Abstract
Little information is available regarding incidence and severity of pulmonary embolism (PE) across the periods of ancestral strain, Alpha, Delta, and Omicron variants. The aim of this study is to investigate the incidence and severity of PE over the dominant periods of ancestral strain and Alpha, Delta, and Omicron variants. We hypothesized that the incidence and the severity by proximity of PE in patients with the newer variants and vaccination would be decreased compared with those in ancestral and earlier variants. Patients with COVID-19 diagnosis between March 2020 and February 2022 and computed tomography pulmonary angiogram performed within a 6-week window around the diagnosis (−2 to +4 weeks) were studied retrospectively. The primary endpoints were the associations of the incidence and location of PE with the ancestral strain and each variant. Of the 720 coronavirus disease 2019 patients with computed tomography pulmonary angiogram (58.6 ± 17.2 years; 374 females), PE was diagnosed among 42/358 (12%) during the ancestral strain period, 5/60 (8%) during the Alpha variant period, 16/152 (11%) during the Delta variant period, and 13/150 (9%) during the Omicron variant period. The most proximal PE (ancestral strain vs variants) was located in the main/lobar arteries (31% vs 6%–40%), in the segmental arteries (52% vs 60%–75%), and in the subsegmental arteries (17% vs 0%–19%). There was no significant difference in both the incidence and location of PE across the periods, confirmed by multivariable logistic regression models. In summary, the incidence and severity of PE did not significantly differ across the periods of ancestral strain and Alpha, Delta, and Omicron variants.
Keywords: COVID-19, pulmonary embolism, Alpha, Delta, and Omicron variants, CT pulmonary angiogram
1. Introduction
Coronavirus disease 2019 (COVID-19) has been associated with pulmonary embolism (PE) since the inception of pandemic.[1] The endothelial cell injury in the pulmonary vasculature as well as diffuse alveolar damage induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and concomitant systemic inflammation play a crucial role in the development of PE.[2–7] A study conducted during the early phase of the pandemic reported that the incidence of PE in COVID-19 patients was approximately 310 per 100,000 person-years, which is 9 times higher than in that of non-COVID-19 population,[8] although the results were not conclusive.[9,10] COVID-19 patients with PE tended to have poor clinical outcomes, such as mechanical ventilation,[11,12] intensive care unit (ICU) admission,[8,13] and death.[14] Therefore, PE has emerged as a serious adverse event in the management of COVID-19 patients.
With the evolution of the COVID-19 pandemic, variants of the virus have emerged and spread worldwide. In the United States, SARS-CoV-2 variants evolved from the ancestral strain to Alpha in March 2021, to Delta in July 2021, and then to Omicron in December 2021.[15,16] More variants are expected to emerge in the future as the virus keeps evolving.[17,18] The variants contain various mutations, resulting in changes in viral behavior and pathogenesis[19] and an increased rate of virus transmission.[20] There are studies addressing differences in the overall disease severity between the ancestral strain and variants. The Alpha variant presented no difference in severity or death compared with the ancestral strain,[21,22] the Delta variant was associated with more severity and mortality than the ancestral strain and other variants,[16,21,23] whereas the Omicron variant was associated with less disease severity including pneumonia or mortality than the Delta variant.[24–26] However, even though PE remains a serious outcome of COVID-19 patients,[27] little information is available regarding how the variants are related to the incidence and characteristics of PE, which will be potentially influenced by vaccination.[28] Recently, we reported that vaccinated patients had milder COVID-19 pneumonia on chest CT scans in 303 patients.[29] We wonder whether the incidence and severity of PE decreased with newer variants and vaccination.
To address this question of the incidence and severity of PE in patients with the newer variants and vaccination, we investigated 720 patients who underwent computed tomography pulmonary angiogram (CTPA) during the periods of the ancestral strain and Alpha, Delta, and Omicron variants. Our hypothesis was that the incidence and the severity by proximity of PE in patients with the newer variants and vaccination would be decreased compared with those in ancestral and earlier variants.
2. Material and methods
2.1. Patient selection
This study was approved by the local institutional review board (IRB#2021P000981), and it was performed in accordance with principles of the Declaration of Helsinki. Written informed consents were obtained from all the participants. All inpatients and outpatients diagnosed with positive reverse transcription-polymerase chain reaction (RT-PCR) test for SARS-CoV-2 between March 15, 2020 and February 18, 2022, who had CTPA scans within a 6-week window around the COVID-19 diagnosis (−2 to + 4 weeks) were retrospectively studied with no exclusions.
2.2. Time period selection of circulating variants
The time periods for the ancestral strain and variants were defined based on a previous report, which described the predominant variants and their circulating time periods in 21 hospitals across the United States.[16] They included the ancestral strain period: March 15, 2020 to March 10, 2021; the Alpha variant period: March 11, 2021 to July 3, 2021; the Delta variant period: July 4, 2021 to December 25, 2021; and the Omicron variant period: December 26, 2021 to February 18, 2022.
2.3. Demographic and clinical data acquisition
Demographic data, including age, sex, body mass index, smoking status, underlying comorbidities such as lung disease, hypertension, coronary artery disease, diabetes mellitus, chronic kidney disease, malignancy, and vaccination status, were obtained from the electronic medical record. A patient was defined vaccinated if they had received more than 1 dose of messenger ribonucleic acid (mRNA) vaccines (BNT162b2 [Pfizer-BioNTech] and mRNA-1273 [Moderna] vaccines) or adenovirus vector-based Ad26.COV2.S (Johnson & Johnson-Janssen) vaccines. Unvaccinated patients were those with no vaccination records or unknown vaccination status. Lung disease in this study included asthma, chronic obstructive pulmonary disease, interstitial lung disease, lung cancer, and lung surgery.
Clinical data, including the baseline laboratory findings such as platelet, C-reactive protein, and D-dimer at the time of RT-PCR diagnosis, hospitalization, ICU admission, all-cause death, were also collected.
2.4. Image evaluation of pulmonary embolism
One experienced thoracic radiologist (T.H. or N.W.) reviewed all radiology reports of CTPA and documented PE. The confirmed PE would be classified into 3 categories, namely, main/lobar artery, segmental artery, and subsegmental artery, according to the most proximal anatomical location of the emboli described in the reports.[30,31]
2.5. Statistical analyses
Numeric variables were presented as mean ± standard deviation for variables with normal distributions and median (interquartile range [IQR]) for variables with nonnormal distributions. Comparisons employed Fisher exact test for categorical data and the 1-way ANOVA, Wilcoxon rank sum test, and Kruskal–Wallis test, as appropriate, for numerical variables. Multiple comparisons were adjusted by using the Bonferroni method. A multivariable logistic regression analysis examined the associations between the variant type and the development of PE after adjusting for potential confounder factors, and a multivariable multinomial logistic regression model investigated the associations between the variants and the location of PE after adjusting for confounders. Missing values of laboratory data were inferred by multiple imputation. The statistical analyses were performed using JMP Pro 16.0.0 (SAS Institute Inc, Cary, NC) or EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) and graphical user interface for R 4.0.3 (R Foundation for Statistical Computing, Vienna, Austria).[32] A 2-sided P value less than .05 was considered significant.
3. Results
3.1. Patient selection of the cohort
We identified 720 patients (58.6 ± 17.2 years; 374 females) who had COVID-19 diagnosis based on a RT-PCR for SARS-CoV-2 and CTPA scans within a 6-week window around the COVID-19 diagnosis (−2 to +4 weeks) utilizing our institutional research patient data repository. CTPA was performed for clinically-suspected PE at the discretion of individual physicians.
3.2. Demographic and clinical data
Summarized demographic and clinical data for the cohort are provided in Table S1, Supplemental Digital Content, http://links.lww.com/MD/K946. The median interval between diagnosis of COVID-19 and CTPA was 2 (IQR, 0–10) days. The median interval between diagnosis of COVID-19 and the collection dates of platelet counts and C-reactive protein and D-dimer levels were 0 (IQR, 0–11) and 1 (IQR, 1–4) days, respectively. The proportion of patients with unknown vaccination status was 27% (97/358), 15% (9/60), 1% (2/152), and 1% (2/150) during the periods of the ancestral strain and Alpha, Delta, and Omicron variants, respectively.
Demographic and clinical data as stratified by the ancestral strain and the 3 variants are provided in Table 1. Of the 720 patients, 358 (50%), 60 (8%), 152 (21%), and 150 (21%) patients were diagnosed during the periods of the ancestral strain and the Alpha, Delta, and Omicron variants, respectively. The proportion of vaccinated patients significantly increased across the periods: from 2% during the ancestral strain period (7/358), to 25% during the Alpha period (15/60), to 49% during the Delta period (75/152), and to 68% during the Omicron period (102/150) (P < .0001). The Omicron and Alpha variants were associated with lower risk of ICU admission than the ancestral strain (Bonferroni-adjusted P = .009 and P = .04, respectively) (Fig. 1). Sex showed only a marginally different distribution across different variants by using Fisher exact test (P = .049). There was no difference in age, body mass index, smoking history, laboratory findings, comorbidities, hospitalization, and all-cause death between the ancestral strain and variants.
Table 1.
Demographic data and clinical information stratified by ancestral strain and variants (n = 720).
| Ancestral strain (n = 358) | Alpha variant (n = 60) | Delta variant (n = 152) | Omicron variant (n = 150) | P value | |
|---|---|---|---|---|---|
| Age (years) | 59.7 ± 17.8 | 54.6 ± 14.7 | 58.5 ± 16.0 | 57.8 ± 17.6 | .18 |
| Sex (male:female) | 185:173 | 25:35 | 77:75 | 59:91 | .049 |
| BMI (kg/m2) | 30.4 ± 8.5 | 31.0 ± 9.1 | 31.4 ± 9.3 | 30.7 ± 9.8 | .73 |
| (n = 717) | (n = 355) | (n = 60) | (n = 152) | (n = 150) | |
| Smoking history | |||||
| Never | 193 (54%) | 38 (64%) | 77 (51%) | 75 (50%) | .30* |
| Former/current | 140 (39%) | 20 (33%) | 68 (45%) | 67 (45%) | |
| Unknown | 25 (7%) | 2 (3%) | 7 (4%) | 8 (5%) | |
| Comorbidities | |||||
| Lung disease | 94 (26%) | 18 (30%) | 54 (36%) | 55 (37%) | .056 |
| HTN | 205 (57%) | 28 (47%) | 80 (53%) | 75 (50%) | .27 |
| CAD | 51 (14%) | 9 (15%) | 17 (11%) | 19 (13%) | .78 |
| DM | 110 (31%) | 15 (25%) | 44 (29%) | 43 (29%) | .84 |
| CKD | 40 (11%) | 5 (8%) | 16 (11%) | 15 (10%) | .95 |
| Malignancy | 103 (29%) | 17 (28%) | 37 (24%) | 50 (33%) | .39 |
| Vaccination status | |||||
| Unvaccinated | 351 (98%) | 45 (75%)† | 77 (51%)† | 48 (32%)† | <.0001 |
| Vaccinated | 7 (2%) | 15 (25%) | 75 (49%) | 102 (68%) | |
| Laboratory findings | |||||
| Platelet (103/μL) (n = 718) |
215 (166–279) (n = 357) |
227 (178–313) (n = 60) |
213 (157–269) (n = 151) |
230 (167–309) (n = 150) |
.33 |
| CRP (mg/L) (n = 589) |
71 (29–134) (n = 315) |
88 (25–169) (n = 48) |
76 (40–153) (n = 116) |
66 (14–149) (n = 110) |
.41 |
| D-dimer (ng/mL) (n = 630) |
1159 (622–2383) (n = 337) |
1093 (665–2525) (n = 48) |
1140 (693–2166) (n = 126) |
1262 (689–2303) (n = 119) |
1.0 |
| Hospitalization | 300 (84%) | 56 (93%) | 127 (84%) | 119 (79%) | .09 |
| ICU admission | 102 (28%) | 7 (12%)‡ | 31 (20%) | 23 (15%)§ | .001 |
| All-cause death | 59 (16%) | 6 (10%) | 29 (19%) | 23 (15%) | .45 |
BMI = body mass index, CAD = coronary artery disease, CKD = chronic kidney disease, CRP = C-reactive protein, DM = diabetes mellitus, HTN = hypertension, ICU = intensive care unit.
Fisher exact test was performed using 2 variables: never and former/current smoking history.
The difference among ancestral strain, Alpha variant, Delta variant, and Omicron variant, respectively, was statistically significant (Bonferroni-adjusted P < .05).
The difference between ancestral strain and Alpha variant was statistically significant (Bonferroni-adjusted P < .05).
The difference between ancestral strain and Omicron variant was statistically significant (Bonferroni-adjusted P < .05).
Figure 1.
Changes in the proportion of vaccination, hospitalization, ICU admission, and all-cause death along the course of evolution of COVID-19 variant among patients who had CTPA. * ICU admission rate was significantly lower during the Alpha variant period than during the ancestor strain period (Bonferroni-adjusted P = .04). ** ICU admission rate was significantly lower during the Omicron variant period than during the ancestor strain period (Bonferroni-adjusted P = .009). *** The proportion of vaccination significantly increased across the periods (P < .0001). COVID-19 = coronavirus disease 2019, CTPA = computed tomography pulmonary angiogram, ICU = intensive care unit.
3.3. Incidence and location of pulmonary embolism
The incidence and the most proximal anatomical location of PE, stratified by the ancestral strain and the 3 variants, are provided in Table 2. PE was diagnosed in 11% (76/720) during the study period, 12% (42/358) during the ancestral strain period, 8% (5/60) during the Alpha variant period, 11% (16/152) during the Delta variant period, and 9% (13/150) during the Omicron variant period. The most proximal PE during the ancestral strain was 31% in the main/lobar pulmonary arteries, 52% in the segmental arteries, and 17% in the subsegmental arteries, while the most proximal PE during the variants period was 6% to 40% in the main/lobar pulmonary arteries, 60% to 75% in the segmental arteries, and 0% to 19% in the subsegmental arteries. There were no significant differences in the incidence and location of PE between each period of the ancestral strain and the 3 variants. Among the ICU patients, the incidence of PE was 17% (27/163) during the whole study period, which was significantly higher than 9% (49/557) among non-ICU patients (P = .0085), and there were no significant differences in both incidence and location of PE between the periods of ancestral strain and variants (Table 3). Among the vaccinated patients, the incidence of PE during the whole study period was 12% (23/199), which was not significantly different from 10% (53/521) among the unvaccinated patients; there were no significant differences in both incidence and location of PE between the periods of ancestral strain and variants (Table S2, Supplemental Digital Content, http://links.lww.com/MD/K947). Representative cases of PE located in the main/lobar, segmental, and subsegmental arteries are shown in Figures 2–4.
Table 2.
Incidence and location of pulmonary embolisms stratified by ancestral strain and variants (n = 720).
| Total | Ancestral strain | Alpha variant | Delta variant | Omicron variant | P value | |
|---|---|---|---|---|---|---|
| Frequency of pulmonary embolism | 76/720 (11%) | 42/358 (12%) | 5/60 (8%) | 16/152 (11%) | 13/150 (9%) | .75* |
| Most proximal anatomical location | ||||||
| Main/lobar | 19/76 (25%) | 13/42 (31%) | 2/5 (40%) | 1/16 (6%) | 3/13 (23%) | .41* |
| Segmental | 46/76 (61%) | 22/42 (52%) | 3/5 (60%) | 12/16 (75%) | 9/13 (69%) | |
| Subsegmental | 11/76 (14%) | 7/42 (17%) | 0/5 (0%) | 3/16 (19%) | 1/13 (8%) | |
Fisher exact test was performed among ancestral strain, Alpha variant, Delta variant, and Omicron variant.
Table 3.
Incidence and location of pulmonary embolisms in ICU patients stratified by ancestral strain and variants (n = 163).
| Total | Ancestral strain | Alpha variant | Delta variant | Omicron variant | P value | |
|---|---|---|---|---|---|---|
| Frequency of pulmonary embolism | 27/163 (17%) | 16/102 (16%) | 1/7 (14%) | 7/31 (23%) | 3/23 (13%) | .84* |
| Most proximal anatomical location | ||||||
| Main/lobar | 8/27 (30%) | 6/16 (37.5%) | 1/1 (100%) | 0 (0%) | 1/3 (33%) | .16* |
| Segmental | 14/27 (52%) | 6/16 (37.5%) | 0/1 (0%) | 6/7 (86%) | 2/3 (67%) | |
| Subsegmental | 5/27 (18%) | 4/16 (25%) | 0/1 (0%) | 1/7 (14%) | 0/3 (0%) | |
ICU = intensive care unit.
Fisher exact test was performed among ancestral strain, Alpha variant, Delta variant, and Omicron variant.
Figure 2.
CT pulmonary angiograms in a 38-year-old man with PE in the main arteries, who had COVID-19 diagnosis during Omicron variant period. The patient had diabetes mellitus, hypertension, chronic kidney disease, and vaccination. CT pulmonary angiography was performed 8 days after diagnosis. (A) The image shows a saddle embolus to right and left main pulmonary arteries (yellow arrows). (B) The image shows multifocal bilateral ground-glass opacities and subpleural wedge-shaped consolidation. COVID-19 = coronavirus disease 2019, CT = computed tomography.
Figure 4.
CT pulmonary angiograms in a 75-year-old woman with PE in the right lower lobe subsegmental artery, who had COVID-19 diagnosis during ancestral strain period. The patient had diabetes mellitus, without vaccination. CT pulmonary angiography was performed 1 day after diagnosis. (A) The image shows PE in right lower lobe subsegmental artery (yellow arrow). (B) The image shows extensive ground-glass opacities and organizing consolidations were extended in subpleural region. COVID-19 = coronavirus disease 2019, CT = computed tomography, PE = pulmonary embolism.
Figure 3.
CT pulmonary angiograms in a 63-year-old woman with PE in the right lower lobe segmental artery, who had COVID-19 diagnosis during Delta variant period. The patient had lung disease, without vaccination. CT pulmonary angiography was performed 9 days after diagnosis. (A) The image shows PE in right lower lobe segmental artery (yellow arrow). (B) The image shows diffuse ground-glass opacities and peripheral subpleural consolidation accompanying focal spared areas. COVID-19 = coronavirus disease 2019, CT = computed tomography, PE = pulmonary embolism.
3.4. Demographic and clinical data stratified by the presence or absence of PE
Demographic and clinical data, stratified by the presence or absence of PE during the periods of the ancestral strain, Alpha variant, Delta variant, and Omicron variant, are shown in Tables S3 to S6, Supplemental Digital Contents, http://links.lww.com/MD/K948, http://links.lww.com/MD/K949, http://links.lww.com/MD/K950, and http://links.lww.com/MD/K951, respectively. During the ancestral strain period, platelets (P = .005) and the D-dimer level (P = .003) were significantly higher in patients with PE than in those without PE (Table S3, Supplemental Digital Content, http://links.lww.com/MD/K948). There were no significant differences in demographic and clinical findings in the Alpha variant between those with and without PE (Table S4, Supplemental Digital Content, http://links.lww.com/MD/K949). During the Delta variant period, ICU admission rates (P = .02) were significantly higher in patients with PE than in those without PE (Table S5, Supplemental Digital Content, http://links.lww.com/MD/K950). During the Omicron variant period, the D-dimer level (P = .0001) was significantly higher in patients with PE than in those without PE (Table S6, Supplemental Digital Content, http://links.lww.com/MD/K951).
3.5. Associations of PE and variant type
With multivariable (and multinomial) logistic regression models that adjust for age, sex, vaccination status, and D-dimer level, we found that none of the variants were significantly associated with the incidence and location of PE (Tables 4 and 5). Male patients (P = .02) and D-dimer level higher than 1000 ng/mL (P = .001) were independently associated with the presence of PE (Table 4), whereas male patients (P = .03) were less likely to have the emboli in the subsegmental arteries compared to in the main/lobar arteries (Table 5).
Table 4.
Odds ratios of candidate predictors for development of pulmonary embolism from multivariable logistic regression analysis.
| Multivariable OR (95% CI) | P value | |
|---|---|---|
| SARS-CoV-2 variant type | ||
| Alpha variant | 0.57 (0.21–1.56) | .27 |
| Delta variant | 0.62 (0.29–1.31) | .21 |
| Omicron variant | 0.48 (0.20–1.12) | .09 |
| (Ref: ancestral strain) | ||
| Age (years) | ||
| ≥65 | 0.77 (0.47–1.28) | .32 |
| (Ref: <65) | ||
| Sex | ||
| Male | 1.79 (1.09–2.93) | .02 |
| (Ref: female) | ||
| Vaccination status | ||
| Vaccinated | 1.70 (0.82–3.52) | .15 |
| (Ref: unvaccinated) | ||
| Laboratory findings | ||
| D-dimer (ng/mL) > 1000 | 2.64 (1.47–4.73) | .001 |
| (Ref: ≤1000) | ||
CI = confidence interval, OR = odds ratio, Ref = reference, SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.
Table 5.
Associations of candidate predictors with locations of pulmonary embolism based on a multinomial logistic regression model.
| OR (95% CI) | P value | |
|---|---|---|
| Segmental (Ref: main/lobar) | ||
| SARS-CoV-2 variant type | ||
| Alpha variant | 1.08 (0.13–9.15) | .94 |
| Delta variant | 8.46 (0.72–98.9) | .09 |
| Omicron variant | 3.18 (0.34–30.2) | .31 |
| (Ref: ancestral strain) | ||
| Age (years) | ||
| ≥65 | 0.58 (0.17–2.03) | .39 |
| (Ref: <65) | ||
| Sex | ||
| Male | 0.32 (0.083–1.25) | .10 |
| (Ref: female) | ||
| Vaccination status | ||
| Vaccinated | 0.77 (0.10–5.64) | .79 |
| (Ref: unvaccinated) | ||
| Laboratory findings | ||
| D-dimer (ng/mL) >1000 | 0.25 (0.043–1.41) | .12 |
| (Ref: ≤1000) | ||
| Subsegmental (Ref: main/lobar) | ||
| SARS-CoV-2 variant type | ||
| Alpha variant | 1.67 × 10−6 (0–Inf) | .98 |
| Delta variant | 1.31 (0.045–37.9) | .87 |
| Omicron variant | 0.12 (0.0031–4.48) | .25 |
| (Ref: ancestral strain) | ||
| Age (years) | ||
| ≥65 | 0.98 (0.17–5.63) | .98 |
| (Ref: <65) | ||
| Sex | ||
| Male | 0.14 (0.023–0.84) | .03 |
| (Ref: female) | ||
| Vaccination status | ||
| Vaccinated | 9.20 (0.48–177) | .14 |
| (Ref: unvaccinated) | ||
| Laboratory findings | ||
| D-dimer (ng/mL) > 1000 | 0.37 (0.034–3.93) | .41 |
| (Ref: ≤1000) | ||
CI = confidence interval, Inf = infinity, OR = odds ratio, Ref = reference, SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.
4. Discussion
Among multiple studies on the incidence and characteristics of PE in COVID-19 patients, the majority of them were conducted in the first half of 2020,[27] and the associations between PE and the subsequent COVID-19 variants are less studied. Therefore, we examined the incidence and the severity by proximity of PE and the demographic and clinical data during the periods of ancestral strain and Alpha, Delta, and Omicron variants using CTPA obtained within a 6-week window around COVID-19 diagnosis (−2 to +4 weeks). The proportion of vaccinated patients significantly increased across the periods, and the proportion of ICU admission was significantly lower during the periods of Alpha and Omicron variants than during the period of ancestral strain. However, our study demonstrated that there was no statistically significant difference in the incidence of PE nor the severity of PE measured by proximity of anatomic location along the course of evolution of COVID-19 variants.
In our study, the incidence of PE was 12% (42/358), 8% (5/60), 11% (16/152), and 9% (13/150) in all patients and 16% (16/102), 14% (1/7), 23% (7/31), and 13% (3/23) in ICU patients for the periods of ancestral strain, Alpha, Delta, and Omicron variants, respectively, and there was no significant difference among them, respectively. Multiple logistic regression models adjusted for potential confounder factors confirmed that there were no differences. Though the incidence of PE in COVID-19 remains unclear due to wide-ranging results across previous studies, a recent systematic literature review reported that the incidence of PE was 0% to 1.1% in outpatients, 0.9% to 8.2% in inpatients, and 1.8% to 18.9% in ICU patients and was higher in more severely ill patients.[27] Law et al reported that the incidence of PE on CTPA in COVID-19 patients was 15%, 10.65%, and 9.23% during the periods of ancestral strain and Delta and Omicron variants at a tertiary care center in the United States and that there was no significant difference among the groups,[28] consistent with the results of our study.
The location of the most proximal PE, a known predictor of disease severity,[30,31] during the Alpha to Omicron variant period was in the main/lobar arteries (6%–40%), segmental arteries (60%–75%), and the subsegmental arteries (0%–19%), with the highest incidence in the segmental arteries, and there also was no significant difference between the ancestral strain and each variant in the multinomial logistic regression analysis. In the studies conducted during the early pandemic, PE was more frequently distributed in the segmental and subsegmental arteries than in the main/lobar arteries (56.5%–83% and 17%–44%, respectively),[33–36] which is consistent with our results in the periods of Alpha, Delta, and Omicron variants.
In general, infection by viral, bacterial, and fungal pathogens triggers a complex systemic inflammatory response that results in subsequent activation of coagulation and prothrombotic properties.[2] The pathogenesis of venous thromboembolism in COVID-19, in addition to large-vessel thrombosis and thromboembolism caused by the hypercoagulable state, is likely prominent microvascular immunothrombosis, which is considered a specific characteristic of COVID-19 rather than the epiphenomenon of other viral pneumonia or acute respiratory distress syndrome.[3,4,37] SARS-CoV-2 infects host cells by binding to angiotensin-converting enzyme 2 receptors, which is expressed with high density in the lungs, heart, veins, and arteries.[5] The development of microvascular immunothrombosis is caused by the proinflammatory milieu associated with increased cytokines and activation of platelets, endothelium, and complement due to COVID-19.[3–6] Although our study did not examine the pathogenetic changes during the evolution from ancestral strain to variants, the results suggest that at least the incidence and imaging phenotype of PE may not have changed. This study also provides an important reference for comparing the incidence and imaging findings of PE of COVID-19 variants that are expected to emerge in the future with those of previous variants.
We found that the D-dimer level more than 1000 ng/mL and male gender were independently associated with the presence of PE, consistent with previous studies.[27,33,38] The D-dimer level reflects vascular bed thrombosis with fibrinolysis linked to extensive alveolar and interstitial inflammation with infection,[7] while the gender effect may be explained by the biological differences in the immune response to infection.[39] In addition, our analysis revealed that male sex was less likely to have the emboli in the subsegmental arteries compared to in the main/lobar arteries. However, among non-COVID-19 patients with clinically-suspected PE, male gender and risk factors such as age, recent surgery, and estrogen use were found to be independent predictors for subsegmental PE.[40] This difference may hint that COVID-19–associated PE may have a different pathogenesis from conventional PE.
In the present study, 12% (23/199) patients with vaccination developed PE in the whole cohort. Even during the Omicron variant period, when vaccination was most widespread, PE occurred in 10% (10/102) of the vaccinated patients, compared to 7% (3/46) of the unvaccinated patients. Vaccines are highly effective in preventing infection, severe disease, hospitalization, and death associated with COVID-19.[16,41] A previous study showed that vaccines were effective in significantly reducing the risk of deep vein thrombosis and PE even in the event of a breakthrough infection.[42] Our study did not reproduce those finding. The reason for this observation is unclear and puzzling; however, the plausible reasons may include selection bias among patients who underwent CTPA and small sample size.
There are several limitations. First, this was a retrospective single-center investigation, and the sample size was small, especially during the Alpha variant period. Additional larger-scale studies are needed to compare the PE characteristics between the ancestral strain and variants. Second, changes in the severity of COVID-19 variants and vaccine coverage throughout the study period may have affected CTPA usage patterns. Third, PE that occurred later than 4 weeks after COVID-19 diagnosis was not examined in the present study. Espallargas et al reported that the median time from the onset of the symptom to acute PE diagnosis on CTPA was 16 days (range, 2–29).[43] Therefore, we believe that the time frame used would be expected to capture most PEs that occurred.
In conclusion, there was no statistically significant difference in the incidence of PE nor the severity of PE measured by proximity of anatomic location along the course of evolution of COVID-19 variants across the periods of ancestral strain and Alpha, Delta, and Omicron variants. These data may provide the evidence for monitoring of the behavior of the emerging future variants.
Author contributions
Conceptualization: Noriaki Wada.
Data curation: Noriaki Wada, Takuya Hino, Vladimir I. Valtchinov.
Formal analysis: Noriaki Wada, Yi Li.
Investigation: Noriaki Wada, Takuya Hino.
Methodology: Noriaki Wada, Takuya Hino, Hiroto Hatabu.
Writing—original draft: Noriaki Wada.
Writing—review & editing: Yi Li, Staci Gagne, Takuya Hino, Vladimir I. Valtchinov, Elizabeth Gay, Mizuki Nishino, Mark M. Hammer, Bruno Madore, Charles R. G. Guttmann, Kousei Ishigami, Gary M. Hunninghake, Bruce D. Levy, Kenneth M. Kaye, David C. Christiani, Hiroto Hatabu.
Resources: Hiroto Hatabu.
Project administration: Hiroto Hatabu.
Supervision: Hiroto Hatabu.
Supplementary Material
Abbreviations:
- CAD
- coronary artery disease
- CKD
- chronic kidney disease
- COVID-19
- coronavirus disease 2019
- CTPA
- computed tomography pulmonary angiogram
- DM
- diabetes mellitus
- HTN
- hypertension
- ICU
- intensive care unit
- PE
- pulmonary embolism
- RT-PCR
- reverse transcription-polymerase chain reaction
- SARS-CoV-2
- severe acute respiratory syndrome coronavirus 2.
MN is supported by NIH (R01CA203636, U01CA209414, R01HL111024, and R01CA240592); YL is supported by NCI (R01CA249096); BM is supported by NIH (R01EB030470); BDL is supported by NIH/NHLBI (1OT2HL162087); KMK is supported by NIH (R01AI150575, R01AI165382, and R01DE025208); HH is supported by NIH (R01CA203636, 5U01CA209414, and R01HL135142), NIH/NHLBI (R01HL111024 and R01HL130974); DCC is supported by NIH (5U01CA209414).
MN reports research grant to the institution from Merck, Canon Medical Systems, AstraZeneca, and Daiichi Sankyo; and consulting fees from Daiichi Sankyo and AstraZeneca, outside the submitted work. CRGG reports stock ownership of GSK, Roche, and Novartis, outside the submitted work. GMH reports consulting fees from Boehringer Ingelheim, Gerson Lehrman Group, and Chugai Pharmaceuticals, outside the submitted work. BDL reports grants or contacts from NIH, Pieris Pharmaceuticals, SRA, and Sanofi; royalties or licenses from Propeller Health; consulting fees from AstraZeneca, NControl, Cartesian, Novartis, Gossamer Bio, and Thetis Pharmaceuticals; participation on a data safety monitoring board or advisory board from NIAID; and stock or stock options from Entrinsic Biosciences and Nocion Therapeutics, outside the submitted work. HH reports grants or contracts from Canon Medical Systems Inc and Konica-Minolta Inc; and consulting fees from Canon Medical Systems Inc and Mitsubishi Chemical Co, outside the submitted work. The other authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Supplemental Digital Content is available for this article.
How to cite this article: Wada N, Li Y, Gagne S, Hino T, Valtchinov VI, Gay E, Nishino M, Hammer MM, Madore B, Guttmann CRG, Ishigami K, Hunninghake GM, Levy BD, Kaye KM, Christiani DC, Hatabu H. Incidence and severity of pulmonary embolism in COVID-19 infection: Ancestral, Alpha, Delta, and Omicron variants. Medicine 2023;102:48(e36390).
Contributor Information
Yi Li, Email: yili@umich.edu.
Staci Gagne, Email: SGAGNE@BWH.HARVARD.EDU.
Takuya Hino, Email: hino.takuya.372@m.kyushu-u.ac.jp.
Vladimir I. Valtchinov, Email: VVALTCHINOV@BWH.HARVARD.EDU.
Elizabeth Gay, Email: egay@bwh.harvard.edu.
Mizuki Nishino, Email: Mizuki_Nishino11@DFCI.HARVARD.EDU.
Mark M. Hammer, Email: mmhammer@bwh.harvard.edu.
Bruno Madore, Email: bruno@bwh.harvard.edu.
Charles R. G. Guttmann, Email: guttmann@bwh.harvard.edu.
Kousei Ishigami, Email: ishigami.kosei.581@m.kyushu-u.ac.jp.
Gary M. Hunninghake, Email: ghunninghake@bwh.harvard.edu.
Bruce D. Levy, Email: blevy@bwh.harvard.edu.
Kenneth M. Kaye, Email: KKAYE@BWH.HARVARD.EDU.
David C. Christiani, Email: dchris@hsph.harvard.edu.
Hiroto Hatabu, Email: hhatabu@partners.org.
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