In this linked registry analysis using data from the Norwegian Surveillance System for Communicable Diseases, the Norwegian Cardiovascular Disease Registry and the Cancer Registry of Norway on 8 809 individuals who tested positive for SARS-CoV-2, we found that increasing age, male sex, and a history of stroke or of cancer with distant metastasis at the time of diagnosis were all associated with an increased risk of death following a COVID-19 diagnosis. Individuals who died after a COVID-19 diagnosis were more likely than those who survived to have had a previous diagnosis of myocardial infarction, atrial fibrillation, heart failure, hypertension or non-metastatic cancer. However, after adjusting for age and sex in multivariable analyses, we found that these diseases were no longer statistically significant risk factors for mortality.
For individuals who had been hospitalised for stroke in the period 2012–19, the risk of dying after infection with SARS-CoV-2 was increased by 50 % after adjusting for age, sex and comorbidities. Our results confirm findings from several previous studies that have suggested an increased risk of death in patients with cerebrovascular disease (5, 9). A previous stroke may result in poorer functional status and a reduced likelihood of benefiting from intensive care. There has also been discussion as to whether individuals with a history of stroke may be at increased risk of vascular events as a result of COVID-19-induced coagulopathies, which may lead to serious complications and an increased risk of death (9).
With the exception of stroke, none of the other cardiovascular diseases included in our study were associated with a statistically significant increase in mortality risk. The results of previous studies have been somewhat mixed in terms of the risk of death in individuals with underlying cardiovascular disease (10). Our findings are in line with results from Denmark (6), where the risk of death was found to be lower in individuals with ischaemic heart disease (OR 0.7 (CI: 0.5–0.9)) or hypertension (OR 0.6 (CI: 0.5–0.8)) after adjusting for age, sex and the number of comorbidities.
As in our study, the Danish study found no significant increase in the risk of death in association with atrial fibrillation or heart failure, whereas a study from England found an increased risk in association with heart failure or ischaemic heart disease in both sexes, and in association with atrial fibrillation in women only (5). In our study, we were unable to detect sex differences within diagnostic subgroups as there were too few deaths in each group following stratification, and therefore high levels of uncertainty. The number of deaths in our study is relatively low, and thus we cannot exclude the possibility that the other cardiovascular diseases besides stroke are independent risk factors for death after COVID-19 (cf. wide confidence intervals, Table 3).
A recently published review on clinical characteristics of cancer patients with COVID-19 found that, after adjusting for age and other comorbidities, cancer was not an independent risk factor for death (11). This is consistent with findings from our study for all cancer stages combined (data not shown). However, we found a significantly increased risk of death in patients with cancer with distant metastasis at the time of diagnosis. Patients with metastatic disease at diagnosis have a poorer prognosis and functional status than patients without metastasis, and often receive more intensive chemotherapy than other cancer patients. This group may therefore be more likely to experience a severe COVID-19 disease course. Chemotherapy has previously been identified as a possible risk factor for death from COVID-19 (5). In our study, we did not have information about cancer type or the treatment that patients had received, and therefore could not draw any specific conclusions about which cancer patients had an increased risk of death after COVID-19. It would also be beneficial to repeat our analyses with a larger dataset, owing to the small size of the group of individuals with metastatic cancer at diagnosis. Any misclassification of stage or cause of death for these patients could potentially affect the results.
After adjusting for other risk factors for which information was available, our results show that the risk of death was significantly increased in those aged 60 and above compared to those in the age groups under 60. The estimated absolute risk of death for a person without any of the comorbidities included in our study was 0.17 % for those under 60, 2.1 % for those aged 60–69 years and 7.8 % for those aged 70–79 years. The results of our study are consistent with those from Denmark, where the case fatality rate in persons without comorbidities was less than 5 % for those aged under 80 (6).
We found that men had a 50 % (all age groups) to 70 % (< 85 years) increased risk of death relative to women after adjusting for age and other risk factors. This is consistent with the results of many previous studies (3, 4, 12, 13), and some have argued that this phenomenon may, in part, reflect sex differences in the immune response (14). Another possibility that has been considered is that the sex differences may reflect greater alcohol consumption among men than women, but studies that have attempted to correct for this difference have not found alcohol to be a confounding factor (13).
In Norway, the proportion of deaths among those diagnosed (case fatality rate) was 3.0 % in total over the study period. Reported case fatality rates vary greatly between different countries and patient populations. In studies from China, Denmark and Italy, the reported case fatality rates were 2.3 %, 5.2 % and 7.2 %, respectively (6, 15). The main reason for Italy's very high case fatality rate is the high proportion of elderly persons among those who tested positive. As well as differences related to treatment, differences in testing strategies and in how COVID-19-associated deaths are defined may also lead to differences between countries. The case fatality rate can also change significantly over time as a result of changes in testing practices, age composition and treatment. In Norway, low testing capacity in the first wave of the pandemic meant that many of those who were ill were not tested. From August onwards, the amount of testing increased significantly, and a larger proportion of infections were identified. In addition, the average age of those infected dropped. As a result of this, and probably also improvements in treatment, the case fatality rate in Norway has decreased. A rough estimate based on the total number of infected individuals as per 8 November 2020 (25 520) and the number of deaths as per 8 December 2020 (361), yields a case fatality rate for Norway for the entire period from February to December of approximately 1.4 %.
A key strength of our study is that we have examined the risk of death for individuals who tested positive for SARS-CoV-2 across an entire national population. Most studies, with the exception of that by Reilev et al. in Denmark (6), have examined risk factors in selected patient groups and therefore cannot draw any firm conclusions about the general population risk of death from COVID-19 among those with underlying diseases (16). The individuals with positive test results in our study may also be a somewhat selected group, as the criteria used for testing during the study period may have meant that those with underlying diseases were more likely to be tested than those without such conditions. However, the results of a previous analysis on the same patient dataset in Norway found that there were small differences in the incidence of underlying diseases between people who had tested positive for COVID-19 and the general population (17). Future studies comparing the total mortality in a group with positive tests to that in a control group with negative tests will be needed to obtain further information on the impact of various risk factors on COVID-19 mortality.
Our data on comorbidities other than cardiovascular disease and cancer are incomplete. The Norwegian Cardiovascular Disease Registry contains information only on diseases noted during the same hospital stay/episode as the cardiovascular diagnosis. It is reasonable to assume that those in hospital with multiple diagnoses and a comorbid cardiovascular diagnosis are the most severe cases. Knowing this allows us to adjust for patient morbidity in order to obtain better estimates for the other factors in the analysis models. The impact of comorbidities other than cardiovascular disease and cancer on mortality after a diagnosis of COVID-19 in Norway should be investigated in future studies with more comprehensive information about other diseases.
The leading risk factor for death among individuals who tested positive for SARS-CoV-2 in the first half of 2020 was age. Male sex, a history of stroke, and cancer with distant metastasis were also associated with an increased risk of death after a diagnosis of COVID-19. Further studies are needed to determine the impact of cancer type on mortality after a diagnosis of COVID-19 in Norway.