Data are mounting for COVID-19 and Aspergillus co-infections
March 30 2020
Invasive pulmonary aspergillosis is a well-known complication of severe influenza, but data are lacking to show how commonly it causes co-infection in COVID-19 cases. We will update this page as more information becomes available. If you find any publications or cases of COVID-19 with aspergillosis you can email us or join the conversation on Twitter. Please consider submitting your cases to FungiScope and/or Radiopaedia (if you would like to but don't have time, email us and we can help).
As well as having overlapping clinical symptoms (fever, cough), there are several practical barriers to laboratory testing for COVID-associated aspergillosis:
- Collecting a respiratory sample by bronchoscopy generates aerosolised droplets of SARS-CoV-2 and requires full PPE
- In some cases recovery of Aspergillus by culture may represent colonisation of the airways rather than a true infection
- Beta-D-glucan tests can give a false positive if
- However, rapid bedside (point of care) tests that measure galactomannan antigen in serum or BAL are available from OLM Diagnostics (AspLFD video protocol) and IMMY, which give a result in around 30 minutes (read more)
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. They highlight the need for large registries with sufficient detail for each case, and the need for effective diagnostic process early in the course of treatment:
"A 2-step process could associate an efficient syndromic molecular approach (qPCR for Aspergillus, Pneumocystis jiroveci, and mucorales) with culture for respiratory samples. In case of positivity of any of these tests, a confirmation step with blood biomarkers will be implemented depending on the positive results, with serum galactomannan and/or serum beta-D-glucan and/or cryptococcal antigenemia and/or blood qPCR for Aspergillus or mucorales"
The French High Council for Public Health recommends systematic screening for fungal pathogens in patients admitted with pneumonia. They speculate that epidemiological data obtained in future may support antifungal prophylaxis and/or environmental measures.
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.
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.
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.
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.
Read a blog post by Neil J. Clancy at Science Speaks about COVID-19 superinfections
Alanio et al (2020) carried out a prospective study across two ICU units in Paris. 27 consecutive ventilated COVID-19 patients had respiratory samples taken on day 3 post-intubation. Criteria for influenza-associated aspergillosis were used to determine cases. Six patients (22%) met 2 or more of the following mycological criteria, and a further three (11%) grew Aspergillus fumigatus in cultures. One patients was given caspofungin, then later switched to voriconazole, which was to treat a concomitant Candida glabrata infection. Three patients died of bacterial septic shock but most are still currently on ventilators. Criteria:
- Aspergillus fumigatus grown in cultures
- BAL galactomannan >0.8 AND BDG >80pg/ml
- Positive Aspergillus fumigatus qPCR
- Serum galactomannan >0.5 AND serum BDG >80pg/ml
Koehler et al (2020) reviewed the charts of 19 consecutive COVID-ARDS patients admitted to an ICU Cologne (Germany), and found that 5 (26%) also had putative invasive pulmonary aspergillosis (IPA). On chest CT all patients had ground glass opacities and nodular infiltrates, but only patient #3 had the air crescent typical of IPA. Two had previously been receiving inhaled corticosteroids and one had previous IV corticosteroids.
- Patient #1 (62F) had severe ARDS and received ECMO and tranexamic acid for severe intrapulmonary bleeding. BAL was positive for galactomannan and cultures grew Aspergillus fumigatus. She received IV voriconazole.
- Patient #2 (70M) had ARDS and acute renal failure. BAL tested positive for galactomannan and Aspergillus fumigatus PCR. Two days prior his serum had tested positive for galactomannan. He received IV isavuconazole.
- Patient #3 (54M) Tracheal aspirates grew Aspergillus fumigatus in culture, and BAL was positive for galactomannan. He received IV voriconazole.
- Patient #4 (73M) had underlying bullous emphysema. Tracheal aspirates tested positive for Aspergillus fumigatus by both PCR and culture. He received IV voriconazole.
- Patient #5 (54F) Serum galactomannan was positive in two consecutive samples. She received IV caspofungin.
The authors recommend that testing for Aspergillus in respiratory samples and serum galactomannan should be considered for COVID-19 patients in the ICU
Blaize et al (2020) reported a case of a 74yo immunocompetent man with underlying untreated myelodysplastic syndrome, hypertension and Hashimotos thyroiditis. He had been unwell for a week before hospitalisation in Paris.
- On day 4 in the ICU, a tracheal aspirate tested positive by Aspergillus PCR (430 copies/ml; 2.6 log) but galactomannan and culture were negative.
- On day 9 another tracheal aspirate tested positive by Aspergillus PCR (3,600 copies/ml; 3.55 log)and branched hyphae were visible upon silver staining. Cultures grew Aspergillus fumigatus.
- Serum samples taken on days 4 and 8 were negative for galactomannan, beta-D-glucan and Aspergillus PCR.
- The patient died of respiratory failure on day 9, before antifungal therapy could be initiated.
- Test intubated patients for galactomannan weekly (started by Carol Garcia-Vidal))
- Aspergillus is being found at autopsy (started by Tatiana Prowell)
- Unbalanced CD4/CD8 ratios seen in both COVID-19 and aspergillosis (started by Tatiana Prowell)
- Poll of cases (started by LIFE Worldwide)
- Have HCWs seen mold and fungal infections (started by Tobias Hohl)
- 33% prevalence of putative COVID-associated aspergillosis in Paris (started by Alexandre Alanio)
Diagnosis & treatment:
- You can find out more about diagnosing Aspergillus on our laboratory diagnostics page
- Many video lectures are found on our YouTube channel
- Suveer Singh (@Respitudoc of @RBandH) has shared a great video describing ways to reduce aerosol formation during bronchoscopy of ventilated patients bit.ly/3e2s2WK This should make testing for COVID-19 coinfections safer for staff involved.
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.