To the editor,
Superinfections, including invasive pulmonary aspergillosis (IPA), are well-known complications of severe viral pneumonia in critically ill patients [1].
Pathological studies of individuals with severe coronavirus disease 2019 (COVID-19) -associated acute respiratory distress syndrome reported diffuse alveolar damage combined with intra-alveolar neutrophilic infiltration and vascular congestion, assuming an impaired mucociliary activity that might pave the way for secondary infections [2,3].
Our report of two critically ill patients suggests that IPA might be a relevant complication of severe COVID-19 pneumonia in analogy to experiences in severe influenza pneumonia.
Both individuals were without typical risk factors for IPA, e.g. steroid medication or other immunospuppression, and were admitted from a secondary-care hospital with pneumonia caused by COVID-19 to our intensive care unit (ICU) after progression to severe acute respiratory distress syndrome.
In the initial bronchoalveolar lavage of both patients only COVID-19 was found (PCR negative for influenza virus and respiratory syncytial virus); a follow-up bronchoalveolar lavage because of ongoing fever a few days later (days 5 and 6 after ICU admission) showed elevated galactomannan and growth of Aspergillus fumigatus in standard culture, suggesting IPA (Table 1 ). All patients received a chest computed tomography scan before ICU admittance with typical signs for COVID-19 pneumonia but no specific signs for IPA. Follow-up computed tomography scans were not performed for safety reasons.
Table 1.
Results of galactomannan (bronchoalveolar lavage and serum) and standard culture
| Patient 1 (80 years, male, suspected pulmonary fibrosis) |
Patient 2 (70 years, male, no risk factors) |
|
|---|---|---|
| Galactomannan from BAL (ODI; normal range <1.0) | 6.3 | 6.1 |
| Galactomannan from serum (ODI; normal range <0.5) | 1.5 | <0.5 |
| Standard culture | Aspergillus fumigatus | Aspergillus fumigatus |
| SARS-CoV-2 (at follow up) | positive | positive |
| Laboratory parameters, mean at IPA diagnosis | ||
| CRP (mg/dL) | 26 | 5.1 |
| IL-6 (pg/mL) | 460 | 82 |
| PCT (ng/mL) | 3.7 | 0.4 |
| D-Dimer (μg/L) | 4820 | 14 151 |
| LDH (U/L) | 481 | 530 |
| Leucocyte count (G/L) | 10.38 | 14.55 |
| Lymphocytes (%) | 15 | 7 |
| Renal failure | Yes | Yes |
| Classical risk factors for invasive pulmonary aspergillosis | No | No |
Abbreviations: BAL, bronchoalveolar lavage; CRP, C-reactive protein; IL-6, interleukin 6; IPA, invasive pulmonary aspergillosis; LDH, lactate dehydrogenase; ODI, optical density index; PCT, procalcitonin.
The time-point of IPA diagnosis is in line with previous studies that demonstrated a median time to IPA diagnosis between 3 and 9 days after ICU admission of patients with severe influenza pneumonia [1,3]. In these patients also, high incidence and mortality rates could be observed [1,3].
Both patients in our report died as the result of ongoing acute respiratory distress syndrome with multiorgan failure.
Growth of Aspergillus spp. in a respiratory culture from an ICU patient is often interpreted as colonization rather than infection. Other typical diagnostics for IPA, such as biopsy or imaging techniques, may be more challenging in critically ill COVID-19 patients for several reasons.
Therefore, additional testing of bronchoalveolar lavage specimens for galactomannan is easy, and the specificity of an ODI cut-off of >1·0 is about 90% to detect IPA [4,5].
Early and sufficient antifungal medication is the cornerstone for effective IPA treatment. Our patients were treated with liposomal amphotericin-B (3 mg/kg) because of multiorgan failure including hepatic failure; however, voriconazole and isavuconazole are sufficient alternatives.
In conclusion, COVID-19-associated IPA may lead to a poor outcome even in immune competent individuals.
Further studies are needed to indicate if COVID-19-associated invasive pulmonary aspergillosis is a relevant complication in critically ill patients with severe COVID-19 pneumonia.
Transparency declarations
None of the authors has any potential financial or non-financial conflicts of interest related to this manuscript. None of the authors has received any funding or financial support regarding this manuscript. The manuscript has not been submitted or accepted elsewhere. All authors fulfil the criteria given in the authorship paragraph. No writing assistance other than copy editing was provided in the preparation of the manuscript.
Research funding
Nothing to declare.
Employment or leadership
Nothing to declare. Tobias Lahmer received travel grants from Pfizer, Gilead and MSD.
Editor: L Leibovici
References
- 1.Schauwvlieghe A.F.A.D., Rijnders B.J.A., Philips N., Verwijs R., Vanderbeke L., Van Tienen C. Dutch-Belgian Mycosis Study Group. Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study. Lancet Resp Med. 2018;6:782–792. doi: 10.1016/S2213-2600(18)30274-1. [DOI] [PubMed] [Google Scholar]
- 2.Tian S., Xiong Y., Liu H., Niu L., Guo J., Liao M. Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies. Mod Pathol. 2020 doi: 10.1038/s41379-020-0536-x. [Epub ahead of print] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Chen N., Zhou M., Dong X., Qu J., Gong F., Han Y. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395:507–513. doi: 10.1016/S0140-6736(20)30211-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.van de Veerdonk F.L., Kolwijck E., Lestrade P.P., Hodiamont C.J., Rijnders B.J., Van Paassen J. Influenza-associated aspergillosis in critically ill patients. Am J Respir Crit Care Med. 2017;196:524–527. doi: 10.1164/rccm.201612-2540LE. [DOI] [PubMed] [Google Scholar]
- 5.Leeflang M.M., Debets-Ossenkopp Y.J., Wang J., Visser C.E., Scholten R.J., Hooft L. Galactomannan detection for invasive aspergillosis in immunocompromised patients. Cochrane Database Syst Rev. 2015;12:CD007394. doi: 10.1002/14651858.CD007394.pub2. [DOI] [PMC free article] [PubMed] [Google Scholar]