Comparison of clinical characteristics and outcomes of hospitalized patients with seasonal coronavirus infection and COVID-19: a retrospective cohort study

Coronaviruses are large, enveloped, single-stranded RNA viruses found in humans and other animals, such as dogs, cats, bats, chickens, cattle, pigs, and birds. These viruses have the potential to cause respiratory, enteric, hepatic, and neurologic diseases. The most common coronaviruses in clinical practice are 229E, OC43, NL63, and HKU1, which typically cause common cold symptoms in immunocompetent individuals and contribute 15% to 30% of common cold cases [1, 2]. Two other strains, the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV), are associated with severe respiratory disease and are responsible for the first significant coronavirus outbreaks [2, 3]. On December 21, 2019, a novel coronavirus was identified in hospitalized patients with pneumonia in Wuhan, China. Genetic analysis revealed that this novel coronavirus fits into the genus betacoronavirus. Further phylogenetic analysis showed that the SARS-CoV-2 virus belongs to the subgenus Sarbecovirus and that is more similar to two bat-derived coronavirus strains, bat-SL-CoVZC45 and bat-SL-CoVZXC21, than to known human-infecting coronaviruses, including SARS-CoV [3, 4].

Because seasonal coronaviruses are regarded as mild upper respiratory pathogens with a known peak prevalence during December–March each year in the U.S. (coinciding with the winter respiratory virus season), molecular testing is not frequently performed in the clinical outpatient practice, and it is reserved for surveillance purposes [5]. However, because of the increased availability of molecular test methods and the adoption of sCoV testing as part of routine multiplex diagnostic screens, particularly for patients with severe respiratory illness or admitted to critical care units where a precise microbiologic diagnosis is more clinically relevant, it is now possible to recognize and characterize the associated disease spectrum of severe sCoV infections and compare it to that of COVID-19 [5, 6]. The clinical presentation, diagnostics, and outcomes of patients with COVID-19 have been well described in multiple case series and cohort studies [7‐10] and compared to hospitalized patients with other respiratory viruses [11‐14]. Nevertheless, there is limited data on how COVID-19 compares clinically to seasonal coronaviruses (sCoV). Unlike SARS-CoV and MERS-CoV, SARS-CoV-2 carries the potential to become a recurrent seasonal infection; hence, it is essential to compare the clinical spectrum of COVID-19 to the existent endemic coronaviruses in an attempt to help clinicians distinguish both entities during potential co-circulation throughout winter seasons and guide further management [5, 15, 16]. Thus, this study compares the clinical characteristics, course, and outcomes of hospitalized patients with COVID-19 with hospitalized patients with sCoV infection.

This retrospective cohort study examined the characteristics and clinical outcomes of hospitalized patients with sCoV infection compared to patients with COVID-19. Patients with COVID-19 presented a higher case fatality rate and an almost fourfold increased risk of death than patients with sCoV. Interestingly, the rates of ICU admission and IMV use were not significantly different. However, more patients with sCoV were extubated and were more likely discharged from the ICU than patients with COVID-19. Seasonal coronaviruses are usually associated with mild upper respiratory illness in adults and are not a considerable public health burden [16]. Though, elderly individuals and immunocompromised hosts can sometimes develop life-threatening bronchiolitis, pneumonia, and even neurological infection (hCoV-OC43) [2]. In one study of community-acquired pneumonia requiring hospitalization among U.S. adults, the incidence of coronaviruses in individuals 80 years of age or older was similar to that of Streptococcus pneumoniae [23]. Besides, previous studies have linked common respiratory viruses, including sCoV, with COPD exacerbations, asthma exacerbations, and worsening cardiovascular disease [24‐27]. In our cohort, patients admitted with sCoV were found to be initially admitted due to exacerbation of a pre-existing condition, namely heart failure exacerbation and COPD or asthma exacerbation, and later found to have a sCoV infection, where coronaviruses were likely responsible for disease aggravation, as demonstrated by the significantly higher proportions of patients with sCoV infection and underlying cardiovascular disease, obstructive pulmonary disease, and immunodeficiency in comparison to patients with COVID-19. In contrast, most patients with SARS-CoV-2 infection were merely admitted due to COVID-19 and its complications.

The clinical spectrum of hospitalized patients with SARS-CoV-2 infection has been mainly compared to SARS, MERS, and other pandemic viruses [28, 29]; nevertheless, our data shows significant differences with these viruses and important similarities with hospitalized patients with sCoV infection. For instance, although all coronaviruses can affect persons in all age groups, hospitalized patients with COVID-19 and sCoV infection were found to be older (median age 69 and 74 years, respectively). In contrast, previous series reported younger populations affected by SARS and MERS (median age 39 and 56 years, respectively) [30‐35]. COVID-19 and MERS affected more male patients, while sCoV and SARS affected predominately female patients. Overall, SARS series reported fewer patients with pre-existing underlying conditions (10 to 30%) [30‐32], while in MERS series, 50 to 96% of patients were reported to have at least one underlying condition [33‐35]. Similar to MERS series, more than 80% of hospitalized patients with sCoV and COVID-19 had two or more underlying comorbidities in our cohorts. For COVID-19, sCoV, and MERS, the most common presenting symptoms included fever, cough, and shortness of breath, while in SARS series, fever and cough were more prominent relative to shortness of breath [30‐35]. Leukopenia on admission was less common in our cohort of patients with sCoV (6.3%) and COVID-19 (9.5%) compared to previous MERS (14–42%) and SARS (25–35%) series [34, 35], whereas lymphopenia rates were similar in patients with sCoV (71.6%), COVID-19 (78.9%), and SARS (68–85%) in comparison to MERS (34%) [35]. As expected, rates of bilateral or multifocal infiltrates at admission were overall higher in patients with COVID-19 (61.6%), SARS (29–45%), and MERS (26–80.3%) than in patients with sCoV infection (30.5%) [30‐34]. The rates of ICU admission among patients with sCoV (35.3%) and COVID-19 (32.1%) in our cohorts were higher than in SARS series (20–26%) but lower than in MERS series (78–89%) [30‐33, 35]. Overall, the rates of IMV were higher in MERS series (24.5–80%), followed by our cohort of patients with COVID-19 (19.5%), SARS series (13.8–21%), and our cohort of patients with sCoV infection (14.2%) [30‐35]. Case fatality rates were higher in series of hospitalized patients with MERS (20.4–65%), followed by our cohort of hospitalized patients with COVID-19 (34.7%), SARS series (3.6–13.6%), and our cohort of hospitalized patients with sCoV infection (11.6%) [30‐35]. Considering all patients, including outpatients and inpatients, the estimated case-fatality rate of COVID-19 is around 1–3%, 9.5–15% for SARS, and 34.4% for MERS. The overall case-fatality rate for seasonal coronaviruses is not well described [28, 29]. However, using data from the Underlying Cause of Death tool in the CDC Wide-ranging ONline Data for Epidemiologic Research (CDC WONDER) Online Database and the National Respiratory and Enteric Virus Surveillance System (NREVS), we estimated a rough case fatality rate of 0.0027% (108 deaths from unspecified coronavirus illness reported between the years 2014–2017 in the CDC WONDER Online Database and 39 588 cases of HCoV reported to the NREVSS during the same period) [5, 36].

Compared to other respiratory pathogens other than coronaviruses, COVID-19 shares some similarities but also has a unique disease spectrum. In a study by Shah et al., similarly to our results, most comorbidities, medications, symptoms, vital signs, laboratories, treatments, and outcomes did not differ between patients with and without COVID-19. However, patients with COVID-19 were more likely to be admitted to the hospital (79% vs. 56%, p = 0.014), have more extended hospitalizations (median 10.7 days vs. 4.7 days, p < 0.001), and develop ARDS (23% vs. 3%, p < 0.001), and were unlikely to have co-existent viral infections compared with patients with an acute respiratory illness different that COVID-19 [11]. Furthermore, Spieza et al. showed that patients with COVID-19 pneumonia had significantly shorter clot formation time and higher maximum clot firmness (P < 0.01 and P < 0.05, respectively) than patients with non-COVID-19 pneumonia [12].

In a systematic review that compared COVID-19 to influenza, comorbidities such as cardiovascular diseases, diabetes, and obesity were significantly higher in COVID-19 patients. In contrast, pulmonary diseases and immunocompromised conditions were significantly more common in influenza patients, similar to our population with sCoV infection. Neurologic symptoms and diarrhea were statistically more frequent in COVID-19 patients compared to influenza patients, reminiscent of our cohort of COVID-19 patients. Ground-grass opacities and a peripheral distribution were more common in COVID-19 patients than in influenza patients, where consolidations and linear opacities were described instead. In comparison, our patient population with COVID-19 also most commonly presented diffuse opacities with bilateral distribution compared with patients sCoV infection. Lastly, COVID-19 patients were found to have significantly worse outcomes than influenza patients: More often transferred to intensive care unit with a higher rate of mortality [13]. The severity of COVID-19 compared to influenza was demonstrated again in a study by Talbot et al., where patients with COVID-19 showed greater severity and complications, including more ICU admissions (aOR 5.3, 95% CI 11.6–20.3), ventilator use (aOR 15.6, 95% CI 10.7–22.8), seven additional days of hospital stay in those discharged alive, and death during hospitalization (aOR 19.8, 95% CI–12.0, 32.7) [14].

With the expansion of SARS-CoV-2 worldwide, the emergence of new, more transmissible variants [37, 38], and the variable effectiveness of current vaccines against those variants [39], there is little hope for eliminating the virus from the human population. Unlike SARS-CoV and MERS-CoV, which were locally contained, SARS-CoV-2 will likely transition to endemicity and continued circulation with the other sCoVs [16]. Seasonal coronaviruses have annual circulation peaks in the winter months in the U.S., and individual species show variable circulation from year to year [5]. Recent data from the NREVSS showed that during the 2019–20 winter season, HCoV-HKU1 was the most common sCoV circulating in the U.S., followed by HCoV-NL63. In comparison, during the 2020–21 winter season, HCoV-OC43 was the most common sCoV circulating in the U.S., again followed by HCoV-NL63 [40]. Our cohort encompassing nine years, the most common isolated sCoV was HCoV-OC43, followed by HCoV-HKU1. Although it is not clear whether COVID-19 will become a chronic seasonal disease, numerous epidemiological studies and models have explored the relationship between COVID-19 transmission and meteorological factors. These models have shown that infectivity of SARS-CoV-2 and mortality of COVID-19 are more substantial in colder climates and that COVID-19 seasonality is more pronounced at higher latitudes where larger seasonal amplitudes of environmental indicators are observed [15, 41], supporting the circulation of SARS-CoV-2 as a seasonal respiratory pathogen.

This study has several limitations. As mentioned before, one of the most significant limitations is the selection bias associated with the inpatient use of the respiratory multiplex panel by PCR. Since its availability and up to the writing of this manuscript, there is no formal protocol in place within the Integrated Health System regarding when to order this test. Physicians can order the panel at their discretion. In consequence, there may be a selection bias towards patients with more severe disease, whereas patients with less severe disease were omitted. We tried to address this issue with a sensitivity analysis, including only critically ill patients. Another significant limitation is the fact that the data of the COVID-19 population analyzed in this study were obtained during the initial wild-type (Wuhan-Hu-1) phase in the United States and before the emergence of variants of concern that later replaced the wild-type virus, namely Alpha, Delta, and Omicron, that have been shown to have different biological, epidemiological and clinical characteristics [42, 43]. This was a retrospective cohort study, and clinical data were retrospectively collected through electronic medical records and manual chart review. Therefore, a degree of inter-rater variability is expected. Second, the present study was observational and included populations of patients distributed at different points in time; thus, unknown risk factors and bias might have been unequally distributed between the two groups in the analysis. The subjects with COVID-19 included for analysis encompass a series of consecutively admitted patients early in the pandemic before using steroids as the standard of care and the development of standardized, evidence-based management guidelines, and widespread availability of COVID-19 vaccines, which have shown to have a significant impact on morbidity and mortality. On the other hand, the cohort of subjects with sCoV infection included patients from a period of 9 years, during which progress in medical knowledge and patient care are expected; hence, the crude case-fatality ratio must be taken with caution. Finally, the analyzed population was limited to one Integrated-Delivery Health system in the Chicago metropolitan area and may have limited external generalizability.

In conclusion, the clinical spectrum of hospitalized patients with COVID-19 is more similar to SARS and MERS in terms of illness severity and case-fatality rate than hospitalized patients with sCoV infection. However, the demographics and baseline characteristics of patients hospitalized with COVID-19 and sCoV infection are more similar, affecting older populations with many underlying conditions, making it difficult to distinguish both entities solely on a clinical basis. Thus, should SARS-CoV-2 transition into an endemic virus after the pandemic, clinical findings alone may not help confirm or exclude the diagnosis of COVID-19 during high acute respiratory illness seasons. With the availability of specific COVID-19 therapies and infection prevention protocols, the respiratory multiplex panel by PCR that includes SARS-CoV-2 in conjunction with local epidemiological data may be a valuable tool to assist clinicians with management decisions.