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European Journal of Applied Sciences – Vol. 12, No. 3
Publication Date: June 25, 2024
DOI:10.14738/aivp.123.17113.
Naidu, K., Richards, G. A., Cruickshank, D., Wadee, B., Naidu, J., & Kajee, N. (2024). The Incidence of Fungal Infections in Patients
Treated with Tocilizumab for Severe COVID-19 Pneumonia Requiring High Care or ICU Admission: A Retrospective Cohort Study.
European Journal of Applied Sciences, Vol - 12(3). 378-388.
Services for Science and Education – United Kingdom
The Incidence of Fungal Infections in Patients Treated with
Tocilizumab for Severe COVID-19 Pneumonia Requiring High
Care or ICU Admission: A Retrospective Cohort Study
Kuven Naidu
East Rand Physicians, 36 Park Street,
Benoni, Gauteng, South Africa, 1501
Guy A Richards
University of Witwatersrand, Faculty of Health Sciences,
Johannesburg, Private Bag 3, Wits, South Africa, 2050
Deborah Cruickshank
East Rand Physicians, 36 Park Street,
Benoni, Gauteng, South Africa, 1501
Bilaal Wadee
East Rand Physicians, 36 Park Street,
Benoni, Gauteng, South Africa, 1501
Jayseelan Naidu
East Rand Physicians, 36 Park Street,
Benoni, Gauteng, South Africa, 1501
Nabeela Kajee
East Rand Physicians, 36 Park Street,
Benoni, Gauteng, South Africa, 1501
ABSTRACT
Background: Critically ill COVID-19 patients often experience immune
dysregulation, leading to cytokine release syndrome and an increased
susceptibility to nosocomial infections, including invasive fungal infections. Early
detection and treatment of fungal infections is paramount due to associated high
mortality rates. Tocilizumab, an IL-6 receptor-blocking monoclonal antibody used
in treating COVID-19 patients, has shown efficacy in managing the cytokine storm
but is linked to a heightened risk of secondary fungal infections. Aims: This study
aimed to investigate the association between Tocilizumab use and fungal
infections in COVID-19 patients admitted to an ICU in South Africa. Methods: We
conducted a retrospective cohort study at a private hospital in Johannesburg,
South Africa, from April 2020 to August 2021. Data from 373 COVID-19 patients
admitted to high care or ICU were analysed. Patients were categorized based on
positive fungal cultures. Demographics, Tocilizumab usage, and relevant factors
were collected from electronic databases. Results: Fungal infections were
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Naidu, K., Richards, G. A., Cruickshank, D., Wadee, B., Naidu, J., & Kajee, N. (2024). The Incidence of Fungal Infections in Patients Treated with
Tocilizumab for Severe COVID-19 Pneumonia Requiring High Care or ICU Admission: A Retrospective Cohort Study. European Journal of Applied
Sciences, Vol - 12(3). 378-388.
URL: http://dx.doi.org/10.14738/aivp.123.17113
identified in 15.6% of the patients. Tocilizumab use did not significantly correlate
with fungal infections (OR: 0.342 [95%CI: 0.115-1.019]; P=0.054). Factors
associated with fungal infections included extended hospital stays (OR: 1.098
[95% CI: 1.038-1.163], P=0.050 and elevated D-dimer values (OR:1.20; [95% CI:
1.035-1.390]; P=0.015). Females were less likely to develop a fungal infection
(OR:0.224; [95% CI: 0.054-0.928], P=0.039). Conclusions: Tocilizumab
administration was not significantly linked to an increased risk of fungal
infections in COVID-19 patients in the ICU. This study underscores the
multifactorial nature of fungal infection risk, emphasizing the need for
comprehensive risk assessment.
Keywords: Fungal, Tocilizumab, Covid-19, D-Dimer
INTRODUCTION
The world has recently been in the midst of the worst public health crisis since the 1918
influenza pandemic with COVID -19 officially declared to be a pandemic on March 11th 2020,
by the World Health Organisation (WHO).
It has been previously reported that 5–30% of COVID-19 patients become critically ill and
require intensive care unit (ICU) admission [1] . Severe COVID-19 is associated with immune
dysregulation, affecting both T-helper cell 2 (Th2) and Th1 responses, including the cytokine
release syndrome, which contribute to lung pathology, promote pulmonary microbial
proliferation and a subsequently secondary infection. Critically ill COVID-19 patients have
higher pro-inflammatory (IL-1, IL-2, IL-6, tumor necrosis alpha) and anti-inflammatory (IL-4,
IL-10) cytokine levels and less CD4 interferon-gamma expression, and fewer CD4 and CD8
cells [2] all of which increase the potential for nosocomial infection, including invasive fungal
infections.
Fungal infections, which could be co- or superinfections, have been reported in severely ill
COVID-19 patients admitted to the ICU, with a preponderance of aspergillus and candida
infections[3].
Awareness of the possibility of fungal superinfection in COVID-19 patients is essential to
avoid delays in diagnosis and treatment as these are associated with high mortality [5].
Coşkun et al examined the electronic health records of 627 patients hospitalized in ICU with a
diagnosis of COVID-19 [4].
Opportunistic fungal infections were detected in 32 patients (5.10%) of whom 25 (78.12%)
died and seven (21.87%) were discharged alive from the ICU. Candida parapsilosis (43.7%)
was the opportunistic fungal agent isolated most frequently from blood samples and the
mortality rate with candidemia was 80% [4].
A review of fungal infections in the United States in 2020-2021 revealed that patients
hospitalised with COVID-19 associated fungal infections had a 48.5% mortality rate compared
to 12.3% in those patients who had fungal infections without a concurrent COVID-19 infection
[5].
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Tocilizumab is a monoclonal antibody that blocks the IL-6 receptor and is registered for the
treatment of rheumatoid arthritis. It has been shown to have a significant effect on the
infection- induced cytokine storm and has been used extensively in critically ill patients
during the COVID-19 pandemic [6]. The National Institute of Health (NIH) , quoting results of
the RECOVERY [7] and REMAP-CAP trials [8], has recommended the use of this agent along
with corticosteroids in severely ill patients that are rapidly deteriorating with increasing
oxygen requirements and who have a significant inflammatory response as it offers a modest
mortality benefit.
However, an association has been reported between the use of Tocilizumab in these
circumstance and a significant increase in the risk of developing secondary fungal infections,
which increase mortality, duration of mechanical ventilation and hospital length of stay [9].
This study looks at the incidence of fungal infections in patients who had received
Tocilizumab as part of their therapy. It is our hypothesis that the incidence will be higher in
those who received Tocilizumab compared to those who did not.
METHODS
Study Design
This was a retrospective cohort study evaluating the incidence of fungal infections in patients
admitted to high care or ICU and receiving treatment with Tocilizumab for severe COVID-19
pneumonia compared to those who did not receive Tocilizumab as part of their treatment.
All patients admitted to a High care or ICU with COVID-19 pneumonia at the Life Glynnwood
Hospital (a private hospital in Johannesburg, South Africa) between 01 April 2020 and 31
August 2021, were included in the study population. The hospital numbers of all these
patients were utilised to access patient information via the electronic database (ICNET and
Impilo) in use at the hospital. This database included treatments prescribed and
microbiological culture results for each patient.
The patients were categorised into two cohorts: those with evidence of a fungal infection and
those without. A positive fungal infection was defined as a positive fungal culture on blood,
sputum or urine.
Baseline data, including demographics, the use of tocilizumab, the presence of a positive
fungal culture and length of stay were captured onto an Excel spreadsheet for review. No
personal identifiers were used.
Statistical Analysis
To assess the risk factors that could have contributed to the development of fungal infections,
unadjusted and adjusted logistic regression analyses were performed to generate odds ratios.
Variables that had a P-value below 0.2 were included in the multivariable logistic regression
models to determine significant predictors of fungal infection. A goodness-of-fit test was used
to assess the suitability of the model for analysis of the data and the likelihood ratio test was
used to compare various adjusted models to determine the best model.
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Naidu, K., Richards, G. A., Cruickshank, D., Wadee, B., Naidu, J., & Kajee, N. (2024). The Incidence of Fungal Infections in Patients Treated with
Tocilizumab for Severe COVID-19 Pneumonia Requiring High Care or ICU Admission: A Retrospective Cohort Study. European Journal of Applied
Sciences, Vol - 12(3). 378-388.
URL: http://dx.doi.org/10.14738/aivp.123.17113
RESULTS
Table 1: Summary statistics of patient characteristics by fungal infection post
Tocilizumab treatment
Variable No (N=315, 84.4%) Yes (N=58, 15.6%) Total (N=373) P-value
Sex Male 195 (62.1) 41 (70.7) 236 (63.4) 0.212
Female 119 (37.90 17 (29.3) 136 (36.6)
Age (years) mean (SD) 58.3 (13.0) 59.4 (10.1) 58.5 (12.6) 0.547
Diabetes
Mellitus
No 266 (84.4) 44 (75.9) 310 (83.1) 0.109
Yes 49 (15.6) 14 (24.1) 63 (16.9)
Hypertension No 208 (66.0) 29 (50.0) 237 (63.5) 0.02
Yes 107 (34.0) 29 (50.0) 136 (36.5)
CRP (mg/L) median (IQR) 107.4 (62.0-171.9) 126.4 (54.0-176.6) 110.0 (60.9-173.0) 0.723
CRP Category 0 76 (24.1) 15 (25.9) 91 (24.4)
0.458
1 82 (26.0) 10 (17.2) 92 (24.7)
2 77 (24.5) 14 (24.1) 91 (24.4)
3 80 (25.4) 19 (32.8) 99 (26.5)
CRP levels 10 mg/L or less 17 (5.5) 3 (5.7) 20 (5.5) 0.958
>10 mg/L 293 (94.5) 50 (94.3) 343 (94.5)
PCT (ng/L) median (IQR) 0.23 (0.10-0.75) 0.22 (0.09-0.62) 0.23 (0.10-0.75) 0.767
D-dimer
(mg/L)
median (IQR) 1.31 (0.76-2.68) 3.59 (1.53-6.64) 1.51 (0.79-3.63) <0.001
LOS (days) median (IQR) 16 (11-22) 22 (15-37) 16 (11-23) <0.001
Length of
stay (days)
2-7 23 (7.4) 2 (3.4) 25 (7.8)
<0.001
8-14 112 (36.1) 11 (19.0) 123 (33.4)
15-28 142 (45.8) 25 (43.1) 167 (45.4)
29 or more 33 (10.7) 20 (34.5) 53 (14.4)
Bacterial
infection
No 228 (72.4) 18 (31.0) 246 (66.0) <0.001
Yes 87 (27.6) 40 (69.0) 127 (34.0)
Deaths No 200 (63.5) 20 (34.5) 220 (59.0) <0.001
Yes 115 (36.5) 38 (65.5) 153 (41.0)
Tocilizumab
administered
No 208 (67.1) 49 (84.5) 257 (69.8) 0.008
Yes 102 (32.9) 9 (15.5) 111 (30.2)
Steroid
treatment
No steroid 2 (0.6) 0 (0.0) 2 (0.5)
0.238
methylprednisolone 206 (65.4) 35 (60.3) 241 (64.6)
Dexamethasone 43 (13.7) 4 (6.9) 47 (12.6)
Hydrocortisone 26 (8.3) 9 (15.5) 35 (9.4)
other 2 (0.6) 0.0) 2 (0.5)
missing 36 (11.4) 10 (17.2) 46 (12.3)
Descriptive Analysis
A total of 373 patients were analysed, and their epidemiological characteristics are
summarised in Table 1. Most patients were male (63.4%) (236/373). The mean age was 58
years (SD: 12.6 years) and there was no significant difference between patients who
developed fungal infection and those who did not. (P>0.05)
Diabetes and hypertension were present in 16.9% and 36.5% of patients, respectively. There
was a significant difference in the proportion of patients with hypertension among individuals
without fungal infection and those with fungal infection (P=0.020). The median CRP and PCT
were not different between patients with and without fungal infection (P>0.05).
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Although most patients had high values of D-dimer, the median D-dimer was significantly
lower among patients without fungal infection, 1.31 mg/L (IQR: 0.76-2.68) compared to those
with fungal infection, 3.59 mg/L (IQR: 1.53-6.64) (P<0.001).
The median length of stay in hospital was significantly lower among patients without fungal
infection 16 days (IQR:11-22) compared to those with fungal infection, 22 days (IQR:15-37)
(P<0.001). Close to 60% of the patients were admitted in hospital for 2 weeks or more. The
proportion of patients who also had a bacterial infection was significantly higher among those
with fungal infections (69%) compared to those without (28%) (P<0.001). The mortality was
also significantly higher among those with a fungal infection (65.5%) compared to those
without (36.5%) (P<0.001). The majority of patients received corticosteroids consisting of
methyl-prednisolone (64.6%) and dexamethasone (12.6%). The overall incidence of fungal
infections was 15.6% (N=58). The proportion of patients who developed fungal infection was
significantly lower in the group that was administered Tocilizumab (8%) compared to those
that did not receive it (19%) (P=0.01).
Age, sex, Diabetes Mellitus, CRP, and PCT values were not significantly associated with the
development of fungal infection in the unadjusted regression models (P>0.100) (Table 2).
After adjusting for potential confounders (sex, age, hypertension, CRP, PCT, D-dimer, LOS,
bacterial infection, and steroid treatment), the development of fungal infection was
significantly and negatively associated with females (OR:0.224; [95% CI: 0.054-0.928],
P=0.039), higher D-dimer values (OR:1.20; [95% CI: 1.035-1.390]; P=0.015) and longer
hospital stay (OR: 1.098 [95% CI: 1.038-1.163], P=0.050). The use of dexamethasone was
associated with an 8 times lower risk of developing a fungal infection as compared to the use
of hydrocortisone. (P<0.05).
There was a trend for Tocilizumab to reduce the odds of developing a fungal infection (OR:
0.342 [95%CI: 0.115-1.019]; P=0.054 and whereas hypertension was significantly associated
with fungal infection in the unadjusted analysis (OR: 1.916, P=0.024) it was not significantly
associated to the outcome in the final adjusted model (OR:0.910; P>0.05). Mortality was not
considered in the final model as it is not a risk factor of fungal infection, but fungal infection
was itself significantly associated with mortality.
Table 2: Logistic regression of factors associated with fungal infections.
Unadjusted logistic regression Adjusted logistic regression (full model) Parsimonious Adjusted model
Variable UOR 95% Confidence
intervals
P- value
AOR 95% Confidence
intervals
P- value
AOR 95%
Confidenc
e intervals
P- value
Sex Male 1 reference 1 reference
Female 0.679 0.369-1.250 0.214 0.224 0.054-0.928 0.039 0.296 0.098-
.0.892
0.031
Age (years) 1.007 0.984-1.031 0.545 1.040 0.990-1.092 0.119
Diabetes Mellitus No 1 reference 1 reference
Yes 1.727 0.880-3.390 0.112 2.232 0.659-7.555 0.197
Hypertension No 1 reference 1 reference
Yes 1.944 1.105-3.420 0.021 0.485 0.142-1.652 0.247
CRP 1.001 0.998-1.004 0.381 1.002 0.997-1.008 0.439
PCT 0.997 0.983-1.012 0.717 0.986 0.955-1.018 0.391
D-dimer 1.177 1.070-1.294 0.001 1.200 1.035-1.390 0.015 1.209 1.069-
1.367
0.002
Length of stay (days) 1.065 1.039-1.091 <0.001 1.098 1.038-1.163 0.001 1.072 1.029-
1.117
0.001
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Naidu, K., Richards, G. A., Cruickshank, D., Wadee, B., Naidu, J., & Kajee, N. (2024). The Incidence of Fungal Infections in Patients Treated with
Tocilizumab for Severe COVID-19 Pneumonia Requiring High Care or ICU Admission: A Retrospective Cohort Study. European Journal of Applied
Sciences, Vol - 12(3). 378-388.
URL: http://dx.doi.org/10.14738/aivp.123.17113
Bacterial
infection
No 1 reference 1 reference
Yes 5.824 3.169-10.704 <0.001 1.361 0.486-3.809 0.557
Tmab
administered
No 1 reference 1 reference
Yes 0.375 0.177-0.792 0.01 0.405 0.100-1.644 0.206 0.342 0.115-
1.019
0.054
Steroid
treatment
No steroid empty empty empty
methylprednisolo
ne
1.826 0.617-5.407 0.277 13.739 1.155-163.375 0.038 3.626 0.687-
19.129
0.129
Dexamethasone 1 reference 1 reference 1 reference
Hydrocortisone 3.721 1.040-13.310 0.043 24.844 1.541-400.626 0.024 8.006 1.158-
55.377
0.035
Table 3 gives results of a regression analysis of factors associated with fungal infection (only
fungal cultures that were positive on blood samples). It should be noted that only one patient
received Tocilizumab among the 17 who had a blood culture positive fungal infection. In the
adjusted model, only the presence of bacterial infection is significantly associated with fungal
infection (blood culture only).
Table 3: Logistic regression of factors associated with fungal infections in blood only
cultures.
Unadjusted logistic regression Adjusted logistic regression (full model) Parsimonious Adjusted
model
Variable UOR 95% Confidence
intervals
P- value
AOR 95% Confidence
intervals
P- value
AOR 95%
Confidenc
e
intervals
P- valu
e
Sex 1 1 reference 1 reference
2 0.519 0.166-1.625 0.260 Empty
Age (years) 1.005 0.967-1.045 0.799 1.016 0.920-1.121 0.757
Diabetes Mellitus No 1 reference 1 reference
Yes 1.533 0.483-4.867 0.468 2.169 0.187-25.199 0.536
Hypertension No 1 reference 1 reference
Yes 3.344 1.208-9.258 0.020 0.732 0.082-6.523 0.780
CRP 1.001 0.996-1.006 0.678 1.007 0.994-1.020 0.300
PCT 0.806 0.422-1.539 0.513 0.611 0.170-2.192 0.449
D-dimer 1.141 0.997-1.305 0.055 1.225 0.857-1.750 0.266
Length of stay (days) 1.048 1.016-1.081 0.003 1.062 0.935-1.205 0.357 1.02
9
0.996-
1.063
0.08
7
Bacterial infection No 1 reference 1 reference 1 reference
Yes 6.903 2.202-21.642 0.001 2.133 0.269-16.918 0.473 5.18
3
1.557-
17.25
0.00
7
Tocilizumab
administered
No 1 reference 1 reference
Yes 0.139 0.018-1.065 0.058 Empt
y
Steroid treatment No steroid empt
y
Empt
y
methylprednisolo
ne
1.714 0.212-13.874 0.613 0.794 0.064-9.800 0.857
Dexamethasone 1 reference 1 reference
Hydrocortisone 5.677 0.605-53.276 0.128 Empt
y
Table 4 indicates the different fungal organisms which were identified. Patients may have had
more than one fungal organism cultured during their ICU admission.
Table 4: Fungal organisms cultured.
Fungal Pathogen Number
Candida Albicans 30
Candida Glabrata 3
Candida Auris 18
Candida Parapsilosis 3
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Candida Lusitaniae 1
Candida Tropicalis 2
Canidida Species 4
Aspergillus 4
ROC Analysis of D-Dimer Values in Relation with Fungal Infection Among Patients
Admitted with COVID-19
A Receiver Operating Characteristics (ROC) analysis was conducted on 245 patients in whom
D-Dimer values were available to determine if D-dimer values could identify the presence of a
fungal infection at different cut-off points as shown in the figure 1 below. The Area Under the
Curve (AUC) was 0.71 (95% CI: 0.62 – 0.79), suggesting reasonable diagnostic accuracy with a
subjective optimal cutoff point of 1.87 with a sensitivity of 0.72, specificity of 0.63, and an AUC
of 0.68. At this cut point, 72% of patients with fungal infection and 63% without fungal
infection could be correctly identified with a Positive Likelihood Ratio (LR+) of 1.96 and a
Negative Likelihood Ratio (LR-) of 0.44. (Note: These results should only be considered within
the context of clinical guidelines and other relevant factors when making decisions about the
diagnosis and management of fungal infections).
Figure 1: ROC Analysis of D-Dimer values in relation with fungal infection among patients
admitted with COVID-19
DISCUSSION
The study describes the lack of association between tocilizumab and the development of a
fungal infection. This was contrary to our hypothesis that tocilizumab would result in an
increased incidence of fungal infections. Hospital acquired infections (HAI) in general have
previously been noted to be increased in patients with SARS-Cov-2 infection [10] [11] and in
0.00 0.25 0.50 0.75 1.00
Sensitivity
0.00 0.25 0.50 0.75 1.00
1 - Specificity
Area under ROC curve = 0.7069
For COVID-19 admitted patients in a private hospital -South Africa
ROC Analysis of D-Dimer in relation to Fungal infection post-Tocilizumab treatment
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Naidu, K., Richards, G. A., Cruickshank, D., Wadee, B., Naidu, J., & Kajee, N. (2024). The Incidence of Fungal Infections in Patients Treated with
Tocilizumab for Severe COVID-19 Pneumonia Requiring High Care or ICU Admission: A Retrospective Cohort Study. European Journal of Applied
Sciences, Vol - 12(3). 378-388.
URL: http://dx.doi.org/10.14738/aivp.123.17113
particular, were noted to be increased in COVID-19 patients that had received tocilizumab and
or steroids during the course of their treatment [12] [13] . This in particular applied to both
fungal and bacterial infections in those that had received tocilizumab [14]. This was not
surprising as it was considered that the use of immunosuppressive therapies would make
patients more susceptible to infection. However numerous studies have contradicted this
presumption. A large meta-analysis performed by the WHO Rapid Evidence Appraisal for
COVID-19 Therapies (REACT) Working Group noted that there was no significant difference
between the use of IL-6 receptor inhibitors and the development of secondary infections at 28
days (OR 0.99 CI [ 0.86-1.16])[15].
A study performed in a hospital in Milan also indicated that there was no difference in the
incidence of fungal or bacterial infection between patients who received tocilizumab and
those who did not [16] and this was mirrored by a study by Kimmig et al. which also showed
no significant association (5.6% vs 0% P=0.112). [14]. Our findings were similar as we found
no significant association between the administration of tocilizumab and the development of
a fungal infection. This is despite the fact that the incidence of fungal infections at 15.6% was
higher than in comparative studies - in an ICU in Turkey fungal infections were isolated in
5.1% of patients admitted with COVID-19 [4], an Italian hospital and Greek hospital had
incidences of 5.5% [17] and 10.7% respectively [18].
The results obtained by Atinori et al in a period in March 2020 in which 43 patients with
COVID-19 were treated with Tocilizumab and 3 (6.9%) developed candidaemia [19] were
consistent with our study in which out the 111 patients who received Tocilizumab, only 9
developed a fungal infection (8%). Overall, although our incidence of fungal infections was
higher than expected fewer of these could be attributed to the use of tocilizumab. This overall
high rate of fungal infection could be explained by other risk factors such as the prolonged use
of corticosteroids and prolonged hospitalisation. Corticosteroid use, in particular, has been
linked to the development of fungal infection and even before the results of the RECOVERY
study most patients admitted to ICU with COVID were treated with steroids. A systematic
review performed by Li et al found that corticosteroid therapy was associated with worse
outcomes for invasive and chronic pulmonary aspergillosis, invasive candidiasis and
mucormycosis [20]. It is interesting however that in our study dexamethasone appeared to be
less likely that hydrocortisone to result in a fungal infection.
Both the increased length of stay and mortality associated with fungal infections noted in our
study was in keeping with multiple previous studies in which fungi conferred a significant
negative impact on ICU outcomes. [18] [17] [4]. Furthermore, it is noted that the majority of
our patients with fungal infections had a candida as a most likely organism. Candidaemia was
noted to have been present in approximately a quarter of COVID-19 patients in a review
performed in the US during 2020 [21].
Females were noted to have a decreased risk of developing fungal infections as compared to
males. It has previously been reported that males are at a greater risk from being infected and
dying from infectious disease compared to females[22]. This may be due the positive effects of
estrogens and the negative effects of androgens on the immune system, although this is not
certain [22].
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The association between a D-Dimer and the presence of a fungal infection is interesting. There
have been previous studies which have shown an elevated D-Dimer in patients with COVID-19
infection [23, 24] and it is well documented that elevated D-dimers are also noted in patients
with venous thromboembolism, cancer and pneumonia [25]. However, there is limited data
on the significance of a positive D-dimer and associated fungal infections and this may require
further study. A correlation with positive fungal markers such as B-D-glucan and an elevated
D-Dimer would have been interesting but these values were not available. Our study has
tentatively suggested that a cut point of 1.87ug/ml for the D-dimer could be the point at
which patients should be screened for fungal infections. Whether this applies only to COVID- 19 patients is not known currently.
CONCLUSION
In conclusion, this study has shed light on the relationship between tocilizumab and the
development of fungal infections in patients with COVID-19 admitted to the ICU. Contrary to
our initial hypothesis and previous concerns about immunosuppressive therapies, we found
no significant association between tocilizumab use and the incidence of fungal infections. This
study contributes to our understanding of the complex factors influencing fungal infections in
COVID-19 patients, highlighting the need for a multifaceted approach to assess risk factors
and potential screening criteria. The use of an elevated D-Dimer as a marker for possible co- existing fungal infection is one of the potential screening factors, however further research
designed to assess the validity of its use in this regard is warranted. The study has limitations
worth considering: it was a retrospective design with a relatively small sample size, raising
concerns about selection and confounding biases. One of the major selection biases was that
the decision to administer tocilizumab may have been influenced by the patient’s condition
and other factors such as availability of the drug. The study was also not able to account for all
potential confounders that may contribute to the development of fungal infections. It is also
important to note that fungal organisms cultured from any source was included and not only
fungal organisms cultured in blood samples raising the issue of possible colonization versus
active fungal infection. Generalizability may be limited, as the findings might be specific to the
study population and the time frame. Acknowledging these limitations is crucial for a
balanced interpretation of its results.
Ethical Approval Statement: National Health Research Ethics Committee Registration: REC
251015-048
References
[1.] Peman J, Ruiz-Gaitan A, Garcia-Vidal C, Salavert M, Ramirez P, Puchades F, et al. Fungal co-infection in
COVID-19 patients: Should we be concerned? Rev Iberoam Micol. 2020;37(2):41-6.
[2.] Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for monocytes and
macrophages. Nat Rev Immunol. 2020;20(6):355-62.
[3.] Ezeokoli OT, Gcilitshana O, Pohl CH. Risk Factors for Fungal Co-Infections in Critically Ill COVID-19
Patients, with a Focus on Immunosuppressants. J Fungi (Basel). 2021;7(7).
[4.] Coskun AS, Durmaz SO. Fungal Infections in COVID-19 Intensive Care Patients. Pol J Microbiol.
2021;70(3):395-400.
Page 10 of 11
387
Naidu, K., Richards, G. A., Cruickshank, D., Wadee, B., Naidu, J., & Kajee, N. (2024). The Incidence of Fungal Infections in Patients Treated with
Tocilizumab for Severe COVID-19 Pneumonia Requiring High Care or ICU Admission: A Retrospective Cohort Study. European Journal of Applied
Sciences, Vol - 12(3). 378-388.
URL: http://dx.doi.org/10.14738/aivp.123.17113
[5.] Gold JAW, Adjei S, Gundlapalli AV, Huang YA, Chiller T, Benedict K, et al. Increased Hospitalizations
Involving Fungal Infections during COVID-19 Pandemic, United States, January 2020-December 2021.
Emerg Infect Dis. 2023;29(7):1433-7.
[6.] Di Giambenedetto S, Ciccullo A, Borghetti A, Gambassi G, Landi F, Visconti E, et al. Off-label use of
tocilizumab in patients with SARS-CoV-2 infection. J Med Virol. 2020;92(10):1787-8.
[7.] Group RC. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised,
controlled, open-label, platform trial. Lancet. 2021;397(10285):1637-45.
[8.] Investigators R-C, Gordon AC, Mouncey PR, Al-Beidh F, Rowan KM, Nichol AD, et al. Interleukin-6 Receptor
Antagonists in Critically Ill Patients with Covid-19. N Engl J Med. 2021;384(16):1491-502.
[9.] Epps S, Cardenas VM, Meena NK, Jagana R, Atchley WT. Tocilizumab Is Associated with Increased Risk of
Fungal Infections Among Critically Ill Patients with COVID-19. TP51 TP051 COVID: LUNG INFECTION,
MULTIORGAN FAILURE, AND CARDIOVASCULAR. p. A2635-A.
[10.] Kwon JH, Nickel KB, Reske KA, Stwalley D, Dubberke ER, Lyons PG, et al. Risk factors for hospital-acquired
infection during the SARS-CoV-2 pandemic. J Hosp Infect. 2023;133:8-14.
[11.] De Francesco MA, Signorini L, Piva S, Pellizzeri S, Fumarola B, Corbellini S, et al. Bacterial and fungal
superinfections are detected at higher frequency in critically ill patients affected by SARS CoV-2 infection
than negative patients and are associated to a worse outcome. J Med Virol. 2023;95(7):e28892.
[12.] Kumar G, Adams A, Hererra M, Rojas ER, Singh V, Sakhuja A, et al. Predictors and outcomes of healthcare- associated infections in COVID-19 patients. Int J Infect Dis. 2021;104:287-92.
[13.] Morena V, Milazzo L, Oreni L, Bestetti G, Fossali T, Bassoli C, et al. Off-label use of tocilizumab for the
treatment of SARS-CoV-2 pneumonia in Milan, Italy. Eur J Intern Med. 2020;76:36-42.
[14.] Kimmig LM, Wu D, Gold M, Pettit NN, Pitrak D, Mueller J, et al. IL-6 Inhibition in Critically Ill COVID-19
Patients Is Associated With Increased Secondary Infections. Front Med (Lausanne). 2020;7:583897.
[15.] Shankar-Hari M, Vale CL, Godolphin PJ, Fisher D, Higgins JPT, Spiga F, et al. Association Between
Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta- analysis. Jama. 2021;326(6):499-518.
[16.] Campochiaro C, Della-Torre E, Cavalli G, De Luca G, Ripa M, Boffini N, et al. Efficacy and safety of
tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study. Eur J Intern Med.
2020;76:43-9.
[17.] Falcone M, Tiseo G, Giordano C, Leonildi A, Menichini M, Vecchione A, et al. Predictors of hospital-acquired
bacterial and fungal superinfections in COVID-19: a prospective observational study. J Antimicrob
Chemother. 2021;76(4):1078-84.
[18.] Koukaki E, Rovina N, Tzannis K, Sotiropoulou Z, Loverdos K, Koutsoukou A, et al. Fungal Infections in the
ICU during the COVID-19 Era: Descriptive and Comparative Analysis of 178 Patients. J Fungi (Basel).
2022;8(8).
[19.] Antinori S, Bonazzetti C, Gubertini G, Capetti A, Pagani C, Morena V, et al. Tocilizumab for cytokine storm
syndrome in COVID-19 pneumonia: an increased risk for candidemia? Autoimmun Rev.
2020;19(7):102564.
[20.] Li Z, Denning DW. The Impact of Corticosteroids on the Outcome of Fungal Disease: a Systematic Review
and Meta-analysis. Current Fungal Infection Reports. 2023;17(1):54-70.
Page 11 of 11
Services for Science and Education – United Kingdom 388
European Journal of Applied Sciences (EJAS) Vol. 12, Issue 3, June-2024
[21.] Seagle EE, Jackson BR, Lockhart SR, Georgacopoulos O, Nunnally NS, Roland J, et al. The Landscape of
Candidemia During the Coronavirus Disease 2019 (COVID-19) Pandemic. Clin Infect Dis. 2022;74(5):802-
11.
[22.] Kraševec N. The Multifaceted Role of Mating Type of the Fungus and Sex of the Host in Studies of Fungal
Infections in Humans. J Fungi (Basel). 2022;8(5).
[23.] Yao Y, Cao J, Wang Q, Shi Q, Liu K, Luo Z, et al. D-dimer as a biomarker for disease severity and mortality in
COVID-19 patients: a case control study. Journal of Intensive Care. 2020;8(1):49.
[24.] Nemec HM, Ferenczy A, Christie BD, 3rd, Ashley DW, Montgomery A. Correlation of D-dimer and Outcomes
in COVID-19 Patients. Am Surg. 2022;88(9):2115-8.
[25.] Schafer K, Goldschmidt E, Oostra D, Fish J, Russell T, Lurie F. The clinical significance of ultra-high D-dimer
levels. J Vasc Surg Venous Lymphat Disord. 2022;10(1):8-13.