Secondary bloodstream infection in critically ill patients with COVID-19.

OBJECTIVE: Secondary infection, especially bloodstream infection, is an important cause of death in critically ill patients with COVID-19. We aimed to describe secondary bloodstream infection (SBI) in critically ill adults with COVID-19 in the intensive care unit (ICU) and to explore risk factors related to SBI.
METHODS: We reviewed all SBI cases among critically ill patients with COVID-19 from 12 February 2020 to 24 March 2020 in the COVID-19 ICU of Jingmen First People's Hospital. We compared risk factors associated with bloodstream infection in this study. All SBIs were confirmed by blood culture.
RESULTS: We identified five cases of SBI among the 32 patients: three with Enterococcus faecium, one mixed septicemia (E. faecium and Candida albicans), and one C. parapsilosis. There were no significant differences between the SBI group and non-SBI group. Significant risk factors for SBI were extracorporeal membrane oxygenation, central venous catheter, indwelling urethral catheter, and nasogastric tube.
CONCLUSIONS: Our findings confirmed that the incidence of secondary infection, particularly SBI, and mortality are high among critically ill patients with COVID-19. We showed that long-term hospitalization and invasive procedures such as tracheotomy, central venous catheter, indwelling urethral catheter, and nasogastric tube are risk factors for SBI and other complications.

Introduction

The global COVID-19 pandemic is currently ongoing, with more than 130 million infections and nearly three million deaths worldwide. Mortality in critically ill patients is 22.9% to 61.5%.[2,3] In critically ill patients with COVID-19, the presence of acute respiratory distress syndrome (ARDS) is an important risk factor for secondary bloodstream infection (SBI) because of a prolonged stay in the intensive care unit (ICU), with approximately 13.5% SBI reported. At present, there is no specific treatment for severe COVID-19 infection apart from treatment with antivirals, corticosteroids, and mechanical ventilation. However, the use of corticosteroids (CS) in these patients remains controversial, despite reported benefits of CS treatment in patients with ARDS in the ICU.[2,5-7] There are many types of secondary infection in viral pneumonia, such as pulmonary bacterial infection, pulmonary Aspergillus infection, bloodstream infection (sepsis, catheter-related blood stream infection), and urinary tract infection[8-12] The mechanisms are mainly related to physical barriers, immune responses, and flora imbalance. There are many clinical risk factors for clinical secondary infections, such as older age (>60 years) and underlying conditions such as hypertension, diabetes, obesity, and hemodialysis.[5,7] The developments of SBI is closely associated with immunosuppressive therapy (long-term and high-dose glucocorticoid use), invasive procedures (e.g., endotracheal intubation, tracheotomy) and use of broad-spectrum antimicrobial agents. Different types of secondary infection and severe SBI have been observed in the critically ill patients in the COVID-19 ICU of our hospital. In this study, we retrospectively analyzed SBI-related risk factors to provide beneficial evidence for the treatment of critically ill patients with COVID-19 infection.

Methods

We retrospectively analyzed the clinical data of all patients in the COVID-19 ICU of Jingmen First People’s Hospital from 12 February 2020 to 24 March 2020. Our hospital has established a specialized ICU that is dedicated to the treatment of critically ill patients with COVID-19, with 23 beds. All patient infections were confirmed by SARS-CoV-2 nucleic acid detection, and patients were classified as having critical illness according to guidelines for the diagnosis and treatment of COVID-19. The following kits were used for the detection of SARS-CoV-2 nucleic acid and antibody detection: 2019-nCoV Ab, Xiamen Wantai Kairui Biotechnology Co., Ltd, Batch number: 20203400198; 2019-nCoV Nucleic acid detection kit (fluorescence PCR method), Huada Biotechnology (Wuhan) Co., Ltd, Batch number: 20203400060. All bacteria were identified using the VITEK 2 system (bioMérieux, Marcy-l'Étoile, France).

This was a retrospective observational study with no special intervention. The study was approved by the institutional review committee of Jingmen First People's Hospital. The requirement for patient informed consent was waived. All treated patients were critically ill. Our team comprised experts from the ICU and the infection disease department, respiratory treatment department, and respiratory department. The professional nursing team comprised senior nurses from the ICU. Supplemental treatment was provided by the rehabilitation and mental health departments. We strictly followed China’s continuously improved COVID-19 treatment guidelines and professional work standards. In terms of secondary infection, close attention was paid to the possible sites of secondary infection, etiology, and evaluation of synchronous inflammatory markers.

According to the literature and our COVID-19 treatment experience, secondary infections, especially SBI, are primary complications associated with poor prognosis in critically ill patients with COVID-19. Typical systemic signs of infection with positive blood cultures may indicate bloodstream infection. Patients were divided into two groups according to the presence or absence of SBI (SBI group and non-SBI group). We evaluated differences between the two groups with respect to known and possible risk factors related to SBI, such as the use of CS, endotracheal intubation, indwelling central venous catheter, and length of ICU and hospital stay to identify significant risk factors and provide evidence for the treatment of critically ill patients with COVID-19.

Statistical analysis

Continuous variables are presented as mean ± standard deviation and categorical variables as number and percentage. Continuous data were compared using the Student t-test and categorical data were compared with the chi-square or Fisher’s exact test, as appropriate. We set P < 0.05 to indicate statistical significance. We used R software version 3.3.3 in the statistical analysis (The R Project for Statistical Computing, Vienna, Austria).

Results

According to the clinical classification criteria for the diagnosis and treatment of COVID-19, 24 critical patients with COVID-19 and 8 with severe COVID-19 infection were identified. Most treated patients were in the late stage of critical illness. The average patient age was 63.34  ±  12.48 years, with 20/32 (62.5%) male patients. All the results are shown in Table 1. Among the 32 patients, 5 (15.63%) developed SBI; the detected pathogens included three cases of infection with Enterococcus faecium, one case with mixed septicemia (E. faecium and Candida albicans), and one case of C. parapsilosis infection.

Table 1.

Clinical characteristics and risk factors of critically ill patients with COVID-19, with and without SBI.

	All patients (N = 32)	SBI (N = 5)	Non-SBI (N = 27)	P value
All patients		5 (15.63%)	27 (84.37%)
Baseline factors
Age (years), mean ± SD	63.34 ± 12.48	66.20 ± 8.23	62.81 ± 13.04	0.506
Sex (male), n (%)	20 (62.5)	3 (60)	17 (62.96)	0.338
Known risk factors
BMI >30 kg/m2, n (%)	1 (3.13)	0	1 (3.70)	1
Advanced age (>60 years), n (%)	21 (65.63)	4 (80)	17 (62.96)	0.637
Hypertension, n (%)	16 (50)	3 (60)	13 (48.15)	1
Diabetes, n (%)	10 (31.25)	2 (40)	8 (29.63)	0.637
Chronic renal disease
Renal transplant	1 (3.13)	0	1 (3.70)	1
Uremia/hemodialysis	2 (6.25)	0	2 (7.41)	1
Hepatitis B cirrhosis, n (%)	1 (3.13)	0	1 (3.70)	1
Critical illness, n (%)	24 (75)	5 (100)	19 (70.37)	0.296
Risk factors
Corticosteroids	21 (65.63)	3 (60)	15 (55.56)	1
CS>7 days, n (%)	16 (50)	3 (60)	13 (48.15)	1
Cumulative dose of CS (mg),  average (range)	512 (80–1136)	640 (560–720)	462 (80–1136)	0.593
Duration of corticosteroids (days), average (range)	14 (1–26)	10 (10–16)	14.5 (1–26)
CRRT, n (%)	7 (21.86)	3 (60)	4 (14.81)	0.057
Vasopressors, n (%)	10 (31.25)	3 (60)	7 (25.93)	0.087
Mechanical ventilation, n (%)
Endotracheal intubation	14 (43.75)	4 (80)	10 (37.04)	0.142
Tracheotomy	2 (6.25)	2 (40)	0 (0)	0.02*
Non-invasive ventilation	18 (56.25)	1 (20)	17 (62.96)	0.142
ECMO, n (%)	4 (12.5)	3 (60)	1 (3.7)	0.008*
Central venous catheterization	14 (43.75)	5 (100)	9 (33.33)	0.01*
Indwelling urethral catheter	14 (43.75)	5 (100)	9 (33.33)	0.01*
Indwelling nasogastric tube	14 (43.75)	5 (100)	9 (33.33)	0.01*
Pneumonia (bacterial or fungal), n (%)	9 (28.13)	4 (80)	5 (18.52)	0.015*
Alive at hospital discharge, n (%)	23 (71.88)	3 (60)	20 (74.07)	0.121
Duration of disease (days), mean ± SD	44.03 ± 16.56	31.60 ± 13.20	41.96 ± 17.93	0.121
Duration before admission to ICU, mean ± SD	19.43 ± 9.71	19.2 ± 6.04	19.48 ± 10.29	0.932
Length of ICU stay (days), mean ± SD	18.53 ± 13.09	31.60 ± 9.22	16.11 ± 12.24	0.023*
Length of hospital stay (days), mean ± SD	37.56 ± 13.62	49.80 ± 10.13	35.29 ± 12.97	0.042*

*P < 0.05.

SBI, secondary bloodstream infection; ICU, intensive care unit; ECMO, extracorporeal membrane oxygenation; CRRT, continuous renal replacement therapy; CS, corticosteroids; SD, standard deviation; BMI body mass index.

All patients were treated empirically with antibiotics and Abidol (antiviral drug). In terms of known risk factors, one patient was obese and one had hepatitis B cirrhosis. Of the 32 patients, 21 (65.63%) patients were over 60 years old, 16 (50%) had hypertension, 10 (31.25%) had diabetes, and 3 (9.38%) patients had chronic renal disease (1 patient had undergone kidney transplantation, 2 patients had uremia and were undergoing hemodialysis). There was no significant difference between the two groups (SBI group and non-SBI group) for these known risk factors.

In terms of the studied risk factors, 21/32 (65.63%) patients were treated with CS and 16/32 (50%) received CS for more than 7 days; the average cumulative dose of CS was 512 (80–1136) mg. There were no significant differences between the two groups in these factors. In total, 7/32 (21.86%) were treated with continuous renal replacement therapy and 10/32 (31.25%) patients received vasopressors, with no significant differences between groups. Among the total, 14/32 (43.75%) patients were intubated, 2/32 (6.25%) patients underwent tracheotomy (all in the SBI group, 2/5 [40%]), and 18/32 (56.25%) patients were treated with non-invasive ventilation. Tracheotomy had a strong influence on the occurrence of SBI (P = 0.02). Four (12.5%) patients were treated with extracorporeal membrane oxygenation (ECMO) (3/5 [60%] in the SBI group; P = 0.008). Fourteen (43.75%) patients had a central venous catheter, indwelling urethral catheter, and a nasogastric tube. All patients (100%) in the SBI group had an indwelling catheter; thus, an invasive indwelling catheter was identified as a significant risk factor for SBI (P = 0.01).

Nine of the 32 (28.13%) patients were complicated with secondary pneumonia (bacterial or fungal) confirmed by sputum culture, lung imaging, and clinical manifestations; each patient tested positive multiple times. In the SBI group, 4/5 (80%) patients had secondary pneumonia; the detected pathogens were as follows: 1 patient with Escherichia coli (extended-spectrum beta-lactamase +), sensitive Acinetobacter baumannii, C. parapsilosis, C. albicans, sensitive Stenotrophomonas maltophilia, and C. lusitaniae. There was a significant difference between the two groups (P = 0.015).

We also analyzed effects of the course of disease and length of hospital stay on SBI. The average duration of disease was 44.03 ± 16.56 days, and the average duration before admission to the ICU was 19.43 ± 9.71 days; there were no significant differences between the two groups. The total average length of ICU stay was 18.53 ± 13.09 days (31.60 ± 9.22 days in the SBI group; P = 0.023). The total average length of hospital stay was 37.56 ± 13.62 days (49.80  ±  10.13 days in the SBI group, P = 0.042). Thus, both ICU stay and hospital stay had an impact on the occurrence of SBI. A total of 23/32 (71.88%) patients were cured and discharged (3/5 [60%] in the SBI group), with no significant difference between groups.

Discussion

We treated 32 critically ill patients in the COVID-19 ICU. Among them, 15.63% of patients developed SBI; 60% of patients in the SBI group survived. Among patients in a traditional ICU ward, SBI has a high mortality rate of 40% to 60%. In total, 28.13% of patients were complicated with secondary pneumonia in the COVID-19 ICU. In the SBI group, 80% of patients had secondary pneumonia, making this a significant risk factor for death and secondary infection in critically ill patients with COVID-19. The distribution characteristics and drug resistance among pathogens differed from those involved in SBI among patients in a traditional ICU, E. faecium and Candida were the main pathogens detected. No multidrug-resistant bacteria were detected, perhaps because our ICU was newly established for patients with COVID-19 and our team included experts in nosocomial infection control, which were very favorable factors for our patients. These characteristics not only reduce mortality related to multidrug resistance but also reduce the cost of treatment.[8,13]

The average age among our patients was 63.34 years, with 65.63% over age 60 years. Although we found no significant difference in the incidence of SBI between patients younger than 60 years of age and those with advanced age, older age has been reported to be associated with high mortality in critically ill patients.[2,5,7] Among our patients, 62.5% were male. Many studies also report a higher proportion of male patients with serious COVID-19 infection, although the specific mechanism is unclear. [2,5,7]

Having underlying diseases has also been associated with high mortality and greater likelihood of developing severe illness in patients with COVID-19.[2,5,7,14] In our study, only one patient was obese and one had hepatitis B cirrhosis; 50% of patients had hypertension, 31.25% had diabetes (seven cases were complicated with hypertension), three patients had chronic renal disease (one patient had undergone kidney transplantation and was complicated with hypertension, two patients had uremia complicated with hypertension and were undergoing hemodialysis). However, we found no significant difference between the SBI and non-SBI groups with respect to these known risk factors,

Although the use of CS in COVID-19 is controversial, low doses in patients with mild disease and high doses in critically ill patients have been reported to be beneficial.[6,15,16] In this study, 65.63% of patients were treated with CS and 50% were treated for more than 7 days, with an average cumulative dose of 512 mg. CS treatment was not identified as a risk factor for SBI in this study. From our clinical observation, clinical symptoms and lung imaging among patients were improved after treatment with CS.

According to the findings of this study, multiple invasive procedures are important risk factors of SBI, such as tracheotomy, ECMO, and having various indwelling catheters. Among the associated infections, candidemia was most common, and 60% of cases were non-C. albicans infections.[9-12] It is very important to follow extra preventive measures in patients who undergo multiple invasive operations, extubate as soon as possible, evaluate secondary infection regularly, and treat infections early.

The average length of ICU stay and length of hospital stay were longer in the SBI group than in the non-SBI group, which were also factors associated with SBI and poor prognosis.

Conclusion

Our findings confirmed that mortality is high in critically ill patients with COVID-19. According to published reports, these patients can benefit from antiviral therapy, early appropriate mechanical ventilation, treatment with CS, and early admission to the ICU. However, owing to rapid disease progression, older patients and those with underlying diseases are at increased risk of critical illness. Long-term hospitalization and invasive procedures such as tracheotomy or the use of a central venous catheter, indwelling urethral catheter, and nasogastric tube are strong risk factors for SBI and other complications in critically ill patients with COVID-19 infection.

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Supplemental material, sj-pdf-1-imr-10.1177_03000605211062783 for Secondary bloodstream infection in critically ill patients with COVID-19 by Junli Zhang, Peng Lan, Jun Yi, Changming Yang, Xiaoyan Gong, Huiqing Ge, Xiaoling Xu, Limin Liu, Jiancang Zhou and Fangfang Lv in Journal of International Medical Research