Dear Editor,
The understanding and management of COVID-19 among hospitalised patients has evolved
with increased use of dexamethasone and Tocilizumab. The ability of dexamethasone
and Tocilizumab to dampen the excessive host inflammatory response to SARS-CoV-2 may
be associated with improved mortality
1
,
2
. However, an increase in the incidence of secondary infections associated with these
treatments is of concern. In this Journal, Lansbury and colleagues recently reviewed
the occurrence of co-infections amongst patients with COVID-19
3
. We sought to evaluate risk factors associated with the development of bloodstream
infection (BSI) among critically ill patients with COVID-19.
Patients aged ≥18 years admitted to University College London Hospitals with a positive
real-time reverse transcription–polymerase chain reaction (rRT-PCR) test for SARS-CoV-2
RNA between March 2020 and 1st February 2021 were included. The UK has to date experienced
two major waves of COVID-19 infections, the first in March-August 2020 and the second
in September 2020- March 2021. Ethical approval was granted by the London-Westminster
Research Ethics Committee, the Health Research Authority and Health and Care Research
Wales (HCRW) on 2nd July 2020 (REC reference 20/HRA/2505, IRAS ID 284088).
Patient demographics, clinical data, blood culture results, treatments and outcome
were recorded from electronic healthcare records on a standardized data collection
form. Dexamethasone was prescribed on hospital admission at 6mg daily for 10 days.
Tocilizumab was administered when patients progressed to requiring advanced respiratory
support (high flow nasal oxygen, non-invasive ventilation, or invasive ventilation),
as a single dose of 8mg/kg (up to a maximum dose of 800mg). Blood culture contaminants
were defined as those not considered clinically significant at the time and did not
require a clinical intervention.
Continuous and categorical variables are reported as median (interquartile range)
and n (%), respectively. Comparison of non-parametric continuous data between groups
was performed using the Mann Whitney U test. Categorical data were compared using
the chi-square test. Binary logistic regression was used to ascertain independent
risk factors associated with BSI. Graphs were constructed, and statistical analysis
performed using Prism 9.0 (GraphPad Software, La Jolla, CA, USA) and SPSS version
24.0 (IBM Corp).
A total of 404 patients were included (Table 1
), The median age of patients was 61 (51-69) years, 270 (67%) patients were male,
160 (40%) were admitted in the first surge, and 190 (47%) died in hospital. 102 patients
(25%) received dexamethasone alone of who 53 patients (52%) died. An additional 45
patients (11%) received Tocilizumab in addition to dexamethasone of whom 22 (49%)
died. No patients received Tocilizumab without dexamethasone.
Table 1
Characteristics and treatment administered to critically ill COVID-19 patients with
and without bloodstream infections
Table 1
No positive blood cultures
Positive blood cultures
p-value
328
76
BMI
28 (24-33)
28 (24-33)
0.790
Age
62 (52-70)
60 (49-67)
0.104
Symptoms to hospital (days)
7 (5-10)
7 (4-10)
0.611
Follow up time (days)
20 (13-32)
41 (22-60)
<0.001
Sex (Male)
205 (67%)
56 (74%)
0.277
Diabetes mellitus
89 (29%)
29 (39%)
0.120
Surge 1
128 (42%)
22 (29%)
0.038
IMV
196 (64%)
69 (91%)
<0.001
Dexamethasone use
158 (52%)
53 (70%)
0.006
Tocilizumab use
31 (10%)
9 (12%)
0.669
Transfer from another hospital
124 (41%)
46 (61%)
0.002
Continuous positive airway pressure use
248 (81%)
59 (78%)
0.468
Cancer
34 (11%)
8 (8%)
0.417
Immunosuppression
37 (12%)
6 (8%)
0.300
Hospital mortality
145 (47.5%)
40 (52.6%)
0.427
Of the 404 patients with COVID-19, 76 (18.8%) patients had a clinically relevant positive
blood culture (Table 1), most commonly a Coagulase negative Staphylococcus. The median
time from hospital admission to BSI was 18 (11-26) days. Among the 76 patients who
had a BSI, six (8%) had more than one organism isolated. The proportion of patients
who died was similar between those with and without a BSI (p=0.202).
Factors associated with BSI on univariate analysis included longer duration of follow
up time (p<0.001), being admitted in the second surge (p=0.038), requirement for mechanical
ventilation (p<0.001), dexamethasone use (p=0.006), and being transferred from another
centre to ours (p=0.002). On correcting for follow up time, surge, mechanical ventilation,
dexamethasone use, and age, mechanical ventilation (OR=2.1(1.1-3.9); p=0.028), longer
follow up time (OR=1.013 (1.005-1.022); p=0.002), and younger age (OR=0.979 (0.968-0.990);
p<0.001) were associated with a bacteraemia. Dexamethasone and Tocilizumab use were
not independently associated with BSI.
We report independent risk factors associated with the incidence of BSI in a critically
ill patient cohort with COVID-19. Dexamethasone and Tocilizumab were not independently
associated with BSI among critically ill patients with COVID-19. Similar findings
have been reported among hospitalised patients with COVID-19, including non- critically
ill
4
. Additionally, we found that the occurrence of a BSI was not associated with greater
mortality on unadjusted analysis, consistent with findings from a UK national study
5
.
Unsurprisingly, the longer duration of stay on ICU the greater the risk of developing
a bacteremia; the latter being a time- dependent covariate. Invasive mechanical ventilation
was also associated with a bacteremia, this may reflect greater illness severity which
is associated with immune dysregulation in COVID-19
6
,
7
. Following the initial infectious insult and an associated hyperinflammatory state,
a hypoinflammatory state with impaired ability to overcome secondary infections ensues
during prolonged critical illness
8
. The time to develop a secondary infection was between 2 and 3 weeks; similar to
other reports
4
,
9
. Younger age being associated with BSI is intriguing, and may reflect increased investigations
among patients who appear more likely to have a favorable prognosis; including younger
patients and those with fewer co-morbid illness.
At the doses used, dexamethasone and Tocilizumab may not be associated with excessive
immune suppression and increased risk of BSI. However, dexamethasone and Tocilizumab
attenuate clinical features associated with bacteremia, including an elevated temperature
and CRP. We cannot therefore exclude the possibility of occult bacteremia which was
undiagnosed. This is of greater concern closer to the time of receiving dexamethasone
or tocilizumab, which suppress CRP and temperature for a number of days following
administration
9
.
As with all retrospective analyses, we acknowledge the possibility of residual confounding,
and that results are associative. The small number of patients included also warrants
caution in interpreting the findings. There were no predefined criteria for obtaining
blood cultures, and we have focused on positive bacteremia rates, but not infectious
complications without an associated bacteremia.
In summary, dexamethasone and Tocilizumab were not associated with increased risk
of BSI in critically ill patients with COVID-19. Further prospective work investigating
particular at-risk subgroups, and the use of diagnostics with greater sensitivity
are warranted.
Declaration of Competing Interest
The authors have no competing interest to declare
Ethical approval
Ethical approval was granted by the London-Westminster Research Ethics Committee,
the Health Research Authority and Health and Care Research Wales (HCRW) on 2nd July
2020 (REC reference 20/HRA/2505, IRAS ID 284088).
CRediT authorship contribution statement
Tim McMillan: Data curation
Connor Jones: Data curation
CJ O'Connor: Data curation, Project administration, Writing – review & editing
Daniel Nolan: Data curation
Jayne Ellis: Data curation, Writing – review & editing
Claire Thakker: Data curation, Writing – review & editing
Katharina Kranzer: Data curation, Writing – review & editing
Neil RH Stone: Data curation, Writing – review & editing
M Singer: Writing – review & editing, Supervision
APR Wilson: Conceptualization, Methodology, Validation, Resources, Data curation,
Writing – review & editing, Supervision, Project administration
N Arulkumaran: Conceptualization, Methodology, Validation, Resources, Data curation,
Writing - original draft, Writing – review & editing, Supervision, Project administration