COVID-19-Associated Pulmonary Aspergillosis: A Single-Center Experience in Central Valley, California, January 2020–March 2021
by
,
Geetha Sivasubramanian
1,*
,
Hebah Ghanem
1,
Michele Maison-Fomotar
1,
Ratnali Jain
2 and
Robert Libke
1 1
Division of Infectious Diseases, Department of Internal Medicine, University of California, San Francisco, CA 93701, USA
2
UCSF Fresno Research Institute, University of California, San Francisco, CA 93701, USA
*
Author to whom correspondence should be addressed.
J. Fungi 2021, 7(11), 948; https://doi.org/10.3390/jof7110948
Submission received: 25 September 2021
/
Revised: 4 November 2021
/
Accepted: 9 November 2021
/
Published: 10 November 2021
(This article belongs to the Special Issue Fungal Infections and COVID-19)
Abstract
:Reports of coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) have been widely published across the world since the onset of the pandemic with varying incidence rates. We retrospectively studied all patients with severe COVID-19 infection who were admitted to our tertiary care center′s intensive care units between January 2020 and March 2021, who also had respiratory cultures positive for Aspergillus species. Among a large cohort of 970 patients admitted to the ICU with severe COVID-19 infections during our study period, 48 patients had Aspergillus species growing in respiratory cultures. Based on the 2020 European Confederation of Medical Mycology and the International Society for Human and Animal Mycology (ECMM/ISHAM) consensus criteria, 2 patients in the study had proven CAPA, 9 had probable CAPA, and 37 had possible CAPA. The incidence of CAPA was 5%. The mean duration from a positive COVID-19 test to Aspergillus spp. being recovered from the respiratory cultures was 16 days, and more than half of the patients had preceding fever or worsening respiratory failure despite adequate support and management. Antifungals were given for treatment in 44% of the patients for a mean duration of 13 days. The overall mortality rate in our study population was extremely high with death occurring in 40/48 patients (83%).
1. Introduction
Invasive pulmonary aspergillosis (IPA) is a devastating infection associated with high morbidity and mortality. IPA was traditionally encountered in the immunocompromised host, typically patients with prolonged neutropenia, hematologic malignancy, allogeneic hematopoietic stem cell or solid organ transplantation, prolonged use of high dose corticosteroids and T-cell immunosuppressive agents [1]. In the past decade, evidence started to accumulate that IPA also occurred in patients admitted to the intensive care unit (ICU) who did not otherwise have the classic host factors [2]. A cohort of these ICU patients had preceding respiratory viral illnesses such as influenza [3,4]. IPA was already a challenging diagnosis in patients with traditional risk factors due to the difficulty of obtaining tissue samples to confirm diagnosis. IPA in post-viral illness and critically ill patients is even more difficult to diagnose due to the absence of characteristic clinical and imaging findings. Clinical algorithms have been designed specifically to define IPA in this context [5,6].
Since the onset of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated pandemic, multiple reports of IPA have emerged in critically ill patients with severe pneumonia [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25]. The incidence of COVID-19-associated pulmonary aspergillosis (CAPA) in these studies has been variable, ranging from 3 to 34% largely due to differences in diagnostic criteria as well as regional differences in obtaining culture specimens and bronchoscopies [14,26]. Expert consensus definition criteria for CAPA have been published [27]. We report our experience on CAPA among patients with severe COVID-19 infection in Fresno, Central California, from January 2020 through March 2021.
2. Materials and Methods
The study was conducted in a tertiary care center located in Fresno, Central California, United States of America with 685 beds and 55 intensive care unit beds. During the surge of cases, the number of ICU beds was expanded up to two or three times the normal capacity, averaging between 85 and 150 ICU beds.
We conducted a retrospective analysis of patients who were admitted to the intensive care unit with COVID-19 infection and had Aspergillus species growing from their respiratory cultures. All patients above the age of 18 who were admitted to the intensive care unit between January 2020 and March 2021, who had a confirmed SARS-Cov-2 PCR test and had positive Aspergillus cultures from subsequent respiratory tract specimens were included in the study. Data were collected from the patient charts including demographics, underlying medical conditions, clinical features, length of stay, mortality, radiological and laboratory findings as well as treatments. We also compared the total number of positive Aspergillus respiratory cultures in the intensive care unit patients between January 2020 and March 2021 with the previous two years of positive Aspergillus respiratory cultures in the intensive care unit patients. COVID-19-associated pulmonary aspergillosis (CAPA) was defined using the 2020 ECMM/ISHAM consensus criteria and categorized as proven, probable, and possible.
2.1. Laboratory Methods
Patients were identified as positive for COVID-19 by having a positive polymerase chain reaction (PCR) for SARS-CoV-2 from nasopharyngeal swab, endotracheal aspirate or bronchoalveolar lavage specimens. The Aspergillus species was identified from fungal culture plates which had been initially set up on Sabouraud′s 2% dextrose agar (SDA) (Remel, Lenexa, KS, USA) and Inhibitory Mold Agar (Remel, same). Aspergillus fumigatus could be identified after 48–72 h of incubation at 35 °C, with identification made by macroscopic observation of colony morphology and microscopic observation using Lactophenol Cotton Blue dye (Remel, Lenexa, KS, USA). If identification by morphology and stains was not possible from these initial evaluations, specimens were sub-cultured to Potato Dextrose Agar (PDA, Remel, Lenexa, KS, USA) and tested by Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) (Vitek MS, BioMérieux Inc., Durham, NC, USA) wherein the colony from the PDA culture media went through a lysis step before testing. The cells were lysed using an ethanol-acetonitrile-formic acid process to obtain good protein extraction. The cleaned fungal protein was applied to the slide and matrix added following standard procedure. Once dried, the standard protocol was followed for use of the Vitek MALDI-TOF MS to obtain a clean spectrum for evaluation by the MALDI-TOF MS software. Anti-fungal susceptibility testing on the Aspergillus fumigatus isolate of patient 2 was performed by the reference laboratory using the broth microdilution method.
2.2. Statistical Methods
We conducted descriptive data analyses for all parameters that were collected. These values were reported as frequencies, medians with interquartile range and proportions. All statistical analyses were completed using SPSS software (International Business Machines Corp, New York, USA), version 27.
The study was approved by the institutional review board (IRB #2021002).
3. Results
In total, 970 patients were admitted to the ICU for management of COVID-19 infection during the study period of January 2020–March 2021. Among these, respiratory cultures growing Aspergillus species were noted in 48 patients. Using the 2020 ECMM/ISHAM consensus criteria (Table 1) for diagnosis of CAPA, 2 patients had proven CAPA, 9 had probable CAPA, and 37 possible CAPA (Supplementary Table S1). The incidence of CAPA in our study was 5%.
Among those with CAPA, 66% of the patients were male with a median age of 67 (IQR 17), ranging from 49–86 years (Table 2). A total of 77% of the patients were white but predominantly of Hispanic ethnicity (88%), followed by Asians (18%) and non-white Hispanics (4%). More than 65% of them had underlying hypertension and diabetes mellitus, and less frequently, other underlying conditions such as renal disease, liver disease, cardiac disease, stroke, and cancer.
The overall severity of illness and mortality was quite high with 100% requiring positive pressure mechanical ventilation, 87% requiring vasopressors for hemodynamic support, and 35% needing new renal replacement therapy. The mean duration of hospital length of stay for the patient group was 30 days and the length of ICU stay was 23 days. Death occurred in 83% of the patients (40/48).
The mean duration from a positive COVID-19 test to Aspergillus species being recovered from the respiratory cultures was 16 days, ranging from 4 to 50 days. Preceding the recovery of Aspergillus from the cultures, a fever >100.5 was noted in 50% of the patients, and 77% of them had worsening respiratory failure despite adequate support and management. Chest imaging showing cavitation or nodules was seen only in 20% of the patients. Inflammatory markers such as CRP, ferritin, and other parameters such as D dimer and LDH were elevated in most of the patients.
Patients were treated for COVID-19 with remdesivir in 69% of the cases and with steroids in 93%. Dexamethasone was the most used steroid treatment (90%). IL-6 inhibitors such as tocilizumab were not used in any of the patients. Broad-spectrum antibiotics were used in over 90% of the patients for an average duration of 7 days.
The most common type of respiratory culture from which the Aspergillus species were isolated was an endotracheal aspirate (Table 3). Aspergillus fumigatus was the most common species (52%) isolated, followed by a mixed growth with more than one type of Aspergillus species (18%) followed by Aspergillus niger (12%). Serum galactomannan was tested in 14 of the 48 patients, and 6 out of those were positive. Broncho-alveolar lavage (BAL) fluid galactomannan was tested in three patients, none of which were positive. Serum 1,3 beta-D-glucan was tested in 25 of the 48 patients, and 60% of them were positive. In over 60% of these patients, a bacterial co-infection in the lungs was not detected.
Antifungals were given for treatment in 44% of the patients for a mean duration of 13 days. Voriconazole was the most used agent (66%) followed by a combination of more than one agent (28%), echinocandin (9%), and posaconazole (4%).
There were two cases of proven CAPA in our study (Table 4). One of the proven cases had anti-fungal susceptibility testing performed on the second isolate recovered during therapy. The minimum inhibitory concentration to voriconazole and isavuconazole was 2 µg/mL (Supplementary Table S2), concerning for resistance.
The second proven case with severe COVID-19 infection requiring mechanical ventilation was clinically worsening and grew Aspergillus fumigatus from blood and endotracheal cultures, 12 days after the initial SARS-CoV-2 infection. He expired before the availability of these results and never received any anti-fungal therapy.
In the preceding years, in 2018 and 2019, there were 16 and 19 patients with positive Aspergillus cultures from respiratory tract specimens from the intensive care units in our center (Figure 1). There was a total of 57 patients in the intensive care units who had positive Aspergillus respiratory cultures between January 2020 and March 2021. During this time, the culture positivity was higher during the months of August and September 2020 as well January and February 2021, when there was peak surge of COVID-19 cases in our center (Figure 2).
4. Discussion
We describe here a large cohort of 48 patients with CAPA in mechanically ventilated intensive care unit patients at large tertiary care center in Fresno, California, United States of America. The incidence of CAPA in our study was around 5%. Previous studies have shown incidences varying from 3 to 34% [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25]. Practices in obtaining specimens such as tracheal or endotracheal aspirates, bronchoscopy specimens, fungal biomarkers as well local geographic variations in the incidence of Aspergillus likely contributed to these variations. Compared to previous years, the number of Aspergillus cultures from respiratory samples did increase significantly during the study period in our center and coincided with the peak surges of COVID-19 infections. However, this number may likely be reflective of the increase in overall ICU bed capacity, mechanically ventilated patients, and cultures obtained during the pandemic.
Definitions using the 2020 ECMM/ISHAM consensus criteria place emphasis on obtaining bronchoscopy specimens for cultures as well as obtaining galactomannan or polymerase chain reaction (PCR) tests for diagnosis. However, bronchoscopies and galactomannan and PCR testing were carried out sparingly in our center. This contributed to most of the patients being placed under the possible rather than probable category.
Sixty-five percent of patients who had CAPA in our study were male, above the age of 65 and Hispanic with underlying hypertension and diabetes. This represents the demographics that were most affected by the COVID-19 pandemic in the region. Although the clinical and imaging features were quite non-specific, half of the patients with CAPA had new or recrudescent fever as well as worsening respiratory failure despite adequate antibiotic management.
Higher minimum inhibitory concentration (MIC) to voriconazole at 2 µg/mL was noted in the Aspergillus fumigatus isolate of the patient with biopsy proven CAPA. Gene sequencing was not performed to identify an underlying mutation. This patient did not have any identified EORTC/MSG classic host factors for IPA and developed CAPA around 30 days after initial ICU admission for COVID-19. She also had evidence of Aspergillus tracheobronchitis. Cases of voriconazole-resistant CAPA have been reported [28,29,30]. Whether CAPA or the delay in effective anti-fungal therapy due to resistance contributed to her mortality is unclear but a possibility. This adds to the challenges in management of CAPA such as the requirements for therapeutic drug monitoring, neurotoxicity, and hepatotoxicity as well as drug–drug interactions.
Interestingly, the second patient with proven CAPA had Aspergillus fumigatus isolated in their blood cultures. This patient’s illness was quite rapidly fatal, as would be expected with invasive disseminated aspergillosis infection. He also did not have any traditional EORTC/MSG risk factors such as neutropenia, immunosuppression, or prolonged corticosteroids. He had severe COVID-19 infection requiring mechanical ventilation and developed IPA 12 days after diagnosis of COVID-19. He never received any anti-fungal therapy as the diagnosis was only made post-mortem. Detection of Aspergillus species in blood cultures is quite rare. Previous reports of such an occurrence have been in severely immunocompromised patients such as those with leukemia, transplantation, chronic granulomatous disease (CGD), and acquired immunodeficiency syndrome (AIDS), or in patients with device-related infections and endocarditis [31,32,33,34,35,36,37,38]. Aspergillus fungemia in the setting of IPA in the intensive care unit in otherwise non-immunocompromised patients is very unusual. One of the pathological features of SARS-CoV-2 infection seems to be defects in immune cell functions caused by marked hyperinflammation [39]. This resultant reduction in T-lymphocyte numbers as well as their functions is one suggested mechanism for the secondary opportunistic infections seen post-severe COVID-19 infection.
We have here described a large cohort of CAPA cases seen in our center in the past year and more of the pandemic with a rigorous review of patient’s charts. However, our study is limited because it is a retrospective study from a single center. The use of fungal biomarkers, Aspergillus PCR, and pursuing bronchoscopies were limited in our study population.
Despite being well reported, CAPA remains an entity with many uncertainties. In addition to standardizing definitions, practices for timely diagnosis such as obtaining bronchoscopy samples and the use of fungal biomarkers must be standardized.
Supplementary Materials
The following are available online at https://www.mdpi.com/article/10.3390/jof7110948/s1, Table S1: Clinical, radiological, mycological findings in the forty-eight patients and their ECMM/ISHAM CAPA definition categories, Table S2: Antimicrobial sensitivities of Aspergillus fumigatus isolate from patient 2.
Author Contributions
Conceptualization: G.S.; methodology: G.S., M.M.-F., H.G., and R.L.; formal analysis: R.J.; investigation: G.S., M.M.-F., H.G., R.J., and R.L.; data curation: G.S., M.M.-F., and H.G.; writing: G.S., M.M.-F., and H.G.; writing—review and editing: G.S., M.M.-F., H.G., R.J., and R.L. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of UCSF, IRB #2021002.
Informed Consent Statement
Patient consent was waived due to this being a retrospective chart review study and no identifying patient information has been published.
Data Availability Statement
Data is available from the corresponding author upon request.
Acknowledgments
The authors would like to acknowledge Marylin Mitchell, Department of Clinical Microbiology, Community Regional Medical Center, Fresno and Kate Henschel, Epidemiologist and Infection Prevention Supervisor, Community Medical Centers, Fresno for their assistance in data review.
Conflicts of Interest
The authors have no financial interests or conflicts of interest to disclose.
References
- 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. 2019, 71, 1367–1376. [Google Scholar] [CrossRef] [Green Version]
- Meersseman, W.; Lagrou, K.; Maertens, J.; Van Wijngaerden, E. Invasive Aspergillosis in the Intensive Care Unit. Clin. Infect. Dis. 2007, 45, 205–216. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Huang, L.; Zhang, N.; Huang, X.; Xiong, S.; Feng, Y.; Zhang, Y.; Li, M.; Zhan, Q. Invasive pulmonary aspergillosis in patients with influenza infection: A retrospective study and review of the literature. Clin. Respir. J. 2019, 13, 202–211. [Google Scholar] [CrossRef]
- Vanderbeke, L.; Spriet, I.; Breynaert, C.; Rijnders, B.J.A.; Verweij, P.E.; Wauters, J. Invasive pulmonary aspergillosis complicating severe influenza: Epidemiology, diagnosis and treatment. Curr. Opin. Infect. Dis. 2018, 31, 471–480. [Google Scholar] [CrossRef]
- Blot, S.I.; Taccone, F.S.; Abeele, A.-M.V.D.; Bulpa, P.; Meersseman, W.; Brusselaers, N.; Dimopoulos, G.; Paiva, J.A.; Misset, B.; Rello, J.; et al. A Clinical Algorithm to Diagnose Invasive Pulmonary Aspergillosis in Critically Ill Patients. Am. J. Respir. Crit. Care Med. 2012, 186, 56–64. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Schauwvlieghe, A.F.A.D.; Rijnders, B.J.A.; Philips, N.; Verwijs, R.; Vanderbeke, L.; Van Tienen, C.; Lagrou, K.; Verweij, P.E.; Van De Veerdonk, F.L.; Gommers, D.; et al. Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: A retrospective cohort study. Lancet Respir. Med. 2018, 6, 782–792. [Google Scholar] [CrossRef]
- Benedetti, M.F.; Alava, K.H.; Sagardia, J.; Cadena, R.C.; Laplume, D.; Capece, P.; Posse, G.; Nusblat, A.D.; Cuestas, M.L. COVID-19 associated pulmonary aspergillosis in ICU patients: Report of five cases from Argentina. Med. Mycol. Case Rep. 2021, 31, 24–28. [Google Scholar] [CrossRef]
- Machado, M.; Valerio, M.; Álvarez-Ur-a, A.; Olmedo, M.; Veintimilla, C.; Padilla, B.; De La Villa, S.; Guinea, J.; Escribano, P.; Ruiz-Serrano, M.J.; et al. Invasive pulmonary aspergillosis in the COVID-19 era: An expected new entity. Mycoses 2021, 64, 132–143. [Google Scholar] [CrossRef] [PubMed]
- Alanio, A.; Dellière, S.; Fodil, S.; Bretagne, S.; Mégarbane, B. Prevalence of putative invasive pulmonary aspergillosis in critically ill patients with COVID-19. Lancet Respir. Med. 2020, 8, e48–e49. [Google Scholar] [CrossRef]
- Permpalung, N.; Chiang, T.P.-Y.; Massie, A.B.; Zhang, S.X.; Avery, R.K.; Nematollahi, S.; Ostrander, D.; Segev, D.L.; A Marr, K. Coronavirus Disease 2019—Associated Pulmonary Aspergillosis in Mechanically Ventilated Patients. Clin. Infect. Dis. 2021. [Google Scholar] [CrossRef] [PubMed]
- Falces-Romero, I.; Ruiz-Bastián, M.; D-az-Pollán, B.; Maseda, E.; Garc-a-Rodr-guez, J. SARS-CoV-2 Working Group Isolation of Aspergillus spp. in respiratory samples of patients with COVID-19 in a Spanish Tertiary Care Hospital. Mycoses 2020, 63, 1144–1148. [Google Scholar] [CrossRef]
- Paramythiotou, E.; Dimopoulos, G.; Koliakos, N.; Siopi, M.; Vourli, S.; Pournaras, S.; Meletiadis, J. Epidemiology and Incidence of COVID-19-Associated Pulmonary Aspergillosis (CAPA) in a Greek Tertiary Care Academic Reference Hospital. Infect. Dis. Ther. 2021, 10, 1779–1792. [Google Scholar] [CrossRef]
- Bartoletti, M.; Pascale, R.; Cricca, M.; Rinaldi, M.; Maccaro, A.; Bussini, L.; Fornaro, G.; Tonetti, T.; Pizzilli, G.; Francalanci, E.; et al. Epidemiology of invasive pulmonary aspergillosis among COVID-19 intubated patients: A prospective study. Clin. Infect. Dis. 2020, ciaa1065. [Google Scholar] [CrossRef] [PubMed]
- Nasir, N.; Farooqi, J.; Mahmood, S.F.; Jabeen, K. COVID-19-associated pulmonary aspergillosis (CAPA) in patients admitted with severe COVID-19 pneumonia: An observational study from Pakistan. Mycoses 2020, 63, 766–770. [Google Scholar] [CrossRef] [PubMed]
- Salmanton-Garc-a, J.; Sprute, R.; Stemler, J.; Bartoletti, M.; Dupont, D.; Valerio, M.; Garc-a-Vidal, C.; Falces-Romero, I.; Machado, M.; de la Villa, S.; et al. COVID-19—Associated Pulmonary Aspergillosis, March–August 2020. Emerg. Infect. Dis. 2021, 27, 1077–1086. [Google Scholar] [CrossRef] [PubMed]
- Pintado, M.V.; Camiro-Zúñiga, A.; Soto, M.A.; Cuenca, D.; Mercado, M.; Crabtree-Ramirez, B. the ARMII study gruop COVID-19-associated invasive pulmonary aspergillosis in a tertiary care center in Mexico City. Med. Mycol. 2021, 59, 828–833. [Google Scholar] [CrossRef]
- 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, 59, e02136-20. [Google Scholar] [CrossRef] [PubMed]
- Nasrullah, A.; Javed, A.; Malik, K. Coronavirus Disease-Associated Pulmonary Aspergillosis: A Devastating Complication of COVID-19. Cureus 2021, 13, e13004. [Google Scholar] [CrossRef]
- Versyck, M.; Zarrougui, W.; Lambiotte, F.; Elbeki, N.; Saint-Leger, P. Invasive pulmonary aspergillosis in COVID-19 critically ill patients: Results of a French monocentric cohort. J. Med. Mycol. 2021, 31, 101122. [Google Scholar] [CrossRef]
- Segrelles-Calvo, G.; Araújo, G.R.D.S.; Llopis-Pastor, E.; Carrillo, J.; Hernández-Hernández, M.; Rey, L.; Melean, N.R.; Escribano, I.; Antón, E.; Zamarro, C.; et al. Prevalence of opportunistic invasive aspergillosis in COVID-19 patients with severe pneumonia. Mycoses 2021, 64, 144–151. [Google Scholar] [CrossRef] [PubMed]
- Arastehfar, A.; Carvalho, A.; Van De Veerdonk, F.L.; Jenks, J.D.; Koehler, P.; Krause, R.; Cornely, O.A.; Perlin, D.S.; Lass-Flörl, C.; Hoenigl, M. COVID-19 Associated Pulmonary Aspergillosis (CAPA)—From Immunology to Treatment. J. Fungi 2020, 6, 91. [Google Scholar] [CrossRef] [PubMed]
- Yusuf, E.; Vonk, A.; Akker, J.P.C.V.D.; Bode, L.; Sips, G.J.; Rijnders, B.J.A.; de Steenwinkel, J.; Verkaik, N.J.; Vogel, M.; van der Eerden, M.; et al. Frequency of Positive Aspergillus Tests in COVID-19 Patients in Comparison to Other Patients with Pulmonary Infections Admitted to the Intensive Care Unit. J. Clin. Microbiol. 2021, 59, e02278-20. [Google Scholar] [CrossRef] [PubMed]
- Lamoth, F.; Glampedakis, E.; Boillat-Blanco, N.; Oddo, M.; Pagani, J.-L. Incidence of invasive pulmonary aspergillosis among critically ill COVID-19 patients. Clin. Microbiol. Infect. 2020, 26, 1706–1708. [Google Scholar] [CrossRef] [PubMed]
- Mitaka, H.; Perlman, D.C.; Javaid, W.; Salomon, N. Putative invasive pulmonary aspergillosis in critically ill patients with COVID-19: An observational study from New York City. Mycoses 2020, 63, 1368–1372. [Google Scholar] [CrossRef] [PubMed]
- Dellière, S.; Dudoignon, E.; Fodil, S.; Voicu, S.; Collet, M.; Oillic, P.-A.; Salmona, M.; Dépret, F.; Ghelfenstein-Ferreira, T.; Plaud, B.; et al. Risk factors associated with COVID-19-associated pulmonary aspergillosis in ICU patients: A French multicentric retrospective cohort. Clin. Microbiol. Infect. 2020, 27, 790.e1–790.e5. [Google Scholar] [CrossRef]
- Marr, K.A.; Platt, A.; Tornheim, J.A.; Zhang, S.X.; Datta, K.; Cardozo, C.; Garcia-Vidal, C. Aspergillosis Complicating Severe Coronavirus Disease. Emerg. Infect. Dis. 2021, 27, 18–25. [Google Scholar] [CrossRef]
- Koehler, P.; Bassetti, M.; Chakrabarti, A.; Chen, S.C.A.; Colombo, A.L.; Hoenigl, M.; Klimko, N.; Lass-Flörl, C.; Oladele, R.O.; Vinh, D.C.; et al. Defining and managing COVID-19-associated pulmonary aspergillosis: The 2020 ECMM/ISHAM consensus criteria for research and clinical guidance. Lancet Infect. Dis. 2021, 21, e149–e162. [Google Scholar] [CrossRef]
- 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]
- Meijer, E.F.J.; Dofferhoff, A.S.M.; Hoiting, O.; Buil, J.B.; Meis, J.F. Azole-Resistant COVID-19-Associated Pulmonary Aspergillosis in an Immunocompetent Host: A Case Report. J. Fungi 2020, 6, 79. [Google Scholar] [CrossRef]
- Ghelfenstein-Ferreira, T.; Saade, A.; Alanio, A.; Bretagne, S.; de Castro, R.A.; Hamane, S.; Azoulay, E.; Bredin, S.; Dellière, S. Recovery of a triazole-resistant Aspergillus fumigatus in respiratory specimen of COVID-19 patient in ICU—A case report. Med. Mycol. Case Rep. 2021, 31, 15–18. [Google Scholar] [CrossRef]
- Gucalp, R.; Ciobanu, N.; Sparano, J.; Motyl, M.; Carlisle, P.; Wiernik, P.H. Disseminated aspergillosis after fungemia in a patient with extragonadal germ cell tumor undergoing autologous bone marrow transplantation. Cancer 1991, 68, 1842–1844. [Google Scholar] [CrossRef]
- Schønheyder, H.; Hoffmann, S.; Jensen, H.E.; Hansen, B.F.; Franzmann, M.-B. Aspergillus fumigatus fungaemia and myocarditis in a patient with acquired immunodeficiency syndrome. APMIS 1992, 100, 605–608. [Google Scholar] [CrossRef] [PubMed]
- Duthie, R.; Denning, D. Aspergillus Fungemia: Report of Two Cases and Review. Clin. Infect. Dis. 1995, 20, 598–605. [Google Scholar] [CrossRef] [Green Version]
- Girmenia, C.; Gastaldi, R.; Martino, P. Catheter-related cutaneous aspergillosis complicated by fungemia and fatal pulmonary infection in an HIV-positive patient with acute lymphocytic leukemia. Eur. J. Clin. Microbiol. Infect. Dis. 1995, 14, 524–526. [Google Scholar] [CrossRef] [PubMed]
- Casson, D.H.; Riordan, F.; Ladusens, E.J. Aspergillus endocarditis in chronic granulomatous disease. Acta Paediatr. 1996, 85, 758–759. [Google Scholar] [CrossRef] [PubMed]
- Marec-Berard, P.; Fuhrman, C.; Stamm, D.; Frappaz, D.; Brunat-Mentigny, M.; Couillioud, D.; Bouffet, E. Aspergillar Fungemia in an Infant with Hepatoblastoma. Clin. Infect. Dis. 1996, 23, 1326–1327. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Atra, A.; Soler, P.; Calvagna, V.; Meller, S.; Riley, U. Successful treatment of Aspergillus fungaemia in two children with acute lymphoblastic leukaemia. J. Infect. 1998, 36, 323–324. [Google Scholar] [CrossRef]
- Girmenia, C.; Nucci, M.; Martino, P. Clinical significance of Aspergillus fungaemia in patients with haematological malignancies and invasive aspergillosis. Br. J. Haematol. 2001, 114, 93–98. [Google Scholar] [CrossRef]
- Qin, C.; Zhou, L.; Hu, Z.; Zhang, S.; Yang, S.; Tao, Y.; Xie, C.; Ma, K.; Shang, K.; Wang, W.; et al. Dysregulation of Immune Response in Patients with Coronavirus 2019 (COVID-19) in Wuhan, China. Clin. Infect. Dis. 2020, 71, 762–768. [Google Scholar] [CrossRef]
Figure 1.
The numbers of Aspergillus species recovered from respiratory samples of intensive care unit patients at our center between January 2018 and March 2021.
Figure 1.
The numbers of Aspergillus species recovered from respiratory samples of intensive care unit patients at our center between January 2018 and March 2021.
Figure 2.
The numbers of COVID-19 patients in the intensive care units and the numbers of Aspergillus species recovered from respiratory samples of intensive care unit patients at our center between March 2020 and February 2021.
Figure 2.
The numbers of COVID-19 patients in the intensive care units and the numbers of Aspergillus species recovered from respiratory samples of intensive care unit patients at our center between March 2020 and February 2021.
Table 1.
2020 ECMM/ISHAM£ consensus criteria for COVID-19-associated pulmonary aspergillosis (CAPA).
Table 1.
2020 ECMM/ISHAM£ consensus criteria for COVID-19-associated pulmonary aspergillosis (CAPA).
| Host Factors | Clinical Factors | Mycological Evidence | |
|---|---|---|---|
| Proven | COVID-19 * needing intensive care and a temporal relationship | Pulmonary infiltrate, or cavitating infiltrate (not attributed to another cause) | One of the following:
|
| Probable | COVID-19 needing intensive care and a temporal relationship | Pulmonary infiltrate, or cavitating infiltrate (not attributed to another cause) | One of the following:
|
| Possible | COVID-19 needing intensive care and a temporal relationship | Pulmonary infiltrate, or cavitating infiltrate (not attributed to another cause) | One of the following:
|
£ European Confederation of Medical Mycology and the International Society for Human and Animal Mycology; * coronavirus disease 2019; ** polymerase chain reaction; Ɨ bronchoalveolar lavage; ¥ lateral flow assay.
Table 2.
Patient demographics and characteristics of COVID-19 * infection.
| Characteristics | n (%) |
|---|---|
| Total | 48 (100%) |
| Demographics | |
| Age in years median with IQR | 67 (17%) |
| Sex (Male) | 32 (66%) |
| Ethnicity (Hispanic) | 33 (68%) |
| Comorbidities | |
| Hypertension | 38 (79%) |
| Diabetes | 31 (64%) |
| Obesity | 22 (45%) |
| Coronary artery disease | 17 (35%) |
| Lung disease | 12 (25%) |
| Renal disease | 12 (25%) |
| Stroke/dementia | 11 (22%) |
| Liver disease | 6 (12%) |
| Cancer | 4 (8%) |
| Severity of COVID-19 * | |
| Mechanical ventilation | 48 (100%) |
| Pressor support | 42 (87%) |
| Extracorporeal membrane oxygenation | 1 (2%) |
| Renal replacement therapy | 17 (35%) |
| Treatment of COVID-19 * | |
| Remdesivir | 29 (60%) |
| Hydroxychloroquine | 2 (3%) |
| Steroids | 45 (93%) |
| Convalescent plasma | 13 (27%) |
| All-cause mortality (death during admission) | 40(83%) |
* Coronavirus disease 2019.
Table 3.
Characteristics of COVID-19-associated pulmonary aspergillosis (CAPA).
| Characteristics | n (%) |
|---|---|
| Type of respiratory culture | |
| Endotracheal aspirate | 39 (81%) |
| Bronchoalveolar lavage fluid | 9 (19%) |
| Type of Aspergillus species recovered | |
| Aspergillus fumigatus | 25 (52%) |
| Aspergillus niger | 6 (12%) |
| Aspergillus flavus | 2 (4%) |
| More than 1 species | 9 (18%) |
| Other Aspergillus species | 6 (12%) |
| Clinical features of aspergillus infection | |
| New or recrudescent fever despite appropriate antibiotics for 3 days | 25 (52%) |
| Worsening respiratory failure despite appropriate treatment | 37 (77%) |
| Imaging features | |
| Cavitation | 5 (10%) |
| Nodules | 5 (10%) |
| Other findings (consolidation, ground glass opacities) | 38 (79%) |
| Biomarkers | |
| Serum 1,3 Beta-D-Glucan | 13/21 (61%) |
| Serum Aspergillus galactomannan | 6/14 (42%) |
| Bronchoalveolar lavage fluid Aspergillus galactomannan | 0/3 (0%) |
| Anti-fungal therapy given | 21 (44%) |
| Type of anti-fungal used | |
| Voriconazole | 14/21 (66%) |
| More than 1 antifungal | 6/21 (28%) |
| Echinocandin | 2/21 (9%) |
| Posaconazole | 1/21 (4%) |
| Response to antifungal treatment | |
| Defervescence within 72 h | 10/21 (47%) |
| Improvement in oxygen support in 96 h | 4/21 (19%) |
Table 4.
Characteristics of patients with proven COVID-19-associated pulmonary aspergillosis (CAPA).
Table 4.
Characteristics of patients with proven COVID-19-associated pulmonary aspergillosis (CAPA).
| Patient 2 | Patient 44 | |
|---|---|---|
| Age | 49 | 82 |
| Ethnicity | Hispanic | Hispanic |
| Medical conditions | Obesity, hypertension, diabetes mellitus | Hypertension, coronary artery disease, prostate cancer in remission, diabetes mellitus |
| EORTC/MSG * risk factors | None | None |
| Severity of COVID-19 ** | Severe ARDS, mechanical ventilation | Severe ARDS, mechanical ventilation |
| Steroid therapy | Dexamethasone 10 days | Dexamethasone 10 days |
| Duration between COVID-19 and CAPA *** | 30 days | 12 days |
| Clinical features | Worsening fever, hypoxia | Worsening fever, septic shock and multi organ failure |
| Source of CAPA diagnosis | Biopsy of bronchoalveolar tissue, Bronchoalveolar cultures | Blood cultures, endotracheal aspirate cultures |
| Bacterial co-infection at the time CAPA | None | None |
| Imaging finding | Bilateral consolidations with cavitation | Bilateral ground glass opacities |
| BAL Aspergillus galactomannan | Not tested | Not tested |
| Serum Aspergillus galactomannan | Not tested | Not tested |
| 1,3, Beta D glucan | Not tested | Not tested |
| Aspergillus species | A. fumigatus and A. niger | A. fumigatus |
| Anti-fungal therapy | Voriconazole, posaconazole, caspofungin | None |
| Anti-fungal resistance | Possible | Not tested |
| Outcome | Died | Died |
* European Organization for Research and Treatment of Cancer/Mycoses Study Group; ** coronavirus disease 2019; *** COVID-19-associated pulmonary aspergillosis.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
MDPI and ACS Style
Sivasubramanian, G.; Ghanem, H.; Maison-Fomotar, M.; Jain, R.; Libke, R. COVID-19-Associated Pulmonary Aspergillosis: A Single-Center Experience in Central Valley, California, January 2020–March 2021. J. Fungi 2021, 7, 948. https://doi.org/10.3390/jof7110948
AMA Style
Sivasubramanian G, Ghanem H, Maison-Fomotar M, Jain R, Libke R. COVID-19-Associated Pulmonary Aspergillosis: A Single-Center Experience in Central Valley, California, January 2020–March 2021. Journal of Fungi. 2021; 7(11):948. https://doi.org/10.3390/jof7110948
Chicago/Turabian StyleSivasubramanian, Geetha, Hebah Ghanem, Michele Maison-Fomotar, Ratnali Jain, and Robert Libke. 2021. "COVID-19-Associated Pulmonary Aspergillosis: A Single-Center Experience in Central Valley, California, January 2020–March 2021" Journal of Fungi 7, no. 11: 948. https://doi.org/10.3390/jof7110948
Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.
