Comparison of the clinical presentation across two waves of COVID-19: a retrospective cohort study

Coronavirus disease 2019 (COVID-19) is a global pandemic with more than 236 million confirmed cases worldwide as of October 10, 2021 [1]. Since COVID-19 on March 11, 2020, was declared a pandemic by the World Health Organization, several countries have observed a wave pattern in the number of COVID-19 cases with increased numbers of cases in the high peak months of 2020 [2‐4]. The first confirmed COVID-19 patient in Denmark was reported on February 27, 2020, and the disease soon became widely spread in the Danish community [5, 6]. The current population of Denmark is approximately 5.8 million. Denmark has as of October 10, 2021, 2669 confirmed deaths related to COVID-19 and 363,900 confirmed cases of which 17,553 has been hospitalized [6]. The daily number of diagnosed and hospitalized Danish patients has changed over time, and the outbreak in Denmark has likewise been observed as two waves in 2020 [6]. In line with other countries and as a consequence of the increasing number of COVID-19 cases in wave 1, the Danish government introduced a series of prevention measures that gradually were removed during the Danish summermonths and reintroduced in the third quarter of 2020. Most Danish and international studies of the clinical characteristics have primarily focused on patients from the first wave of COVID-19 [7‐13]. Only a few studies have performed comprehensive investigations of the similarities and differences between hospitalized patients in different wave periods [2, 3, 14‐16]. To our knowledge no Danish study has previously compared patients from the first and second waves.

Thus, the primary aim of this study was to compare and identify differences in the demographic, clinical, and laboratory characteristics of patients hospitalized in the western part of Denmark during the first and second wave periods of COVID-19 in 2020. Furthermore, we aimed to identify risk factors for critical COVID-19 disease and describe the given information on the sources of infection 14 days prior to infection.

In the comparison of the clinical presentation of hospitalized patients admitted during the first and second waves of COVID-19 in the western part of Denmark, we found a milder course of disease during the second wave period from July to December 2020 compared to the first wave period from March to June 2020. Fewer patients experienced critical disease during wave 2. Furthermore, patients admitted during wave 2 were hospitalized and received oxygen supplementation for a shorter time than patients from wave 1. In addition, fewer patients received mechanical ventilation and experienced symptoms such as fever, cough, and dyspnea. Despite a milder course of disease, patients hospitalized in wave 2 were admitted significantly sooner after the onset of symptoms than those hospitalized in wave 1. Patients admitted during wave 2 were mostly infected with COVID-19 at home, and only a few were infected at the hospital. We found no significant differences in sociodemographics, lifestyle information, or laboratory data in the comparison of patients admitted during the first and second waves of COVID-19 in 2020.

Recent studies have compared the characteristics of hospitalized patients from different waves of COVID-19 [2, 3, 14‐16, 19‐22]. However, the studies reported different measurements, inclusion criteria, and aims. To our knowledge, only a few studies have performed a comprehensive comparison of the clinical characteristics with the inclusion of laboratory data [14, 15]. Likewise, comparisons of the sources of infection from different waves of COVID-19 have only been investigated to a limited degree [21].

In agreement with our study, studies from Spain, Japan, and Iran indicated a milder course of disease during the second wave period [2, 3, 20]. These studies likewise reported a lower mortality among hospitalized patients with COVID-19 in the second wave than in the first wave [2, 3, 20]. Similar to our study, Iftimie et al. reported a shorter hospitalization during the second wave, Saito et al. reported a shorter period from disease onset to admission during the second wave, and Jalali et al. reported a decreased percentage of individuals admitted to the ICU during the second wave [2, 3, 20]. In contrast, a Swiss study reported similar in-hospital mortality and risk of ICU admission in waves 1 and 2 [16].

Although not statistically significant, we observed a tendency toward higher CRP and creatinine levels among patients admitted in wave 1 than in wave 2. This finding is in line with higher CRP and creatinine levels among patients with a critical disease since more patients from wave 1 experienced critical disease. In comparison, Mollinedo-Gajate et al. also reported a higher CRP level among patients with a critical or fatal disease and a higher level of CRP during the first COVID-19 wave [15]. To our knowledge, the present study is the first to compare levels of creatinine between different waves of COVID-19.

Likely explanations for a milder course of disease during the second wave compared to the first wave of COVID-19 are numerous. First, vulnerable and elderly persons were more likely to be exposed to the virus at the beginning of the pandemic compared to wave 2. Different restrictions, prohibitions, and orders were applied in Denmark from mid-March 2020 to control the spread of the disease and to protect vulnerable and elderly persons. Thus, we assume that a larger percentage of the population was at risk of critical disease during the first wave of COVID-19. Second, the initial treatment of COVID-19 was mostly symptomatic, however, as the clinical management was refined over time, this could possibly have improved the outcome for those hospitalized later during the pandemic. Refined clinical management could likewise have resulted in a reduced length of hospitalization in wave 2 compared to wave 1. Third, potential changes in SARS-CoV-2 genomic variations from wave 1 to wave 2 could have influenced the disease severity among patients, as SARS-CoV-2 genomic variations have been associated with the mortality rate of COVID-19 [23]. Finally, the Danish testing strategy may have increased the number of patients with a milder course of disease during wave 2 in the present study. The testing strategy was adjusted several times during 2020. In the beginning of the pandemic, the total Danish testing capacity was limited but increased considerably over time. During wave 2, all hospitalized patients were tested before or during admission. In contrast to wave 2, secondary COVID-19 diagnoses were not necessarily registered during wave 1. Thus, the study population from wave 2 may contain more patients with milder courses of disease.

Interestingly, patients were admitted sooner in wave 2 than in wave 1, increasing the likelihood of timely treatment. Potentially, this could have decreased the number of individuals experiencing critical disease.

Most studies investigating risk factors for COVID-19 were conducted during the beginning of the pandemic [11, 24‐26]. Thus, a secondary aim of our study was to identify risk factors for critical COVID-19 disease in a study population with the inclusion of patients from two different waves in 2020. As expected, we identified older age, male sex, smoking, comorbidities, fever and dyspnea as risk factors for a critical COVID-19 disease course. Furthermore, we observed significantly increased levels of CRP and creatinine, and lower hemoglobin levels among patients with a critical disease. Our results are thus in line with the results from a systematic review including 207 studies from the spring of 2020 [27]. Izcovich et al. identified sociodemographic characteristics (age, male sex and smoking), comorbidities, and increased levels of CRP and creatinine as prognostic factors for mortality and/or severe COVID-19 disease [27]. Another study investigating the COVID-19 mortality rate in 16 countries likewise found increased risk of COVID-19 death among elderly persons in addition to a higher risk in males than in females [28].

In the beginning of the pandemic, the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was high in the service area of the RHWJ compared to the rest of Denmark [6]. Data on sources of infection from this study did not provide an explanation of this matter. Unfortunately, the sources of infection were unknown for the majority of patients. Interestingly, however, we observed a change in the sources of infection comparing information from the first and second wave. Approximately 10% of the patients were infected at the hospital during wave 1. In contrast, only a few individuals were infected at the hospital in the second wave. A study of the prevalence of SARS-CoV-2 antibodies among hospital employees during wave 1 showed increased seroprevalence among employees at the RHWJ compared to other hospitals [29]. This may have contributed to the increased numbers of hospital acquired COVID-19 infections in the beginning of the pandemic. Furthermore, the testing strategy may have increased the risk of infections at the hospital during wave 1.

By inclusion of all hospitalized COVID-19 patients in a geographical area comprising 5000 km² and a population of approximately 286,000 inhabitants, our study population is representative of the most severely affected COVID-19 individuals in the western part of Denmark in 2020. The Danish healthcare system is universal, publicly funded, and based on the principles of free and equal access to healthcare, including tests, for all citizens. A key strength of this study was that all patients were included consecutively and followed from admission to discharge. Furthermore, all patients were included in the study before the Danish population was offered vaccination against COVID-19. Overall, these factors help eliminate selection bias.

The present study has some limitations due to the study design and number of cases. We performed a single-center study, which affects the external validity. Furthermore, the retrospective study design affects the available data, especially the documentation of sources of infection. The present study did not include individual information on the pharmalogical treatment. In general COVID-19 patients at RHWJ were treated using thromboprophylaxis. During wave 2 the pharmacological treatment also comprised remdesivir, dexamethasone, and tocilizumab. Thus patient outcomes may have been affected by differences in the pharmacological treatment. Wave periods of the pandemic have evolved at different times on continents/countries during the pandemic [30]. In the beginning of the pandemic, the number of COVID-19 admissions at RHWJ was high [6]. However, only 12 patients from our study were hospitalized in the period from July to October. Hereafter, the number of admitted COVID-19 patients increased and remained high at the end of 2020. We chose July 1st as a pragmatic cut-off date between the first and second waves of COVID-19 and in agreement with a study by Iftimie et al. [3]. Importantly, however, the conclusions of the study remained the same if October 1, was chosen as cut-off date. The inclusion of patients in the present study ended December 31, 2020. Thus, hospitalized patients from the second half of wave 2 in 2021 were not included in this study. Potentially, the selection of the cut-off date between the wave periods and the lack of some patients from the second half of wave 2 in 2021 could have introduced minor biases in the study. However, we have no reason to assume differences in symptoms and/or severity for patients admitted during the first and second half of wave 2.

Our study is a new comprehensive investigation comparing demographical, clinical, and laboratory characteristics in addition to sources of infection between two COVID-19 waves in 2020. The results bring new knowledge to the field and confirm and qualify previous findings. In conclusion, the course of disease was worse among patients hospitalized in wave 1 than in wave 2. The length of hospitalization was significantly longer in wave 1 and more patients experienced critical disease. However, we observed no significant differences in baseline or laboratory characteristics among patients admitted in wave 1 compared to wave 2. Presumably, the health conditions of patients upon admission and treatment during admission were better in wave 2 compared to wave 1. In general, a large percentage of patients were infected with COVID-19 at home, and most hospital-acquired COVID-19 infections were observed during the first wave. In agreement with other studies including patients from wave 1, we identified higher age, male sex, smoking, comorbidities, fever and dyspnea as risk factors for critical COVID-19 disease. Furthermore, we observed significantly increased levels of CRP and creatinine, and lower hemoglobin levels among patients with critical disease.

Further studies investigating the laboratory characteristics of COVID-19 patients and sources of infection are warranted. In addition, future studies comparing risk factors for critical diasease in different waves of COVID-19 could be interesting.