1. INTRODUCTION

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) has become an ongoing worldwide pandemic after its first occurrence in 2019.1,2 The majority of COVID-19 patients have been observed to have mild symptoms with no need for hospitalization. However, approximately 20% of infected cases require hospitalization or even intensive care unit (ICU) admission.3 After combatting SARS-CoV-2 initially, COVID-19 inpatients may subsequently experience hospital-acquired infections by other non-SARS-CoV-2 viruses, bacteria, and fungi.4,5 Such situations have been reported in patients infected with influenza during previous epidemics.6,7 This may complicate the clinical course of COVID-19 inpatients and should be an important issue for clinicians.

A pooled analysis from reported research revealed that the incidence of infections developed 48 hours after admission in COVID-19 inpatients was 24% and that these were associated with poor outcomes.5 Due to the geographic discrepancy of these studies, the types of hospital-acquired infections and the distribution of specific causative pathogens differed among the various reports. Successful control measures against the pandemic of the SARS-CoV-2 outbreak by the Central Epidemic Command Center (CECC) and the Taiwan Center for Disease Control (TCDC), ensured that reported COVID-19 cases were limited in Taiwan before May 2021.8 Most reported cases were from other countries and were associated with mild to moderate disease severity, with low risk for hospital-acquired infections.9,10

The first significant community outbreak emerged after May 2021. Within 1 month, more than 5000 new COVID-19 cases had been reported across a spectrum of disease severity (https://nidss.cdc.gov.tw/nndss/disease?id=19CoV), and several infected cases were admitted to hospital, due to their gravity. Hospitalized COVID-19 patients were now similarly at risk for hospital-acquired infections, as had been previously reported from several countries.5

To improve patient care, it is considered that local epidemiological reports on hospital-acquired infections, and risk analyses, may be helpful for clinicians in their provision of appropriate, empirically-based therapy. To this end, the aim of this study was to characterize the hospital-acquired infections of COVID-19 patients in our hospital, focusing upon the epidemiology of different causative organisms, risk factors, and the clinical outcomes of patients.

2. METHODS 2.1. Study design, study population, and hospital settings

A retrospective observational study was conducted at the Tri-Service General Hospital, which is a tertiary referral hospital located in Taipei. Inpatients diagnosed with COVID-19 by means of real-time, reverse-transcriptase polymerase chain reaction (RT-PCR) assays of oropharyngeal or nasopharyngeal swab specimens from January 1, 2020 to July 31, 2021 were included in this study. The clinical characteristics of the included cases were analyzed and divided into two groups for comparison: patients with, and patients without, hospital-acquired infections.

2.2. Clinical data collection and definitions

Clinical information relating to the included patients was retrospectively collected via the electronic medical record system and included age, sex, underlying diseases, disease severity at admission, hospital stay, 28-day, and in-hospital crude mortality. Hospital-acquired infections, including bacteria, fungus, and virus, were defined as “subsequent infections by other pathogens” in COVID-19 patients, 48 hours after admission. Patients with sepsis consistent with bacterial infection at different sites were identified according to the Center for Disease Control and Prevention (CDC) surveillance definitions, along with the growth of bacteria in the respective appropriate culture specimens.11 Cultured bacteria identification and minimum inhibitory concentrations (MICs) against tested antibiotics were assessed with matrix-assisted laser desorption/ionization time of flight mass spectrometry (bioMérieux, USA) and VITEK 2 automatic system (bioMérieux), respectively. The resistance interpretations of isolated bacteria against different antibiotics were made according to the 2021 Clinical and Laboratory Standards Institute (CLSI) criteria. Multiple drug resistance was defined as nonsusceptibility to at least one agent in three or more antibiotic categories.12 Invasive fungal infections, specifically invasive pulmonary aspergillosis and candidiasis were based on the prescribed reports.13,14 Respiratory viral infections other than the SARS-CoV-2 were obtained mainly from nasopharyngeal swabs using the FilmArray Respiratory Panel (BioFire Diagnostics, USA), which can detect adenovirus; coronavirus; human metapneumovirus; parainfluenza virus; respiratory syncytial virus; bacillus pertussis; chlamydia; mycoplasma; human rhinovirus and enterovirus; and influenza A and B. We also detected Epstein-Barr virus (EBV), cytomegalovirus (CMV), and herpes simplex virus (HSV) DNA from plasma using PCR-based techniques in some cases. The Charlson Comorbidity Index (CCI) was used as an aggregate measure for underlying diseases.15 The disease severity of COVID-19 was assessed according to previously described classifications.16 The immunomodulatory drugs targeting COVID-19, including tocilizumab and steroids, were recorded.17 Moreover, an empirical antibiotic, defined as an antibiotic prescription at the time of admission, was also documented. The clinical outcome analysis included the hospital stay, 28-day, and in-hospital mortality, after the COVID-19 diagnosis.

2.3. Statistical analysis

The clinical data were analyzed using a commercially available software package (SPSS, version 21.0; SPSS Inc., Chicago, IL, USA). The categorical and continuous variables were presented as the absolute number (percentage) and median (interquartile range, IQR), respectively. Categorical variables were analyzed using the chi-squared or Fisher’s exact test. The Mann-Whitney U test was used to compare differences between groups in relation to continuous variables. Variables with a p-value < 0.05 on bivariate analysis were subsequently included in a logistic regression model for the multivariate analysis of risk factors for hospital-acquired infections. The cumulated incidence of 28-day mortality and remaining hospitalization until 90 days in COVID-19 inpatients with and without hospital-acquired infections were evaluated by means of the Kaplan–Meier curves. For all analyses, p-values were two-tailed; and a p-value < 0.05 was considered to be statistically significant.

3. RESULTS

During the study period, a total of 204 confirmed COVID-19 patients were admitted to our hospital. The timeline of the included cases is shown in Fig. 1. The majority of cases were admitted between February to April, 2020 and May to July, 2021. Of the 204 enrolled patients, 131 obtained bacterial cultures, 34 obtained fungus cultures, 92 underwent galactomannan tests, 34 received respiratory panel tests, and 75 underwent blood PCR detections for CMV, EBV, and HSV. Forty patients experienced at least one infectious episode (overall incidence, 19.6%). Among 40 patients with concurrent infections during the hospitalization, eight patients experienced eight episodes of infection within 48 hours of admission (five cases of bacterial infections; three cases of viral infections); 32 patients experienced 113 episodes of infection 48 hours after admission as shown in Table 1. The incidence of hospital-acquired infections occurring among COVID-19 inpatients was 15.7%. The median time from hospital admission to the diagnosis of the first episode of hospital-acquired infection was 10.5 days.

Table 1 - Microbial pathogens distribution from hospital-acquired infections of COVID-19 patients Pathogen Number or Number (%) Bacteria 88/113 (77.9)  Acinetobacterspp. 19  Stenotrophomonas maltophilia 14  Pseudomonas spp. 8  Klebsiellaspp. 8  Chryseobacterium indologenes 7  Elizabethkingiaspp. 6  Sphingomonas paucimobilis 5  Enterococcusspp. 4  Serratia marcescens 4  Delftia acidovorans 3  Staphylococcus spp. 2  Escherichia coli 2  Bacteroidesspp. 2  Streptococcus agalactiae 1  Enterobacter cloacae 1  Comamonas testosteroni 1  Tsukamurellaspp. 1 Virus 19/113 (16.8)  Epstein-Barr virus 12  Cytomegalovirus 5  Adenoviruses 1  Respiratory syncytial virus 1 Fungi 4/113 (3.5)  Aspergillus spp 3  Candida tropicailis 1 Atypical organisms 2/113 (1.8)  Mycoplasma pneumonia 1  Chlamydia pneumoniae 1
Fig. 1:

Monthly reported COVID-19 cases in our hospital.

3.1. Etiology of hospital-acquired infections among COVID-19 inpatients

A total of 38 bacterial infection episodes occurred in 23 inpatients. Notably, 28 episodes were lower respiratory tract infections, three were urinary tract infections, six were primary bloodstream infections, and one episode was an infection of the skin and soft tissue. Eighty-eight isolates were cultured from 38 bacterial episodes; 66 isolates (75%) exhibited multiple drug-resistant phenotypes. The most frequently isolated bacteria were Acinetobacter spp. followed by Stenotrophomonas maltophilia. Among 19 patients with Acinetobacter spp. infection, four were admitted to ICU and nine received carbapenem treatment before isolation. Of 14 patients with S. maltophilia infections, three were admitted in ICU, and 11 received carbapenem therapy before S. maltophilia infection. There were four cases of invasive fungal infections. Three of the fungal infections were considered as probable invasive pulmonary aspergillosis and one was determined to be Candida tropicalis candidemia. Nineteen viral infection episodes occurred in 17 inpatients, of which EBV constituted the majority, followed by CMV. A total of 16 of 17 patients infected with EBV or CMV were severe or critical disease severity. Only one Mycoplasma pneumonia and one Chlamydia pneumonia infections were noted. The distributions of the different kinds of pathogens for hospital-acquired infections are shown in Table 1.

3.2. A comparison between patients with and without hospital-acquired infections

As shown in Table 2, the clinical features of 32 patients who experienced at least one hospital-acquired infection were compared to those without hospital-acquired infections. The patients with hospital-acquired infections were more likely to be men, and older in age (75.0% vs 53.5% and 66 vs 56, p = 0.024 and <0.001, respectively). Additionally, they had a higher Charlson morbidity index and were more likely to have diabetes mellitus (1.5 vs 0, 43.8% vs 16.3%, p = 0.002 and <0.001, respectively). With regard to the disease condition, an ICU admission and severe to critical illness at the time of admission were associated with a higher risk for the development of hospital-acquired infection (25.0% vs 6.4% and 84.4% vs 40.7%, p = 0.003 and <0.001, respectively). Empirical antibiotic on admission, tocilizumab and steroids were used significantly more frequently in patients who developed hospital-acquired infections (87.5% vs 61.6%, 43.8% vs 11.0% and 93.8% vs 54.1%; p = 0.005, <0.001, and <0.001, respectively). Among the patients who received empirical antibiotics (n = 134), 98 (73.1%) received a respiratory fluoroquinolones-based regimen (moxifloxacin or levofloxacin). At the time of analysis, three included patients who were still in the hospital. The overall 28-day mortality and in-hospital mortality among the COVID-19 inpatients were 7.8% and 10.0%, respectively. The patients with hospital-acquired infections were at higher risk for 28-day and in-hospital mortality (18.8% vs 5.8% and 31.3% vs 5.8%, p = 0.023 and <0.001, respectively). Additionally, they had a longer hospital stay than those without hospital-acquired infections (34 days vs 19 days, p < 0.001). Consistently, the patients with hospital-acquired infections had a higher mortality rate and a higher incidence of remaining hospitalization until 28 days by survival analysis, as shown in Fig. 2A,B(log-rank test, p = 0.046 and <0.001, respectively). As indicated in Table 3, the multivariate analysis identified that steroid use (OR, 6.97; 95% CI, 1.15–42.43; p = 0.035) was a predictor that was independently associated with the development of hospital-acquired infections. Severe to critical illness and tocilizumab use were associated with a trend toward hospital-acquired infection occurrence (p = 0.092 and 0.080, respectively). Empirical antibiotics on admission were not associated with the occurrence of hospital-acquired infections (p = 0.447).

Table 2 - Clinical characteristics of COVID-19 patients Variable Total
(n = 204) Without Hospital-Acquired
Infection (n = 172) With Hospital-Acquired
Infection (n = 32) p Demographic feature, n (%)  Age, median (IQR) 58 (29) 56 (28.75) 66 (11.75) <0.001  Male gender 116 (56.9) 92 (53.5) 24 (75.0) 0.024  Locally acquired 174 (85.3) 143 (83.1) 31 (96.9) 0.054 Charlson morbidity index (IQR) 1 (2) 0 (2) 1.5 (2) 0.002 Comorbidities, n (%)  Heart failure 16 (7.8) 13 (7.6) 3 (9.4) 1.000  Chronic lung disease 6 (2.9) 3 (1.7) 3 (9.4) 0.051  Old cerebrovascular accident 11 (5.4) 8 (4.7) 3 (9.4) 0.384  Chronic kidney disease 11 (5.4) 7 (4.1) 4 (12.5) 0.074  Diabetes mellitus 42 (20.6) 28 (16.3) 14 (43.8) <0.001  Chronic liver disease 18 (8.8) 16 (9.3) 2 (6.3) 0.744  Malignancy 28 (13.7) 23 (13.4) 5 (15.6) 0.780 Disease condition on admission, n (%)  ICU admission 19 (9.3) 11 (6.4) 8 (25.0) 0.003  Severe to critical illness 97 (47.5) 70 (40.7) 27 (84.4) <0.001 Treatment medicine, n (%)  Antibiotic use on admission 134 (65.7) 106 (61.6) 28 (87.5) 0.005  Tocilizumab 33 (16.2) 19 (11.0) 14 (43.8) <0.001  Steroid 123 (60.3) 93 (54.1) 30 (93.8) <0.001 Clinical outcomes, n (%)  28-day mortality 16 (7.8) 10 (5.8) 6 (18.8) 0.023  In-hospital mortality (n = 201) 20 (10.0) 10 (5.8) 10 (31.3) <0.001  Hospital stay (IQR) (n = 184)a 20 (13) 19 (13) 34 (25.8) <0.001

ICU = intensive care unit; IQR = interquartile range.

aOnly survival cases are included for analysis

Table 3 - Multivariate analysis of factors associated with hospital-acquired infection in COVID-19 patients Variable OR (95% CI) p Age 1.01 (0.98–1.05) 0.593 Male sex 2.14 (0.80–5.74) 0.131 Charlson morbidity index 1.11 (0.86–1.42) 0.434 Diabetes mellitus 1.83 (0.64–5.19) 0.258 ICU admission 1.59 (0.46–5.45) 0.462 Sever to critical illness 2.77 (0.85–9.02) 0.092 Antibiotic use on admission 0.59 (0.13–2.44) 0.447 Tocilizumab 2.44 (0.90–6.61) 0.080 Steroid 6.97 (1.15–42.43) 0.035

CI = confidence interval; ICU = intensive care unit; OR = odds ratio.

Fig. 2:

Kaplan–Meier survival curves for the incidence of (A) mortality and (B) remaining hospitalization among COVID-19 inpatients. The patients with hospital-acquired infection had a higher rate of morality and remaining hospitalization than those without hospital- acquired infection (log-rank test, p = 0.046 and < 0.001, respectively).

4. Discussion

The distribution of the identified pathogens from different types of hospital-acquired infections, presented in our study, may assist clinicians with the provision of appropriate empirical therapy. Our research also indicated that these infections may complicate the hospital course of COVID-19 patients by increasing hospital stay and mortality. Furthermore, steroid use was found to be an independent risk factor, after the adjustment of other variables.

Among the different types of hospital-acquired bacterial infections in our study, the most common was a lower respiratory tract infection. Moreover, the most frequently isolated bacteria were Acinetobacter spp. Both these findings are consistent with previously updated, reported polled data.5 However, S. maltophilia ranked second place in terms of isolated bacteria in our research. This differs from previously reported data. Although additional data are required to determine whether the epidemiological results from our study are consistent with those of other institutions in Taiwan, clinicians should be alerted to this result as S. maltophilia exhibited multiple drug-resistant phenotypes. These may limit the prescription of empirical antibiotics. For influenza infections, empirical antibiotic treatment was recommended for adults with community-acquired pneumonia positive for influenza according to the American Thoracic Society and Infectious Diseases Society of America treatment guidelines for potential bacterial co-infections.18 However, several guidelines for COVID-19 treatment suggest that antibiotics should not be routinely prescribed.19–21 From the real-world clinical settings in Taiwan, COVID-19 patients often present as febrile with respiratory symptoms, such as fever, dry cough, dyspnea, and associated chest X-ray changes, as reported in other countries.10,22,23 It is difficult for clinicians to differentiate COVID-19 patients with and without concurrent bacterial infections at admission. Therefore, we need to note that 65.7% of COVID-19 inpatients were treated with an empirical antibiotic upon admission in our study. However, only five cases (2.5%) were diagnosed with a bacterial infection at admission and subsequent analysis revealed that empirical antibiotic use could not prevent subsequent hospital-acquired infections. Moreover, we observed higher cultured rates of multiple drug-resistant pathogens in COVID-19 patients in our study, which may be related to previous antibiotic exposure as the use of fluoroquinolones has been reported to be associated with multiple drug resistance.24 Given the current proposed recommendations and our study results, an empirical antibiotic prescription for COVID-19 patients on admission should be provided in a cautious manner, especially in those cases with a typical presentation of COVID-19. Further studies are needed to identify the robust biomarkers of concurrent bacterial infections in COVID-19 patients to guide appropriate antibiotic prescriptions by clinicians.

Recent reports have revealed that the cumulative incidence of COVID-19-associated pulmonary aspergillosis in ICUs was estimated to be 10.2%. Due to different diagnostic criteria in various countries and healthcare facilities, the incidence estimates have varied among enrolled studies.25 Up to now, there are still no comprehensive epidemiological data for invasive fungal diseases in COVID-19 patients in Taiwan. Using the updated criteria for hospital-acquired invasive fungal infections in COVID-19 patients, only four cases were found to be lower than previously reported in our study. The results from our research should be interpreted with caution since some included cases that were not accompanied by laboratory data from a galactomannan antigen test, necessary to diagnose COVID-19-associated pulmonary aspergillosis. Additionally, (1-3)-β-D Glucan testing, which is also useful in detecting fungal infections, was not available in our hospital.26 The incidence of invasive fungal infections in our study was probably underestimated and further analysis could not be performed due to the limited number of cases available.

Several reports have revealed different incidences of concurrent infections from other viruses in COVID-19 patients. These may be related to a different study time, population, or detection methods.27–29 The FilmArray Respiratory Panel, PCR methods, and serology test were used to detect evidence of hospital-acquired virus infections in our study. Respiratory viral infections were rarely noted. Only one respiratory syncytial virus and one adenovirus were detected in our study. This may reflect that the timing of the waves of the COVID-19 outbreak in Taiwan (March to April, 2020 and May to July, 2021, Fig. 1) succeeded the traditional respiratory virus peak period. Furthermore, only 34 of 204 patients were assessed on the FilmArray Respiratory Panel to detect respiratory pathogens. This may underestimate its true incidence. Notably, we observed that EBV tended to be followed by CMV. Such infectious cases all presented with viremia without end-organ involvement. Although concurrent EBV and CMV infections were identified less than has been previously reported, they were found to induce immune dysfunction and were associated with the severity of COVID-19.30–33 One report suggested an association of postacute COVID-19 syndrome with EBV reactivation.34 Our study revealed similar findings in that 16 of 17 COVID-19 patients with CMV or EBV infections presented with severe to critical disease severity. Whether antivirus agents for such infected patients may improve clinical outcomes warrants further investigation.

Multivariable analysis revealed that steroid use, which was shown to be a predictive factor for hospital-acquired infections may be an independent risk factor. Steroid use in COVID-19 patients has been approved due to the reduction in mortality based upon meta-analyses from seven randomized clinical trials.35 Due to the immunosuppressive effect of steroids, steroid use in COVID-19 patients raised concern for subsequent infection occurrence. From the results of CoDEX and Metcovid trials evaluating the effect of steroids on COVID-19 patients with a reported incidence of hospital-acquired infections, no difference in the incidence of hospital-acquired infections between patients with and without steroid were noted.36,37 However, several reports from real clinical settings showed an association between steroid use and subsequent occurrences of hospital-acquired infections.38–40 Our results also revealed that steroid use may be a predisposing factor for subsequent infections. To make a conclusion about the influence of steroids on subsequent infections, additional clinical data were warranted.

In our study, COVID-19 patients with hospital-acquired infections had higher 28-day and in-hospital overall mortality indicating the substantial influence on the clinical outcomes of COVID-19 patients consistent with previous reports.5 Moreover, a longer hospital stay of COVID-19 patients with hospital-acquired infection from our study may have more effect on the health care systems during the COVID-19 outbreak. COVID-19 patients remaining in a state of hospitalization would persistently occupy scarce bed days and require additional diagnostic and therapeutic interventions, which would substantially deplete the already limited healthcare system resources during the pandemic. Therefore, future studies should not focus upon therapy directly only against COVID-19. The identification of ways to reduce hospital-acquired infections in COVID-19 patients is equally important.

Despite the findings of this study, certain limitations were noted. Therefore, clinicians must interpret the results with caution. First, the study was retrospective in nature. Second, there was no standardized protocol for screening COVID-19 patients for different types of hospital-acquired infection, and most diagnosed cases relied on the clinical judgment of the treating physicians on requesting microbiological investigations. Therefore, the study analysis may be biased. Third, the relatively small sample size of COVID-19 patients (n = 32) limited our further analysis of different types of infections. Finally, this is a single-center retrospective study, which may limit its generalizability.

In spite of some limitations, our study results of hospital-acquired infections in COVID-19 patients from Taiwan revealed a unique local epidemiology of causative pathogens, risk factors for development, and significant deteriorated influence on the clinical outcomes of infected patients. Future prospective studies, including a larger number of COVID-19 patients involving hospitals of different regions in Taiwan using standard diagnostic protocol were needed to validate our study findings and may be helpful for future targeted preventive measures implementation.

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