Advertisement

A retrospective multicenter analysis of candidaemia among COVID-19 patients during the first UK pandemic wave

Published:February 17, 2021DOI:https://doi.org/10.1016/j.jinf.2021.02.020

      Keywords

      Dear editor

      It is with great interest that we read the recent article by De Francesco et al.
      • De Francesco M.A.
      • Poiesi C.
      • Gargiulo F.
      • Bonfanti C.
      • Pollara P.
      • Fiorentini S.
      • Caccuri F.
      • Carta V.
      • Mangeri L.
      • Pellizzeri S.
      • Rizzoni D.
      Co-infection of Chlamydia pneumoniae and Mycoplasma pneumoniae with SARS-CoV-2 is associated with more severe features.
      , who reported on chlamydia pneumoniae and mycoplasma pneumoniae co-infection in patients with COVID-19. Here, we report our experience with candidaemia co-infection with COVID-19. An increased incidence of candidaemia has been noted in patients with COVID-19 and although patient characteristics, investigations and antifungal therapies have been described,
      • Mastrangelo A.
      • Germinario B.N.
      • Ferrante M.
      • Frangi C.
      • Voti R.L.
      • Muccini C.
      • Ripa M.
      COVID-BioB Study Group. Candidemia in COVID-19 patients: incidence and characteristics in a prospective cohort compared to historical non-COVID-19 controls.
      to our knowledge, compliance with candidaemia management bundles has not.
      • Cornely O.A.
      • Bassetti M.
      • Calandra T.
      • Garbino J.
      • Kullberg B.J.
      • Lortholary O.
      • Meersseman W.
      • Akova M.
      • Arendrup M.C.
      • Arikan-Akdagli S.
      • Bille J
      ESCMID* guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients.
      Here, we present a retrospective review of candidaemias in adult patients (>17 years) with PCR proven COVID-19 between 1st March 2020–31st May 2020 across six acute London hospitals. All yeasts isolated from blood cultures were identified by matrix assisted laser desorption/ionisation-time-of-flight (MALDI-TOF) mass spectroscopy (Bruker Daltonik GmbH, Bremen, Germany). Antifungal susceptibility testing was carried out using broth micro-dilution in accordance with EUCAST guidelines.

      EUCAST – antifungal MIC method for yeast 2020 [Available from: https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/AFST/Files/EUCAST_E_Def_7.3.2_Yeast_testing_definitive_revised_ 2020.pdf

      An episode of candidaemia was defined as blood culture growth of any Candida species.
      Eleven patients with concurrent candidaemia and PCR-proven COVID-19 were identified during the study period; ten were male (90.9%), mean age 62 (33–77 years). Underlying comorbidities were predominantly cardiovascular (10/11). Two patients were immunosuppressed (see Table 1), but neutropenia was not identified.
      Table 1Characteristics of patients with concurrent COVID-19 and candidaemia.
      DemographicsN=11
      Age, years62 (33-77)
      Sex, male10 (90.9%)
      Past medical history
      Type 2 diabetes8 (72.7 %)
      Hypercholesterolaemia8 (72.7%)
      Hypertension3 (27.3%)
      Ischaemic Heart Disease1 (9.1%)
      Permanent Pacemaker1 (9.1%)
      Myaesthenia Gravis1 (9.1%)
      Previous solid organ malignancy2 (18.2%)
      Gastro-oesophageal Reflux Disease1 (9.1%)
      Benign prostatic hypertrophy1 (9.1%)
      Hypopituitarism1 (9.1%)
      Risk factors for candidaemia
      Immunosuppression2 (18.2%)
      One patient received 9mg prednisolone once daily plus 500mg mycophenolate mofetil twice daily for myasthenia gravis A second patient received hydrocortisone 10mg/5mg/5mg for hypopituitarism.
      Broad spectrum antimicrobials11 (100%)
      Neutropenic0 (0%)
      Intensive care (ICU) admission10 (90.9%)
      Intravenous catheter10 (90.9%)
      •Average catheter day6.3 (3-9)
      •Number of patients where catheter day unknown4 (40%)
      Ventilated10 (90.9%)
      Inotropic support10 (90.9%)
      Haemofiltration9 (81.8)
      Urinary catheter11 (100%)
      Total parenteral nutrition0 (0%)
      Candida colonisation
      •Yes4
      •No5
      •Unknown2
      Clinical course
      Days to candidaemia since COVID-19 diagnosis14.8 (7-24)
      Days to candidaemia since ICU admission15.5 (6-24)
      Repeat blood cultures taken at 48 hours6 (54.5%)
      Days to candidaemia clearance2.3 (1-3)
      Non-albicans candidaemia4 (36.4%)
      Beta-D-glucan performed6 (54.5%)
      •positive3 (50%)
      Positive results included values of 256 pg/ml, 154 pg/ml and 110 pg/ml
      •negative3 (50%)
      Galactomannan performed5 (45.5%)
      •positive0 (0%)
      •negative5 (100%)
      Intravascular catheter removed9 (90%)
      •culture confirmation of same Candida spp.1 (10%)
      Echocardiogram performed8 (72.7%)
      •positive0 (0%)
      •negative8 (100%)
      Fundoscopy peformed1 (9.1%)
      •positive0 (0%)
      •negative1 (100%)
      Death at 30 days6 (54.5%)
      Values are reported as mean and range or frequency (%)
      a One patient received 9mg prednisolone once daily plus 500mg mycophenolate mofetil twice daily for myasthenia gravis A second patient received hydrocortisone 10mg/5mg/5mg for hypopituitarism.
      b Positive results included values of 256 pg/ml, 154 pg/ml and 110 pg/ml
      Ten patients (90.9%) were admitted to an intensive care unit (ICU) prior to their candidaemia diagnosis. Of the ICU patients (n = 10), all were intubated and ventilated, had an intravascular and urinary catheter and received inotropes. The non-ICU patient also had a urinary catheter. Nine (90%) of the ICU patients received haemofiltration. None of the patients in our cohort received total parenteral nutrition.
      All eleven patients received broad-spectrum antibacterials. One patient received prior antifungal treatment in hospital with topical clotrimazole and oral terbinafine for a tinea infection.
      The average number of days from PCR-proven COVID-19 to candidaemia was 14.8 days and from ICU admission to candidaemia, 15.5 days (range 6–24 days). Seven out of eleven candidaemias (63.6%) were C.albicans, two (18.2%) C.parapsilosis, one (9.1%) C. glabrata and one (9.1%) C.dubliniensis. All isolates were fluconazole susceptible, except one (Candida glabrata), which showed intermediate susceptibility, although the patient was successfully treated with azole therapy through dose-optimisation.
      An echinocandin was commenced for ten patients, as per local guidelines, pending susceptibility testing. One patient died prior to blood culture positivity and treatment. Four out of ten (40%) patients were switched to fluconazole to complete treatment. In line with recommended practice
      • Cornely O.A.
      • Bassetti M.
      • Calandra T.
      • Garbino J.
      • Kullberg B.J.
      • Lortholary O.
      • Meersseman W.
      • Akova M.
      • Arendrup M.C.
      • Arikan-Akdagli S.
      • Bille J
      ESCMID* guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients.
      six out of eleven patients (54.5%) had repeat blood cultures within 48 h of treatment, eight (72.7%) patients had an echocardiogram, but only one (9.1%) had fundoscopy. Serum (1-3)-β-D-glucan(BDG) testing was performed in 54.4% (6/11) of patients; three were positive(see Table 1).
      Intravascular catheters were removed for nine out of ten patients (90%), the last patient dying prior to candidaemia notification. Seven out of nine patients had line tips sent for culture; two were positive for yeasts. One line tip confirmed an identical Candida spp., and hence constituted a line infection, but no further identification was available for the second.
      Four patients had prior colonization with yeasts; one with the same species as their candidaemia, no further identification was available for the remaining three. Five patients were not colonized and two had an unknown status following transfer from other secondary care providers, developing candidaemia shortly after transfer.
      In concordance with Mastrangelo et al.,
      • De Francesco M.A.
      • Poiesi C.
      • Gargiulo F.
      • Bonfanti C.
      • Pollara P.
      • Fiorentini S.
      • Caccuri F.
      • Carta V.
      • Mangeri L.
      • Pellizzeri S.
      • Rizzoni D.
      Co-infection of Chlamydia pneumoniae and Mycoplasma pneumoniae with SARS-CoV-2 is associated with more severe features.
      there was a high 30-day mortality of 54.4% (6/11) in our patient cohort. The four surviving patients (36.6%) were discharged; average total length of stay 58 days (range 31–78 days). One patient was stepped down after nine weeks in ICU but remained an inpatient until the end of our study period.
      Given the high mortality rate, it is important to identify and address modifiable risk factors in an attempt to prevent the occurrence of candidaemia. Firstly, all our patients received broad-spectrum antibacterials, a recognized risk factor for candidaemia.
      • Barberino M.G.
      • Silva N.
      • Rebouças C.
      • Barreiro K.
      • Alcântara A.P.
      • Netto E.M.
      • Albuquerque L.
      • Brites C.
      Evaluation of blood stream infections by Candida in three tertiary hospitals in Salvador, Brazil: a case-control study.
      ,
      • Yapar N.
      • Pullukcu H.
      • Avkan-Oguz V.
      • Sayin-Kutlu S.
      • Ertugrul B.
      • Sacar S.
      • Cetin B.
      • Kaya O.
      Evaluation of species distribution and risk factors of candidemia: a multicenter case-control study.
      A recent study from Hughes et al.
      • Hughes S.
      • Troise O.
      • Donaldson H.
      • Mughal N.
      • Moore L.S.
      Bacterial and fungal coinfection among hospitalized patients with COVID-19: a retrospective cohort study in a UK secondary-care setting.
      demonstrated a low frequency (3.2%) of early bacterial co-infection in patients hospitalized with COVID-19, suggesting early broad-spectrum antibacterials may not be warranted. Hence, antimicrobial stewardship initiatives to review unnecessary antibacterial use remain important.
      Secondly, intravascular catheters are a well-recognised risk factor for candidaemia
      • Barberino M.G.
      • Silva N.
      • Rebouças C.
      • Barreiro K.
      • Alcântara A.P.
      • Netto E.M.
      • Albuquerque L.
      • Brites C.
      Evaluation of blood stream infections by Candida in three tertiary hospitals in Salvador, Brazil: a case-control study.
      and over 90% of our patients had these. The incidence of candidaemia observed warrants further consideration, and whilst not compared to pre-COVID-19 incidence,
      • Mastrangelo A.
      • Germinario B.N.
      • Ferrante M.
      • Frangi C.
      • Voti R.L.
      • Muccini C.
      • Ripa M.
      COVID-BioB Study Group. Candidemia in COVID-19 patients: incidence and characteristics in a prospective cohort compared to historical non-COVID-19 controls.
      may potentially reflect pandemic unique challenges. Examples include increased ICU capacity, redeployment of less-experienced staff to ICU, challenges to aseptic technique with personal protective equipment (PPE), and patients requiring re-positioning to improve oxygenation, thus increasing possibility of line displacement/contamination. Improved aseptic intravascular catheter training focusing on PPE may be beneficial.
      In addition, although we were unable to identify urinary catheters as a source in our cohort, they are a recognized risk factor for candidaemia
      • Yapar N.
      • Pullukcu H.
      • Avkan-Oguz V.
      • Sayin-Kutlu S.
      • Ertugrul B.
      • Sacar S.
      • Cetin B.
      • Kaya O.
      Evaluation of species distribution and risk factors of candidemia: a multicenter case-control study.
      and all patients in our cohort had these.
      One patient died prior to candidaemia notification. Time to blood culture positivity may be delayed, particularly for non-albicans candidaemias,
      • Fernandez J.
      • Erstad B.L.
      • Petty W.
      • Nix D.E.
      Time to positive culture and identification for Candida blood stream infections.
      and delay in treatment is known to increase mortality,
      • Morrell M.
      • Fraser V.J.
      • Kollef M.H.
      Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality.
      therefore, non-culture-based diagnostics such as galactomannan antigen and BDG should be combine with clinical data to aid diagnosis.
      • Del Bono V.
      • Delfino E.
      • Furfaro E.
      • Mikulska M.
      • Nicco E.
      • Bruzzi P.
      • Mularoni A.
      • Bassetti M.
      • Viscoli C.
      Clinical performance of the (1, 3)-β-D-glucan assay in early diagnosis of nosocomial Candida bloodstream infections.
      54.4% (n = 6) of the patients were tested for BDG, and of those, 50% (n = 3) were positive. Although not possible to demonstrate in this patient cohort, an early positive BDG may herald invasive fungal infection, enabling timely initiation of empirical antifungal therapy.
      Guidelines for management of candidaemia recommend a care bundle, including repeat blood cultures at 48 h, echocardiogram, and fundoscopy to identify disseminated infection. In our cohort, only 54.5% (6/11) of patients had repeat blood cultures within 48 h, 72.7% (8/11) an echocardiogram and only 9.1% (1/11) fundoscopy. COVID-19 infection control concerns, patient positioning and PPE, with resultant challenges to ophthalmic examination, may account for the poor fundoscopy compliance, adding further weight to the need for COVID-19 specific practical training.
      To conclude, during the ongoing COVID-19 pandemic it remains important to consider modifiable risk factors for candidaemia, non-culture based diagnositics to aid early diagnosis, as well as adherence to established treatment bundles.

      Ethics

      Ethical approval was not required for this service evaluation and audit of practice.

      Authors’ contributions

      SD, AR and NM designed the study methodology. SD, TE and XG collated the data. SD drafted the initial manuscript with all authors contributing significantly to revising this for submission. All authors agreed on the final version for submission to the journal.

      Funding

      This research did not receive any grant from funding agencies in the public or commercial sectors.

      Declaration of Competing Interest

      EC has been paid for consultancy fees by bioMerieux.
      SH reports personal fees from Pfizer and Shionogi.
      DAJ holds share options in Pulmocide Ltd and has received research grants from Pulmocide Ltd, Gilead Sciences, Astellas and Pfizer. He has received speaker and consultancy fees from Astra-Zeneca, Pfizer, Gilead, and Astellas.
      LSPM has consulted for DNAelectronics (2015–18), Dairy Crest (2017–2018), Umovis Lab (2020), bioMerieux (2013–2020), received speaker fees from Profile Pharma (2018) and Pfizer (2018–2020), received research grants from the National Institute for Health Research (2013–2020), CW+ Charity (2018–2020), and Leo Pharma (2016), and received educational support from Eumedica (2016–2018).
      NM has received speaker fees from Beyer (2016) and Pfizer (2019) and received educational support from Eumedica (2016) and Baxter (2017).
      All other authors have no conflicts of interest to declare.

      Acknowledgements

      LSPM acknowledges support from the National Institute of Health Research (NIHR) Imperial Biomedical Research Centre (BRC) and the National Institute for Health Research Health Protection Research Unit (HPRU) in Healthcare Associated Infection and Antimicrobial Resistance at Imperial College London in partnership with Public Health England. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research, The Wellcome Trust or the UK Department of Health. DAJ is funded by the DHSC Centre for Antimicrobial Optimisation, at Imperial College, London. The views expressed in this publication are those of the author(s) and not necessarily those of the Department of Health and Social Care, NHS, or the National Institute for Health Research. DAJ is also funded by a Cystic Fibrosis Trust Strategic Research Centre (SRC015) and a Wellcome Trust Collaborative Award (219551/Z/19/Z).

      References

        • De Francesco M.A.
        • Poiesi C.
        • Gargiulo F.
        • Bonfanti C.
        • Pollara P.
        • Fiorentini S.
        • Caccuri F.
        • Carta V.
        • Mangeri L.
        • Pellizzeri S.
        • Rizzoni D.
        Co-infection of Chlamydia pneumoniae and Mycoplasma pneumoniae with SARS-CoV-2 is associated with more severe features.
        J Infect. 2021;
        • Mastrangelo A.
        • Germinario B.N.
        • Ferrante M.
        • Frangi C.
        • Voti R.L.
        • Muccini C.
        • Ripa M.
        COVID-BioB Study Group. Candidemia in COVID-19 patients: incidence and characteristics in a prospective cohort compared to historical non-COVID-19 controls.
        Clin Infect Dis. 2020; 30: ciaa1594
        • Cornely O.A.
        • Bassetti M.
        • Calandra T.
        • Garbino J.
        • Kullberg B.J.
        • Lortholary O.
        • Meersseman W.
        • Akova M.
        • Arendrup M.C.
        • Arikan-Akdagli S.
        • Bille J
        ESCMID* guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients.
        Clin Microbiol Infect. 2012; 18: 19-37
      1. EUCAST – antifungal MIC method for yeast 2020 [Available from: https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/AFST/Files/EUCAST_E_Def_7.3.2_Yeast_testing_definitive_revised_ 2020.pdf

        • Barberino M.G.
        • Silva N.
        • Rebouças C.
        • Barreiro K.
        • Alcântara A.P.
        • Netto E.M.
        • Albuquerque L.
        • Brites C.
        Evaluation of blood stream infections by Candida in three tertiary hospitals in Salvador, Brazil: a case-control study.
        Braz J Infect Dis. 2006; 10: 36-40
        • Yapar N.
        • Pullukcu H.
        • Avkan-Oguz V.
        • Sayin-Kutlu S.
        • Ertugrul B.
        • Sacar S.
        • Cetin B.
        • Kaya O.
        Evaluation of species distribution and risk factors of candidemia: a multicenter case-control study.
        Med Mycol. 2011; 49: 26-31
        • Hughes S.
        • Troise O.
        • Donaldson H.
        • Mughal N.
        • Moore L.S.
        Bacterial and fungal coinfection among hospitalized patients with COVID-19: a retrospective cohort study in a UK secondary-care setting.
        Clin Microbiol Infect. 2020; 26: 1395-1399
        • Fernandez J.
        • Erstad B.L.
        • Petty W.
        • Nix D.E.
        Time to positive culture and identification for Candida blood stream infections.
        Diagn Microbiol Infect Dis. 2009; 64: 402-407
        • Morrell M.
        • Fraser V.J.
        • Kollef M.H.
        Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality.
        Antimicrob Agents Chemother. 2005; 49: 3640-3645
        • Del Bono V.
        • Delfino E.
        • Furfaro E.
        • Mikulska M.
        • Nicco E.
        • Bruzzi P.
        • Mularoni A.
        • Bassetti M.
        • Viscoli C.
        Clinical performance of the (1, 3)-β-D-glucan assay in early diagnosis of nosocomial Candida bloodstream infections.
        Clin Vaccine Immunol. 2011; 18: 2113-2117