, and preferred route of administration.

Reference: Alanio, Alexandre and Dellière, Sarah and Fodil, Sofiane and Bretagne, Stéphane and Mégarbane, Bruno, High Prevalence of Putative Invasive Pulmonary Aspergillosis in Critically Ill COVID-19 Patients (April 14, 2020). Available at SSRN: https://ssrn.com/abstract=3575581 or http://dx.doi.org/10.2139/ssrn.3575581

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Participate in collecting clinical data about Covid-19 associated invasive aspergillosis

An internal registry has been set up by the Dutch-Belgian Mycosis Study Group led by Prof Paul Verweij. The registry aims to collect data from patients admitted to the ICU with suspected or proven COVID-19 associated invasive aspergillosis (CAPA study). This registry involves an online case report form that includes three parts: baseline information; information at ICU admission and at ICU discharge or death.

The main questions that this study aims to address are:

1. What is the frequency of CAPA in ICU patients?

2. Do patients with CAPA have classic risk factors or not?

3. What is the clinical presentation – e.g. tracheobronchitis?

4. What is the outcome compared with COVID-19 without CAPA?

How can you participate?

For this study project, an online registry database called “Castor” is used. To be able to enter data in the database, it is necessary to sign up for Castor.

To achieve this, go to https://data.castoredc.com/ and click on “Sign up here”.

When you are ready to enter data into the database, you need an invitation to be able to access the electronic Case Report Forms.

You need to send an e-mail to mycology@radboudumc.nl, to notify that you wish to participate in the study. You will then receive the invitation email with the access link. Please use the same e-mail address for this as you have used when signing up for Castor.

For any questions regarding this study or problems regarding case entry, you can contact Nico Janssen, MD at nico.janssen@radboudumc.nl.

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List of Publications on #covidANDaspergillosis:  

• Alanio et al. (2020): High Prevalence of Putative Invasive Pulmonary Aspergillosis in Critically Ill COVID-19 Patients. In this study, screening for fungal secondary pneumonia, authors collected the data of our first 27 ICU patients, who underwent bronchoalveolar lavage or bronchial aspirates. Results found 33% of COVID-19 patients with putative invasive pulmonary aspergillosis.
• Antinori et al., 2020, Invasive pulmonary aspergillosis complication SARS-CoV-2 pneumonia: A diagnostic challenge. Travel Med Infect Dis 2020; article in press. 
• Arastehfar, A.; Carvalho, A.; van de Veerdonk, F.L.; Jenks, J.D.; Koehler, P.; Krause, R.; Cornely, O.A.; S. Perlin, D.; Lass-Flörl, C.; Hoenigl, M., on behalf of the ECMM Working Group Immunologic Markers for Treatment Monitoring and Diagnosis in Invasive Mold Infection; COVID-19 Associated Pulmonary Aspergillosis (CAPA)—From Immunology to Treatment. J. Fungi 2020, 6, 91.   J. Fungi 2020, 6, 91; 
• Blaize M et al. (2020): Fatal invasive aspergillosis and coronavirus disease in an immunocompetent patient. Emerg Infect Dis. 2020 Jul. https://doi.org/10.3201/eid2607.201603.
• Borman et al,  J Clin Microbiol 2020. https://jcm.asm.org/content/jcm/early/2020/10/16/JCM.02136-20.full.pdf
• Chen et al. (2020) described 99 RT-PCR-confirmed COVID-19 cases from a hospital in Wuhan, China. One patient tested positive for Aspergillus flavus by culture of respiratory fluids (in addition to Klebsiella penumoniae and antibiotic-resistant Acinetobacter baumanii). There were also 4 cases (4%) of co-infection with Candida (3 Candida albicans; 1 of Candida glabrata). Some received antifungals.
• Donnelly et al, Clin Infect Dis 2020. DOI: 10.1093/cid/ciz1008.
• Gangneux et al, J Fungi 2020. https://www.mdpi.com/2309-608X/6/3/105 
• Gangneux et al (2020), provide a concise summary of what we know - and don't know - about COVID-associated aspergillosis at this early stage. Cases are likely to be underdiagnosed and underreported, despite potentially affecting many people and causing increased mortality.
• Hoenigl et al, (2020), Invasive Fungal Disease complicating COVID-19: when it rains it pours, Clin Infect Dis 2020.
• Koehler et al, Lancet Infect Dis 2020. DOI: 10.1016/S1473-3099(20)30847-1
• Lescure et al. (2020) described a case of an 80yr old Chinese man admitted to hospital in France with fever, diarrhoea and bilateral alveolar opacities on X-ray. He deteriorated rapidly and developed ARDS, kidney/liver failure and sepsis. Tracheal aspirate cultures grew Acinetobacter and Aspergillus flavus. He was treated with remdesivir, multiple antibiotics and antifungals. "We initially treated A. flavus with  voriconazole but switched to isavuconazole because voriconazole and remdesivir both contain sulphobutylether-β-cyclodextrin, and the safety of  this association has not been evaluated yet." Unfortunately he died on day 24 of illness.
• Li and Xia (2020) presented the CT findings of 51 patients who were positive for SARS-CoV-2 by nucleic acid testing of oropharyngeal swabs. Most patients had (generally bilateral) consolidation (6%), ground glass opacity (35%) or both (55%). However, in 9 patients (18%) cases a nodule with ‘halo sign’ was seen, and in 2 patients (4%) the ‘reversed halo’ sign was seen. These signs were not previously reported for SARS or MERS patients but are commonly seen in aspergillosis.
• Meijer et al, 2020, Journal of Fungi 2020, 6, 79; doi:10.3390/jof6020079
• Phillip Koehler et al. (2020): COVID-19 Associated Pulmonary Aspergillosis. https://doi.org/10.1111/myc.13096.
• Prattes et al. (2020), Invasive pulmonary aspergillosis complicating COVID-19 in the ICU - A case report.
• Rutsaert et al, 2020, Ann Intensive Care 2020; 10: 71 
• van Arkel et al. (2020), COVID-19 Associated Pulmonary Aspergillosis
• Verweij et al., (2020), Diagnosing COVID-19-associated pulmonary aspergillosis.
• White et al.(2020),A national strategy to diagnose COVID-19 associated invasive fungal disease in the ICU, Clin Infect Dis 2020
• Yang et al. (2020) reviewed the notes of 52 critical COVID-19 patients, of whom 7 (14%) had additional infections. Aspergillus flavus and Aspergillus fumigatus were cultured from respiratory secretions of one patient (2%) each but the clinical relevance of these is not known.

With thanks to LIFE Worldwide for generating an initial list of publications. 

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If you are looking for guidance or support for patients with aspergillosis: 

As highlighted by LIFE, if you are looking for guidance or support for patients with aspergillosis (e.g. CPA or ABPA) who are concerned about COVID-19, please visit the Aspergillosis Patients & Carers website or direct them towards the Facebook Aspergillosis Support group.

Date: 16 September 2020

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