Fungal Infections in Critically Ill COVID-19 Patients: Inevitabile Malum
Abstract
:1. Introduction
2. Pathophysiology and Risk Factors
2.1. Host Factors
2.2. Healthcare Associated Factors
3. Prevalence of Invasive Fungal Infections in Critically Ill COVID-19 Patients
3.1. Candidiasis
3.2. Aspergillosis
3.3. Mucormycosis
3.4. Pneumocystis
Literature | Trial Design/Population | Type of IFI | Incidence |
---|---|---|---|
Fekkar A. et al. [24] | R, SC, n = 145 COVID-19 ICU MV pts screened for fungal superinfection; 54% on ECMO | prob/putat IFI (1 Fusarium case) | 4.8% |
Chong W.H. et al. [25] | Literature review; 28 O studies, 21 cr/s | Secondary FI | 6.4% |
Chen N. et al. [26] | R, SC, 99 hospital pts | Secondary FI | 5% |
Yang X. et al. [27] | R, SC, O, 52 ICU pts | 5.8% | |
Musuuza J.S. et al. [28] | MA of 118 studies | Fungal co- and superinfections | 4% and 8%, respect |
Bardi T. et al. [29] | R, SC, 140 ICU pts | FI | 15% |
White et al. [30] | MC, P, 137 ICU pts screened for IFI | IFI | 26.7% |
Peng J. et al. [31] | SRMA of 9 studies | IFI | 0.12 (opp) |
Bishburg E. et al. [34] | SC, R, 89 COVID-19 ICU pts | CAC | 8.9% |
Nucci M. et al. [35] | SC | CAC | ×5 comp to prepandemic |
Seagle E.E. et al. [36] | Surveillance data | candidemia | Among 251 candidemia pts, 25.5% were SARS-CoV-2 |
Gouzien L. et al. [42] | R, O, COVID-19 ICU pts | CAPA | 1.5% |
Hoenigl M. et al. [43] | Review of 80 CAM cases | CAM | 0.3–0.8% prevalence in COVID-19 ICU pts |
Meawed T.E. et al. [46] | Cross-sectional study of 197 critically-ill MV COVID-19 pts | Fungal VAP | 16.4% Aspergillus 8.2% mucor |
Selarka L. et al. [47] | P, O, MC | CAM | 1.8% |
Alanio et al. [50] | O, 108 critically-ill COVID-19 pts | PJP | 9.3% |
Blaize et al. [51] | PCR assays on severe COVID-19 pts | PJP | 1.4% |
4. Immunosuppressive Therapy as Risk Factor for Fungal Infections in Critically Ill COVID-19 Patients
4.1. Glucocorticosteroids
4.2. Tocilizumab
5. Mortality and Fungal Infections in Critically Ill COVID-19 Patients
6. Conclusions
Author Contributions
Funding
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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CAPA/Invasive Aspergillus Tracheobronchitis |
---|
1. High/long dose of corticosteroids; |
2. Underlying structural lung disease; |
3. Host factors, such as neutropenia, allogeneic stem cell transplant, immunosuppression, inherited severe immunodeficiency; |
4. Intubation and mechanical ventilation; |
5. Cancer/chemotherapy; |
6. Azithromycin (PMID: 33316401)/broad spectrum antibiotics; |
7. Severe lung damage due to COVID-19. |
CAC |
1. Prolonged hospital stay; |
2. Mechanical ventilation; |
3. Central venous catheters; |
4. Surgical procedures; |
5. Broad-spectrum antibiotics. |
MAC |
1. Diabetes, diabetic ketoacidosis |
Literature | Trial Design and Population | Diagnostic Criteria Used | CS Used | CS Length | Other IST | Comorbidities | IA Incidence | Time to IA Dx | Mortality |
---|---|---|---|---|---|---|---|---|---|
Alanio A. et al. [87] France | P, O, n = 27 ICU pts, 9/27 CAPA, med age 63 [IQR 56–71] | EORTC-MSGERC or IAPA + ser β-D-glucan and qPCR (serum or pulm specimens) | 6/9 pts: dexa IV 20 mg/d (D1–5) then 10 mg/d (D6–10). 2/9 pts on prev GCS | 10 ds | NM | HPN more frequent in IPA (7/9 vs. 6/18, p = 0·046) | Probable IPAs: (4%) putative IPAs: 30% | NM | 4/9 |
van Arkel A.E. et al. [88] Netherlands | O, n = 31 ICU pts on MV | A. fumigatus 5/6, A. Ag GM (+) BAL fluid: 3/6 | 3/6 pts: CS before IPA Dx, dose < 0.3 mg/kg/d | <3 wks | No | 3/6 Pre-existing lung disease | 6/31 (19.35%) presumed IPA | Sx onset—IPA: med 11.5 ds (8–42). ICU admis–IPA: med 5 ds (3–28) | 66.7% died, med 12 ICU ds (11–20) |
Bartoletti et al. [89] Italy | P, MC, n = 822 | CAPA | MP 1 mg/kg | 5–7 ds | TOCI | 27.7% | Intub-CAPA: med 4ds (2–8). sx onset-CAPA: med 14ds (11–22) | ↑↑ ICU mortality after adj for age, RRT, admis severity scores | |
Benedetti et al. [90] Argentina | n = 5 ICU pts | IAPA or EORTC-MSGERC serum markers, or AspICU | 5/5 CS (<0.3 mg/kg) | <3wks | No | 1/5 hematologic malignancy 2/5 diabetes | Sx onset–CAPA: 22 ds (13–52). ICU admis-CAPA: med 12 ds | 1/5 died (rest still on MV) | |
Delliere et al. [92] France | R, O, MC, n = 360 ICU pts; 108 pts sampled on deterioration. 1 SOT. 1 myeloma | EORTC/MSGERC CAPA | NM | NM | Sarilumab 1 pt, eculizumab 6 pts, toci 4 pts | Azithromycin (>3 ds) and prob IPA (OR 3.1, 95% CI, 1.1–8.5, p = 0.02). HD dexa and IPA: 11.5% vs. 28.6%, (p = 0.08), cumul dose ≥100 mg and IPA (OR 3.7, 95% CI 1.0–9.7). | 5.7% in ICU pts 8.5% in MV pts 19.4% in deteriorated pts | Sx onset- IPA: 16 ds (10–23) ICU admis—IPA: 6 ds (1–15) | IPA pts vs. non-IPA: 71.4% vs. 36.8%, p < 0.01). |
Dupont et al. [91] France | R, 153 ICU pts screened for fungi; 106 PCR SARS-Co-V2 (+) | AspICU + serum/BAL GM | 37% CS | short time | NM | HTN 36.8%, DM 36.8%, TB/COPD/asthma 36.8% | 17.9% putative IPA | MV-CAPA: 6 ds | 42% |
Fekkar A. et al. [24] France | R, SC, n = 145 COVID-19 ICU MV pts screened for fungal superinfection; 54% on ECMO | EORTC/MSGERC, Mycology lab (microscopy, cultures, PCR respir samples and serum for Aspergillus, PJP, mucorales, GMI, β-D-glucan | Long-term (>3 wks) CS before COVID-19 and IFI (OR, 8.55; IQR, 6.8–10.3; p = 0.01), CS for COVID-19 (dexa 20 mg/d × 10 ds) no IFI | 10 ds | 6 Toci 3 saril 1 anti-IL1 | 100% MV, 68% ↑BW, 57% HTN, 32% DM, 14% preexisting immunosuppression | 4.8% prob/ putat IFI (1 fusarium case), 17.2% colonization | ICU admis-IFI: med 7 ds (IQR, 2–56) | Survival 74.5% |
Fortarezza et al. [94] Italy | n = 45 COVID-19 autopsies | Histology | CS: 88% of CAPA vs. 54% non-CAPA CS: 12/28 pts 1st wave vs. 16/17 pts 2nd wave | NM | No Toci No antiIL-1 | 7/9 ICU 7/9 HTN 3/9 COPD | 20% proven CAPA, 1st wave 2/28 vs. 2nd wave 7/17 | NM | NA |
Janssen et al. [102] Belgium, Netherlands, France | O, MC, 2 ICU cohorts: N1 = 512 N2 = 304 | ECCM/ISHAM | CS use not more prevalent in CAPA groups vs. non-CAPA | NM | Other IST < 90 ds before ICU admis | CAPA vs. nonCAPA: COPD 19% vs. 8% (p = 0.042). HIV (AIDS) 7% vs. 0.4% (p = 0.011) | 10–15% | ICU admis to CAPA: 6 ds (IQR 3–9) | 43–52% |
Lamoth et al. [109] Switzerland | n = 80 ICU MV pts | IAPA | NM | NA | Toci—IPA Dx: 4 ds | No pt had any predisposing factors acc to EORTC/MSG | 3.8% 1 probable 2 putative | COVID dx- IPA: med 9 ds, ICU admis-IPA: 6 ds, MV start-IPA: med 5 ds | 1/3 died |
Marr et al. [20] Spain, USA | R, MC n = 20 CAPA | Aspergillus recovery in BAS, sputum, BAL or GMI ≥ 1, imaging | NM Systemic and inh CS most common IST associated with CAPA | NM | NM | Age HTN Pulm dis underlying immunosuppressive disease/drugs | NA | Sx onset-CAPA: med 11 ds, ICU admis-CAPA: 9 ds | NM |
Meijer et al. [93] Netherlands | SC, P, 1st wave: 33 MV ICU pts vs. 2nd wave: 33 MV ICU pts | 2020 ECMM/ISHAM | All CAPA pts in 2nd wave on CS: Dexa 6 mg | 10 ds | no | CVD 4/13 DM 3/13 HTN 2/13 COPD 1/13 ARF 1/13 | 1st vs. 2nd wave poss and prob CAPA: 15.2% vs. 25% (p = 0.36) In total: 19.7% | NM | 40–50% mortality in both groups |
Obata R. et al. [95] USA | R, 226 COVID-19 hosp pts, 57 on CS vs. 169 no-CS | NM | Dexa (48/57), P (6/57), MP (1/57), MP + P 1/57, HC 1/57 | Max 10ds | 20/57 Toci | NM | CAPA in CS vs. no-CS: 5.3% vs. 0.6% CAPA in toci vs. no-toci: 5% vs. 5.4% | NM | NM |
Prattes et al. [111] Europe, USA | MC, P, MN 592 COVID-19 ICU pts | 2020 ECMM/ISHAM | Majority on GCS | NM | Toci | Age MV Toci | Proven: 1.9%, Prob 13.5% poss: 3% No-CAPA: 81.6% | ICU admis-CAPA: 8 ds (0–31) | Survival in CAPA pts vs. non-CAPA: 29% vs. 57% |
Rutsaert et al. [99] Belgium | n = 20 MV pts med 66 yo (56–77) | AspICU | 1/7 CS (pemphigus) | NM | NM | 4/7 DL 2/7 obesity 3/7 DM 3/7 HTN | 7/20 (35%) proven IPA | Sx onset—IPA: 11–23 ds | 4/7 died |
Van Biesen et al. [100] Netherlands | 42 MV ICU pts (9 IPA vs. 33 non-IPA) | AspICU + GMI ≥ 1 | No CS | NA | NM | 1/9 SOT COPD and asthma more common in IPA group | 9/42 | NM | 22% IPA vs. 15.1% non-IPA (p = 0.6) |
White et al. [30] UK | MC, P n = 137 ICU pts screened for IFI | AspICU, IAPA, CAPA | 12/25 different CS | N/M | no | 12/25 CRD 8/25 HTN 6/25 DM 6/25 obesity 5/25 CA | 14.1% CAPA | ICU admiss- (+) Aspergillus tests: 8 ds (0–35) | CAPA mortality 57.9% depending on appropriate Tx |
Literature | Trial Design | CS Used | CS Length | Other IST | Comorbidities/ Risk Factors | Candida Infection Incidence | Time to CAC Dx | Mortality |
---|---|---|---|---|---|---|---|---|
Antinori et al. [112] Italy | n = 43 severe COVID-19 pts; 3/43 candidemia | NM | NM | Toci | TPN (3/3), antibiotics (2/3), toci (3/3) | 6.9% BSI | Toci last dose—CAC: med 13 ds | Still hospitalized on publication |
Chowdhary et al. [97] India | n = 596 COVID-19 ICU pts, 420 MV, 15 Candida BSI | NM | NM | NM | ↑ ICU LOS, HTN, DM, CKD, CS (10/15) | 2.5% BSI | Admis-CAC: 10–12 ds | 53% (60% for C. auris) |
Ho et al. [98] USA | R, O, n = 4313 hospitalised, 574 (13.3%) received CS | MP > P > dexa | 6.34–9.53 ds | Toci | HTN 35.4% DM23.4% CKD 13% | BSI | NM | |
Obata et al. [95] USA | R, 226 COVID-19 hosp pts, 57 on CS vs. 169 no-CS | See Table 1 | Max 10ds | 20/57 Toci | NM | CAC in CS vs. no-CS: 7% vs. 0% CAC in toci vs. no-toci: 15% vs. 2.7% | NM | NM |
Riche et al. [96] Brazil | R, candidemia incidence between COVID and non-COVID inpatients | MP > dexa > P | 2–13 ds | No | HD CS CVC 90.9% ICU pts (72.7%) | ×10 increase in candidemia | ICU admis-CAC: 0–22 ds | 72.7% following CS use |
Seagle et al. [36] USA | Candidemia in COVID-19 and non-COVID-19 pts, surveillance data | NM | NM | Toci more likely among pts with COVID-19 compared to non-COVID-19 pts | Candidemia RF in non-COVID pts: LD, malignancy, prior surgeries CAC each >1.3 times more common: ICU, MV, CVC, CS, IST. Common RF in COVID-19 pts: DM, obesity. | CS within 30 ds of CAC: ×2 vs. non-COVID-19 pts | SARS-CoV-2 (+) test-Candida culture: med 15 ds ([IQR]: 8–21 days) | CAC: ×2 mortality (62.5%) vs. candidemia in non-COVID-19 pts (32.1%) |
Segrelles-Calvo [114] et al. Spain | O, P, n = 218 ICU pts | MP | 1–10 ds | Toci-CAC: RR 1.378, p = 0.05. Toci + MP/dexa (p = 0.01) | Malignancies more common in COVID-19 with candida co-infection. ICU, TPN, CVC, ↑LO ICU stay | 14.4% (+) Candida tests |
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Rovina, N.; Koukaki, E.; Romanou, V.; Ampelioti, S.; Loverdos, K.; Chantziara, V.; Koutsoukou, A.; Dimopoulos, G. Fungal Infections in Critically Ill COVID-19 Patients: Inevitabile Malum. J. Clin. Med. 2022, 11, 2017. https://doi.org/10.3390/jcm11072017
Rovina N, Koukaki E, Romanou V, Ampelioti S, Loverdos K, Chantziara V, Koutsoukou A, Dimopoulos G. Fungal Infections in Critically Ill COVID-19 Patients: Inevitabile Malum. Journal of Clinical Medicine. 2022; 11(7):2017. https://doi.org/10.3390/jcm11072017
Chicago/Turabian StyleRovina, Nikoletta, Evangelia Koukaki, Vasiliki Romanou, Sevasti Ampelioti, Konstantinos Loverdos, Vasiliki Chantziara, Antonia Koutsoukou, and George Dimopoulos. 2022. "Fungal Infections in Critically Ill COVID-19 Patients: Inevitabile Malum" Journal of Clinical Medicine 11, no. 7: 2017. https://doi.org/10.3390/jcm11072017