Comparison of the Clinical Characteristics and Mortality of Adults Infected with Human Coronaviruses 229E and OC43

Abstract

Background: There are few studies on the epidemiology and prognosis of coronavirus infections among patients seen in emergency departments and hospital inpatients. The purpose of the study was to compare clinical characteristics and mortality among adults infected with human coronaviruses (HCoV) 229E and OC43.

Methods: We conducted a retrospective cohort study of adults (≥18 years) admitted to the emergency department and ward of a university teaching hospital for suspected viral infection from October 2012 to December 2017. Multiplex real-time polymerase chain reaction (PCR) was used to test for respiratory viruses. Multivariate logistic regression was used to compare mortality among patients with HCoV 229E and HCoV OC43 infections. The main outcome was 30-day all-cause mortality.

Results: Of 8,071 patients tested, 1,689 were found to have a respiratory virus infection. Of these patients, 133 had an HCoV infection, including 12 mixed infections, 44 HCoV 229E infections, and 77 HCoV OC43 infection s. HCoV 229E infections peaked in January and February, while HCoV OC43 infections occurred throughout the year. Sixteen patients (13.2%) with HCoV infections required admission to the intensive care unit. The 30-day all-cause mortality was 22.7% among patients with HCoV 229E infection, and 11.6% among patients with HCoV OC43 infection . Patients infected with HCoV 229E infection had a higher risk of death than those with HCoV OC43 infection (adjusted odds ratio: 2.11, 95% confidence interval: 0.74-6.05).

Conclusions: Infections with HCoVs 229E and OC43 appear to have different seasonal patterns, and HCoV 229E might be more virulent than HCoV OC43.

Background

In adults, respiratory virus infections are more frequent than bacterial infections as a cause of community-acquired pneumonia (CAP) [1]. Respiratory viruses are very contagious and are of public health importance [2, 3]. The demand for information on the clinical characteristics and prognosis of various respiratory virus infections is likely to increase.

In general, coronavirus infections are asymptomatic in healthy people but they are a common cause of upper respiratory infections (URIs) [4-6], which may progress to pneumonia [7, 8]. Coronaviruses are generically diverse [9], and may induce distinctive illnesses, including Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS) [10-13].

There are few studies on the epidemiology and prognosis of coronavirus infections among patients with respiratory symptoms seen in emergency departments and hospital inpatients [7, 14]. The prognosis of viral infections is influenced by age and comorbidities [15]. However, mortality from human coronaviruses (HCoVs) in high-risk population has not been well studied, and studies of the prognosis of HCoV infections need to take comorbidities and age into account.

Coronavirus respiratory infections occur primarily in the winter, although the infection can occur at any time of the year [16]. Multiplex PCR can detect multiple respiratory viruses simultaneously [17, 18], providing an opportunity to determine the seasonal patterns of different types of HCoV infection.

We conducted a study to determine and compare the clinical characteristics and mortality associated with HCoV 229E and OC43 infections among patients seen in the emergency department and hospital inpatients.

Methods

Study Population and setting

This study was performed at Keimyung University Dongsan Hospital, tertiary care teaching hospital in Daegu city, Republic of Korea. We conducted a retrospective cohort study of adults hospitalized with HCoV infections. All patients aged ≥18 years admitted with suspected respiratory virus infections between October 2012 and December 2017were considered. Virus multiplex PCR was performed if physicians suspected a respiratory virus infection. Patients with no viral infections identified, viral infections other than HCoV infections, and mixed viral infections were excluded.

The study was approved by the institutional review board (IRB) at Dongsan Hospital, Keimyung University School of Medicine (2019-08-026). The IRB waived the requirement for informed consent, and the study was conducted in compliance with the Declaration of Helsinki.

Definitions

An upper respiratory infection was defined as the presence of one or more of the following respiratory symptoms: cough, sputum production, rhinorrhea, sore throat, or dyspnea. Pneumonia was defined as the presence of a new or progressive infiltrate found using either chest radiography or chest CT scan, in addition to two or more of the following: fever, sputum production, rhinorrhea, sore throat, dyspnea, or a diagnosis of pneumonia by the attending physician. The outcome was all-cause mortality up at 30 days after hospital admission.

Specimens

Nasopharyngeal specimens were obtained using flocked swabs and stored and transported using the universal transport medium, as described elsewhere [19].

Respiratory virus testing

Respiratory virus (RV) 13 testing was performed to detect the following viruses: adenovirus(A~F), influenza viruses A and B, respiratory syncytial virus (RSV) A, RSV B, parainfluenza viruses 1 to 3, Rhinovirus, metapneumovirus, coronavirus 229E, coronavirus OC43, and bocavirus. During the RV13 test, an internal control was added to each specimen to check the entire process from nucleic acid extraction to PCR, according to the manufacturer's instructions. An Anyplex II RV13 Detection Kit (BioSewoom, Seoul, Korea) was used, according to the manufacturer's instructions.

Data Collection

This study was performed at Keimyung Universi­ty Dongsan Hospital, a 867-bed, tertiary care teaching hospital in Daegu, Republic of Korea. If a patient had an episode of acute respiratory infection at an emergency department or outpatient clinic or within 2 days during admission, he or she underwent multiplex RT-PCR (Reverse transcription polymerase chain reaction) testing. Adult patients (≥18 years of age) who had a multiplex RT-PCR test between October 2012 and December 2017 were identified by searching electronic medical records. We collected clinical data from the electronic medical records on general patient characteristics, co-morbidities, presenting symptoms, lower respiratory tract complications, provision of supplemental oxygen therapy and/or ventilatory support, length of hospital stay, and all-cause mortality. We also collected data on all patients’ chest radiography, including the radiologists’ reports, chest computerized tomography scans (if available), and routine blood test results. Sputum samples were collected for bacterial culture preparation at admission and during hospitalization. Blood cultures were also performed when indicated. Pneumonia severity index (PSI) score was collected every admitted patient. We contacted patients or their families by phone to identify survival and clinical information if the patients were not followed up regularly.

Statistical Analysis

Baseline characteristics (including age, sex, residency in a long-term care facility, comorbidities, presenting symptoms, and complications) at date of admission were summarized between 229E and OC43 infection using descriptive statistics, such as proportion and means (standard deviation, SD). A Chi-squared test was used for comparison between categorical variables, and independent t-tests, for comparison between continuous variables.

The univariate and multivariate logistic regression models were used to evaluate the risk of death from HCoVs infection between their types. Adjustments were made for sex, age, body temperature and bacterial superinfection. Selection of covariates for the model building was based on clinical relevance and availability. Variables showing P value more than 0.2 in univariate analysis also included in the models. P values <0.05 were considered statistically significant. All statistical analyses were performed using IBM SPSS V.21.0.

Results

The process of selecting the patients eligible for inclusion in the analysis is shown in Figure 1. There were 8,071 patients tested for respiratory infections with virus multiplex PCR during the study period, of whom 6,382. had no identifiable viral infections, 1,556 had viral infections other than HCoV infection, 12 had HCoV infections mixed with other viral infections, and 121 had HCoV mono-infections. Of the 121 patients with HCoV mono-infections, 44 had HCoV 229E infection, and 77 had HCoV OC43 infection. Of the 8,071 patients tested with respiratory virus multiplex PCR during the study period 1.6% had HCoV infection, including 1.5% with HCoV mono-infections. Of the 1,689 patients who tested positive for a respiratory virus on PCR, 7.2% had single HCoV infections.

Of the 12 patients with mixed infections. one HCoV OC43 and bocavirus coinfection, one had HCoV 229E and metapneumovirus coinfection, one had HCoV OC43 and parainfluenza type 2 coinfection, one had HCoV OC43 and respiratory syncytial virus A coinfection, one had HCoV 229E and respiratory syncytial virus B coinfection, one had HCoV 229E and rhinovirus A coinfection, four had HCoV 229E and influenza A coinfections, one had HCoV OC43 and influenza B coinfection, and one had HCoV 229E and influenza B coinfection.

Of the 121 patients with HCoV mono-infection, all had chest radiography results, and 72 (59.5%) had chest CT scan results. Thirty-five patients did not have data on arterial blood gas analysis.

Clinical Characteristics

The characteristics of patients with HCoV 229E and HCoV OC43 infections are compared in Table 1. The two groups were similar in terms of age, sex, residence in long-term care facilities and comorbidities, including pneumonia and respiratory bacterial coinfection. Patients with HCoV 229E infection had a significantly higher mean body temperature than patients with HCoV OC43 infection. A higher proportion of patients with HCoV 229E infection than those with HCoV OC43 infection were admitted to the intensive care unit (15.9% versus 11.6%, P = 0.51), but their mean Pneumonia Severity Index (PSI) scores were similar (101.1 versus 98.7, P= 0.70).

Bacterial pathogens were detected in patient sputum of 13.6% of the patients with HCoV 229E infection, and 18.2% of those with HCoV OC43 infection (P = 0.52); and 15.9% of patients with HCoV 229E and 6.5% of those with HCoV OC43 infection had bacterial bloodstream infections (P = 0.09).

Seasonal Variation

There were seasonal peaks in the number of patients admitted with HCoV 229E during January to February in 2014 and 2016, but there were no distinctive seasonal peaks in admissions of patients with HCoV OC43 infection (Fig. 2).

Mortality

The crude 30-day mortality in the patients with HCoV 229E and HCoV OC43 infections was was 22.7% and 11.6%, respectively (Fig. 3). The results of the multivariate analysis showed that the risk death within 30 days (30-day mortality) was higher in patients with HCoV 229E infection than those with HCoV OC43 infection, but this result was not statistically significant (odds ratio: 2.11, 95% confidence interval: 0.74-6.05, P = 0.16) (Table 2).

Bacterial coinfections

Sixty (49.2%) of sputum specimen and 112 (91.8%) of the blood-culture specimens obtained from 121 HCoV infected patients. A pathogen in sputum was detected in 20 (16.5%) patients among 121 virus detected CAP: 12 patients (9.9%) had gram-positive pathogens, and 8 patients (6.6%) had gram-negative pathogens detected on sputum culture. Of the 121 patients, 12 (9.9%) had positive blood culture results. Ten patients (8.3%) had gram-positive pathogens, and 2 (1.7%) had gram-negative pathogens detected on blood culture. Staphylococcus aureus was the most common pathogen isolated in both sputum and blood specimens (Table 3).

Discussion

This study included patients with respiratory symptoms who were seen in the emergency department or hospitalized. HCoV was found in 133 patients (1.6%) of the 8,071 tested for respiratory viruses using multiplex PCR. The 30-day mortality rate of patients with HCoV infection was 22.7% for HCoV 229E and 11.6% for HCoV OC43. HCoV 229E infections peaked in January and February of 2014 and 2016.

In one study, the prevalence of HCoV was 21.7% among healthy, elderly patients with respiratory symptoms, 21.3% in high-risk patients, and 8.2% in inpatients [7]. A study of patients with chronic obstructive pulmonary disease (COPD) and exacerbated respiratory symptoms found that 14% had HCoV 229E or HCoV OC43 infection [20]. In this study, HCoV 229E and HCoV OC43 were found only in 1.6% of patients with respiratory symptoms. However, in a study done in Edinburgh, 1.25% of the respiratory samples tested using multiplex were positive for HCoV 229E or HCoV OC43 [16], which is lower than that found in our study. The variability in the proportion of individuals with HCoV detected across studies suggest that the prevalence of HCoV infection varies depending on the characteristics of the study participants or the geographic region.

In this study, of the 1,689 patients found to have a respiratory virus infection, 133 (7.9%) had HCoV 229E or HCoV OC43 infections, including patients with mixed infections. This suggests that HCoVs account for a significant proportion of respiratory viral infections in high-risk patients. In this study, the prevalence of HCoV infection was slightly lower than that found among patients with CAP in other studies [21, 22]. As this study was conducted among patients admitted to the emergency room or hospitalized with respiratory symptoms, the reports of the prevalence of HCoV 229E and HCoV OC43 infection found in this study should be limited to these patients.

In this study, while HCoV 229E showed clear peaks in January to February 2014 and January to February 2016 during five years, but the frequency of HCoV OC43 infections did not display any substantive seasonal variation. Unlike the present study, other studies have shown biennial peaks of HCoV OC43 in winter., and a higher incidence of HCoV 229E infection in winter [16, 23, 24]. Taken together, it may be difficult to define the occurrence of HCoV infections to specific seasons.

Among patients in this study, some patients with HCoV 229E infection experienced headaches but patients with HCoV OC43 infection did not. The incidence of diarrhea was similar among patients with HCoV 229E infection and HCoV OC43 infection. The prevalence of bacteremia was higher among patients with HCoV 229E infection than those with HCoV OC43 infection, but this difference was not statistically significant. In this study, the prevalence of pneumonia was similar among patients with HCoV 229E infection and those with HCoV OC43 infection, and was higher than that observed in other studies [7]. The mean pneumonia severity index score among patients with HCoV OC43 and HCoV 229E infections was 99 and 101, indicating that the patients with HCoV infection had severe disease. In contrast to this study, previous studies have found a higher prevalence of pneumonia among patients with HCoV OC43 infection than in those with HCoV 229E infection [7]. In contrast to previous studies, in our study, admission to the intensive care unit was more frequent among patient HCoV 229E infections than in those with HCoV OC43 infections [7].

In our study, we did not find any patients with coinfections with two different types of HCoV, but 9.0% of the patients with HCoV infections had coinfections with other respiratory viruses were coinfected with 9.0%.. The most commonly observed coinfections were HCoV 229E and influenza A, which accounted for four of the 12 the coinfections. In contrast to our study, other studies have reported a prevalence of HCoV 229E or HCoV OC43 coinfection, ranging from 20% to 30% [24, 25].

Mortality rates of 28–35% have been reported among patients with MERS [26, 27], and 6–15% among patients with SARS and most deaths have occurred in individuals aged over 60 years [28, 29]. If mortality rate could be translated into virulence of viruses, MERS CoV are more virulent than SARS. In our study, patients with HCoV 229E infection had a higher mortality rate than those with HCoV OC43 infection, although the difference was not statistically significant in the multivariate analysis. this suggest that HCoV 229E might be more virulent than HCoV OC43.

This study has some limitations. We were unable to test patients for HCoV NL63 or HCoV HKU1 virus because test kits only detected HCoV 229E and HCoV OC43. Therefore, we did not have information on HCoV NL63 and HCoV HKU1 infection which is necessary to provide a complete picture of HCoV infection. The study did not include patients with mild respiratory symptoms or patients who were asymptomatic, thus patients with few comorbidities and a good prognosis are likely to have been excluded, preventing the study results from providing a comprehensive clinical picture of HCoV infection. In addition, the prevalence of HCoV infections among the patients tested for respiratory viruses may have been underestimated because lower airway samples were not tested. Data were collected retrospectively, and missing data and inadequate documentation may have resulted in biases in the study results.

Conclusions

Among patients with suspected respiratory infection, 1.6% had HCoV infection. HCoV 229E infections and HCoV OC43 infections appear to have seasonally different patterns. HCoV 229E infection might cause more severe disease than HCoV OC43 infection in adults.

Abbreviations

CAP, community-acquired pneumonia; CI, confidence interval; COPD: chronic obstructive pulmonary disease; HCoV human coronavirus; HCoVs human coronaviruses; MERS Middle East Respiratory Syndrome; OR, odds ratio; PSI, Pneumonia Severity Index; SARS, Severe Acute Respiratory Syndrome; URI, upper respiratory infection

Declarations

Ethics approval and consent to participate

The current study was approved by the institutional review board at Dongsan Hospital, Keimyung University School of Medicine (2019-08-026). The need for written informed consent was waived. This study was conducted in compliance with the Declaration of Helsinki.

Consent for publication

Not Applicable

Availability of data and materials

The datasets supporting the conclusion of this article is available. We presented the datasets in the additional supporting file. Data is available upon request. If someone wants to request the data should be contacted with Won-Il Choi.

Competing interests

All authors declare no potential conflicts of interest.

Funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIP) (No. 2014R1A5A2010008).

Authors’ contributions

Won-Il Choi: Conceptualization, Data curation, Supervision, Writing - original draft, Writing - review & editing. Choong Won Lee: Formal analysis, Methodology, Writing - review & editing.

Acknowledgements

We would like to thanks to Ms. Jin Hee Jeon for the preparing data sets.

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Tables

Table 1. Characteristics, comorbidities, complications, and outcomes of patients infected with human coronavirus 229E and OC43 infections, October 2012 to December 2017 

PSI, Pneumonia severity index; ICU, intensive care unit; SD, standard deviation

Table 2. Factors associated with 30-day all-cause mortality among patients with human coronavirus 229E and OC43 infections

Table 3. Bacterial pathogens identified among patients with human coronavirus 229E and OC43 infections according to sample type and virus type