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DOI: 10.1055/a-2552-1829
Mortality from Pulmonary Embolism in Patients with Post-Coronavirus Disease Syndrome
As of the most recent update in January 2025, the World Health Organization (WHO) reported that over 777 million individuals worldwide have been infected at least once by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19).[1] These figures are likely underestimated owing to factors such as undertesting and underreporting, especially because the widespread availability of rapid diagnostic tests, which facilitate self-testing and self-diagnosis, has further contributed to many cases escaping official surveillance systems.[2]
Accurately determining the true prevalence of SARS-CoV-2 infection in the global population remains challenging. A large seroepidemiological investigation in Ireland has provided some meaningful insights,[3] as the study assessed the seroprevalence in blood donors of antinucleocapsid protein antibodies—a marker of prior SARS-CoV-2 infection in a context where COVID-19 vaccinations only used spike protein-based formulations. The cumulative seroprevalence was estimated at 97% as of the last update on November 27, 2024, indicating that only 3% of blood donors lacked serological evidence of previous SARS-CoV-2 infection. These results imply that the real number of subjects who have experienced at least one SARS-CoV-2 infection is likely to be several times higher than the 777 million cases officially reported by the WHO. To this end, the actual risk of developing medium- or long-term complications, including those associated with the post-(long)-COVID syndrome, is likely to be significantly greater than that reflected in official statistics.
Persistent symptoms following acute SARS-CoV-2 infection represent a relatively frequent complication after recovering from a SARS-CoV-2 infection, collectively termed as post-COVID-19 condition, long-COVID, or postacute sequelae of SARS-CoV-2 infection. To facilitate standardized data collection and analysis, the WHO introduced the International Classification of Diseases, 10th Revision (ICD-10) code U09 in October 2021. This code consolidates the various terminologies under the unified designation of “post-COVID-19 condition”[4] and applies to patients presenting with persistent symptoms or complaints (e.g., fatigue, respiratory issues, neurological impairments, and systemic manifestations including cardiovascular disorders) following the resolution of an acute SARS-CoV-2 infection. Among the cardiovascular complications, pulmonary embolism (PE) is a notable concern during an acute SARS-CoV-2 infection,[5] with reliable evidence indicating that an elevated risk of developing PE may also persist for several months postrecovery.[6] Despite the clinical relevance, official statistics elucidating the potential clinical association between the post-COVID-19 condition and PE remain scarce. To address this gap, the present study aims to provide updated insights into this critical relationship.
We conducted a search using the U.S. National Center for Health Statistics Wide-Ranging Online Data for Epidemiologic Research (WONDER) Provisional Multiple Cause of Death Data interface,[7] which provides nationwide provisional mortality statistics. All death certificates recorded in the WONDER database include a primary underlying cause of death, up to 20 additional contributing causes, together with complete demographic information. For our analysis, we combined the ICD-10 code for pulmonary embolism (I26: pulmonary embolism) with the secondary ICD-10 code for post-COVID (U09: post-COVID-19 condition). We also incorporated variables such as “year,” “gender,” “age groups,” and “place of death” to refine our searches, which spanned in the period between October 2021 (i.e., after the official introduction of the ICD-10 code U09), to the most recent available date (i.e., December 29, 2024). This study was exempt from Institutional Review Board review as WONDER is a deidentified and publicly available database.
The results of our study are summarized in [Fig. 1]. A total number of 89 cases of PE deaths associated with the ICD-10 code for post-COVID-19 condition (U09) were identified in the U.S. National Center for Health Statistics database through the end of 2024 out of a total of 2,653 deaths with post-COVID-19 condition, resulting in a mortality rate for PE of 33.5 (95% confidence interval, 27.3–41.1) per 1,000 post-COVID-19 deaths. Of these, 57 occurred in 2023 (64%) and 32 in 2024 (36%; [Fig. 1A]). The male-to-female ratio indicated a slight predominance for males (53 vs. 47%; [Fig. 1B]), whereas the majority of deaths occurred in individuals aged 65 years or older, accounting for 78% of cases, compared with 22% in those aged < 65 years ([Fig. 1C]). Regarding the place of death, the majority of patients (47%) died at home, followed by deaths in medical facilities (36%) and in nursing or long-term care homes (16%; [Fig. 1D]).
Some noteworthy observations have emerged from our analysis. We found a slight predominance of male mortality and a higher incidence of deaths among older individuals. These findings do not precisely align with the current epidemiological evidence of post-(long)-COVID, which has been reported to affect females nearly twice as frequently as males in various studies, such as that conducted by Robertson et al in a large U.S. cohort.[8] In that study, the authors also found a significantly lower prevalence of long-COVID (∼60% lower) in individuals aged ≥ 65 years compared with those aged 25 to 34 years. While we were unable to precisely estimate age-adjusted or crude death rates due to the limited number of cases retrievable from the U.S. National Center for Health Statistics database, our data suggest that mortality associated with post-COVID-19 PE may disproportionately affect older males, whereas the post-COVID-19 condition appears more prevalently affect younger and middle-aged females.[9] This distinction between the demographic profiles of post-COVID-19-associated PE deaths and post-COVID-19 prevalence underscores the complexity of the condition and the need for further studies to explore these trends in more detail than in our descriptive analysis.
Regarding the place of death, our analysis revealed that the majority of individuals with post-COVID-19 died for PE at home. This trend likely reflects the broader pattern of individuals with chronic or complex conditions opting to manage their health outside of formal health care settings. It also underscores a critical need for enhanced post-COVID-19 care at home, particularly for individuals at higher risk of complications such as PE, which may not present with overt or immediate symptoms but can develop into life-threatening complications. Improved home care strategies, including regular monitoring and early diagnosis, could play a crucial role in preventing PE-related fatal outcomes.
Although these results suggest that the post-COVID-19 condition may contribute to PE-related mortality, the small sample size (only 89 cases were found in the U.S. National Center for Health Statistics database) limits the generalizability of our findings. It is in fact conceivable that the still-developing understanding of post-COVID-19 condition, the heterogeneity in reporting practices, the inaccurate coding and recording of both conditions could have led to underreporting and consequent underestimation of the real number of post-COVID-19 condition-associated PE deaths. Regarding the ICD-10 code I26, the WONDER database does not provide clear information on how the diagnosis of PE has been confirmed. Nevertheless, a study based on emergency department administrative data shows that ICD-10 codes for PE may be effective for identifying PE with a sensitivity exceeding 91% and a specificity approaching 100%.10 Additional studies are needed to complement our descriptive findings and more precisely define the profile of individuals with post-COVID-19 condition who are at higher risk of mortality for PE.
Publication History
Article published online:
28 March 2025
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