Risk of VTE in Nonrespiratory and Respiratory Presentations of COVID-19 in Critically Ill Patients.

A high incidence of VTE is recognized in critically ill patients with COVID-19 pneumonia.1Mansory E.M. Srigunapalan S. Lazo-Langner A. Venous thromboembolism in hospitalized critical and noncritical COVID-19 patients: a systematic review and meta-analysis.TH Open. 2021; 5: e286-e294Crossref PubMed Google Scholar However, the risk of VTE in patients admitted to the ICU with nonrespiratory presentations of COVID-19 is not well understood. We report the 90-day incidence of VTE in patients admitted to the ICU with respiratory and nonrespiratory diagnoses, stratifying by SARS-CoV-2 positivity and vaccination status. We performed a retrospective cohort study of adult Kaiser Permanente Northern California members tested for SARS-CoV-2 by polymerase chain reaction before admission to 21 community-based ICUs between December 1, 2020, and April 30, 2022. If there were multiple ICU admissions per patient, the index admission was the first associated with a positive SARS-CoV-2 test result or the first associated with a negative result if all tests were negative. We grouped patients with primary or secondary admission diagnoses for respiratory conditions (pneumonia, bronchitis, upper or lower respiratory tract infections or disease, respiratory failure, or respiratory signs and symptoms) vs all others by using Healthcare Cost and Utilization Project diagnosis codes. Based on the predominant SARS-CoV-2 variant circulating in California, we defined the pre-Delta (December 1, 2020, to May 31, 2021), Delta (June 1, 2021, to November 30, 2021) and Omicron (BA.1 and BA.2; December 1, 2021, to April 30, 2022) periods. We excluded subjects who had a history of VTE or received anticoagulation in the prior year. We assessed the incidence of VTE within 90 days of hospital admission by using a combination of diagnosis codes, anticoagulant prescriptions, or VTE encounters with a centralized anticoagulation service.2Roubinian N.H. Dusendang J.R. Mark D.G. et al.Incidence of 30-day venous thromboembolism in adults tested for SARS-CoV-2 infection in an integrated health care system in northern California.JAMA Intern Med. 2021; 181: 997-1000Crossref PubMed Scopus (29) Google Scholar Subjects were considered vaccinated 2 weeks after the receipt of two doses of an mRNA vaccine (BNT162b2 or mRNA-1273) or one dose of the Ad.26.COV2.S vaccine. Subjects were considered vaccine boosted 2 weeks after receipt of an additional vaccine dose occurring more than 3 months after primary vaccination. Multivariable logistic regression adjusting for demographics and comorbidities was used to calculate ORs and 95% CIs for the 90-day incidence of VTE. Two-sided P-values less than .05 were considered statistically significant. Statistical analyses were performed using Stata Version 14.2 (StataCorp). The Kaiser Permanente Northern California Institutional Review Board approved the study and waived informed consent. Of 11,143 critically ill patients tested for SARS-CoV-2, 5,440 (49%) were admitted with respiratory diagnoses, and 2,983 (27%) had COVID-19. Among the COVID-19 patients, 2,428 (81%) were admitted with respiratory diagnoses, and 2,313 (78%) were unvaccinated. (Table 1). The unadjusted 90-day incidence of VTE was higher in unvaccinated (16.7% [386 of 2,313]) and vaccinated (11.6% [78 of 670]) patients with COVID-19 compared with SARS-CoV-2-negative patients (8.4% [688 of 8,160]; Bonferroni adjusted P < .02 for both comparisons). Among vaccinated patients with COVID-19, VTE incidence did not differ between subjects who had received a vaccine booster (11.9%; 32 of 270) and those who had completed only a primary vaccine series (11.5%; 46 of 400; P = .89). Although 90-day mortality was higher in COVID-19 compared with SARS-CoV-2-negative patients (47.2% [1,408 of 2,983] vs 24.6% [2,004 of 8,160]; P < .001), VTE incidence was similar between survivors and nonsurvivors for both COVID-19 (14.5% [232 of 1,569] vs 16.7% [236 of 1,414]; P = .10) and SARS-CoV-2-negative patients (8.3% [508 of 6,156] vs 9.0% [180 of 2,004]; P = .31), respectively.Table 1ICU Cohort CharacteristicsCharacteristicSARS-CoV-2 Negative (n = 8,160)COVID-19 Vaccinated (n = 670)COVID-19 Unvaccinated (n = 2,313)PAge, y Mean (SD)65 (17)67 (16)59 (15)< .001Sex.002 Female3,574 (43.8)272 (40.6)922 (39.9) Male4,586 (56.2)398 (59.4)1,391 (60.1)Race/ethnicity< .001 Black1,028 (12.6)87 (13.0)269 (11.6) Asian1,456 (17.8)129 (19.3)361 (15.6) Hispanic1,447 (17.7)155 (23.1)746 (32.3) White3,644 (44.7)244 (36.4)728 (31.5) Missing/other585 (7.2)55 (8.2)209 (9.0)BMI Median (IQR)27 (24-33)28 (24-34)32 (28-38)< .001Comorbidities Hypertension5,794 (71.0)516 (77.0)1,478 (63.9)< .001 Diabetes3,449 (42.3)359 (53.6)1,088 (47.0)< .001 Chronic kidney disease2,671 (32.7)281 (41.9)500 (21.6)< .001 COPD2,206 (27.0)183 (27.3)548 (23.7).005 Congestive heart failure2,834 (34.7)191 (28.5)357 (15.4)< .001 Malignancy1,386 (17.0)110 (16.4)138 (6.0)< .001 Cerebrovascular disease956 (11.7)90 (13.4)119 (5.1)< .001History of thrombophilia49 (0.6)4 (0.6)6 (0.3).132Chronic immobility61 (0.8)4 (0.6)7 (0.3).061Respiratory admission diagnosis3,019 (37.0)431 (64.3)1,997 (86.3)< .001Nonrespiratory admission diagnosis< .001 Cardiovascular1,978 (24.2)67 (10.0)67 (2.9) Cerebrovascular933 (11.4)55 (8.2)78 (3.4) GI603 (7.4)28 (4.2)33 (1.4) Injury/complication360 (4.4)12 (1.8)8 (0.4) Endocrine338 (4.1)31 (4.6)33 (1.4) Genitourinary204 (2.5)2 (0.3)4 (0.2) Hematologic/oncologic142 (1.7)4 (0.6)2 (0.1) Musculoskeletal131 (1.6)6 (0.9)6 (0.3) Pregnancy-related44 (0.5)5 (0.8)40 (1.7) Other408 (5.0)29 (4.3)45 (1.9)COVID-19 period< .001 Pre-Delta2,267 (27.8)9 (1.3)971 (42.0) Delta1,883 (23.1)142 (21.2)882 (38.1) Omicron4,010 (49.1)519 (77.5)460 (19.9)Vaccine type, No. (%)n = 4,775n = 670….773 Pfizer/BioNTech2,570 (53.8)380 (56.7)…… Moderna1,866 (39.1)218 (32.5)…… Janssen339 (7.1)72 (10.8)……Vaccine booster dose2,256 (47.3)270 (40.3)…< .001Length of stay in days, median (IQR)4 (2-8)6 (3-13)13 (6-25)< .00190-d mortality2,004 (24.6)248 (37.0)1,166 (50.4)< .001 Respiratory diagnoses918 (30.5)192 (44.7)1,076 (54.0)< .001 Nonrespiratory diagnoses1,086 (21.1)56 (23.3)90 (28.3)< .00190-d VTE688 (8.4)78 (11.6)386 (16.7)< .001Data are presented as No. (%) unless otherwise specified. Respiratory admission diagnoses include pneumonia, bronchitis, upper or lower respiratory tract infections or disease, respiratory failure, or respiratory signs and symptoms; nonrespiratory admission diagnoses include all other conditions. IQR = interquartile range. Open table in a new tab Data are presented as No. (%) unless otherwise specified. Respiratory admission diagnoses include pneumonia, bronchitis, upper or lower respiratory tract infections or disease, respiratory failure, or respiratory signs and symptoms; nonrespiratory admission diagnoses include all other conditions. IQR = interquartile range. ICU patients admitted with respiratory diagnoses had a higher 90-day incidence of VTE compared with those with nonrespiratory diagnoses (13.4% [729 of 5,440] vs 7.4% [423 of 5,703]; P < .001). Among patients admitted with nonrespiratory conditions (Table 2), VTE incidence was similar in unvaccinated COVID-19 (6.9% [22 of 318]), vaccinated COVID-19 (7.1% [17 of 240]), and SARS-CoV-2-negative patients (7.4% [384 of 5,145]; P = .92). However, among patients with respiratory diagnoses, unadjusted 90-day incidence of VTE was higher in vaccinated (14.2% [61 of 430]) and unvaccinated COVID-19 patients (18.3% [364 of 1,995]) compared with SARS-CoV-2-negative subjects (10.1% [304 of 3,015]; Bonferroni adjusted P < .02 for both comparisons).Table 2Unadjusted and Adjusted 90-Day VTE in ICU Patients by SARS-CoV-2 Positivity and Admission DiagnosesAdmission Diagnoses CategorySARS-CoV-2 Negative (n = 8,160)COVID-19 (+)Vaccinated(n = 670)COVID-19 (+)Unvaccinated(n = 2,313)UnadjustedAdjustedOR (95% CI)UnadjustedAdjustedOR (95% CI)UnadjustedAdjustedOR (95% CI)Nonrespiratory diagnosesaP = .92 for across nonrespiratory group comparisons. (n = 5,696)7.5% (383 of 5,141)[Ref]7.1% (17 of 239)1.0 (0.6-1.7)7.0% (22 of 316)1.0 (0.6-1.5)Respiratory diagnosesbP < .01 for across respiratory group comparisons. (n = 5,447)10.1% (305 of 3,019)1.3 (1.1-1.5)14.2% (61 of 431)2.0 (1.5-2.7)18.3% (364 of 1997)2.9 (2.4-3.4)Respiratory admission diagnoses include pneumonia, bronchitis, upper or lower respiratory tract infections or disease, respiratory failure, or respiratory signs and symptoms; nonrespiratory admission diagnoses include all other conditions. ORs with 95% CIs presented for logistic regression of 90-d VTE in patient subgroups relative to the reference of SARS-CoV-2-negative subjects with nonrespiratory diagnoses with adjustment for demographics and comorbidities presented in Table 1. Ref = reference.a P = .92 for across nonrespiratory group comparisons.b P < .01 for across respiratory group comparisons. Open table in a new tab Respiratory admission diagnoses include pneumonia, bronchitis, upper or lower respiratory tract infections or disease, respiratory failure, or respiratory signs and symptoms; nonrespiratory admission diagnoses include all other conditions. ORs with 95% CIs presented for logistic regression of 90-d VTE in patient subgroups relative to the reference of SARS-CoV-2-negative subjects with nonrespiratory diagnoses with adjustment for demographics and comorbidities presented in Table 1. Ref = reference. With multivariable regression, the adjusted OR for 90-day VTE with nonrespiratory diagnoses was 1.0 (95% CI, 0.6-1.5) for unvaccinated and 1.0 (95% CI 0.6-1.7) for vaccinated COVID-19 patients compared with nonrespiratory SARS-CoV-2-negative patients (Table 2). In contrast, ORs for VTE with respiratory diagnoses in unvaccinated COVID-19, vaccinated COVID-19, and SARS-CoV-2-negative patients was 2.9 (95% CI, 2.4-3.4; P < .001), 2.0 (95% CI, 1.5-2.7; P < .001), and 1.3 (95% CI, 1.1-1.5; P = .002), respectively. When comparisons were limited to the Omicron period, the risk of 90-day VTE remained increased for unvaccinated (OR 3.9 [95% CI, 2.9-5.4]) and vaccinated (OR 1.8 [95% CI, 1.2-2.7]) COVID-19 patients with respiratory diagnoses. In this community-based cohort study, we found that SARS-CoV-2 infection was not associated with an increased risk of VTE among patients admitted to the ICU with nonrespiratory diagnoses, regardless of vaccination status. In contrast, the risk of VTE remained increased in critically ill vaccinated and boosted COVID-19 patients with respiratory diagnoses. The increased risk of VTE in unvaccinated and vaccinated COVID-19 patients with respiratory diagnoses persisted during the period of SARS-CoV-2 Omicron variant predominance. Endothelial injury occurring with SARS-CoV-2 infection is thought to play a critical role in disease pathogenesis of COVID-19, including the increased incidence of VTE.3Libby P. Luscher T. COVID-19 is, in the end, an endothelial disease.Eur Heart J. 2020; 41: 3038-3044Crossref PubMed Scopus (524) Google Scholar However, asymptomatic or nonrespiratory presentations of COVID-19 are increasingly recognized, especially in patients with SARS-CoV-2 vaccine breakthrough infections.4Fowlkes A.L. Yoon S.K. Lutrick K. et al.Effectiveness of 2-dose BNT162b2 (Pfizer BioNTech) mRNA vaccine in preventing SARS-CoV-2 infection among children aged 5-11 years and adolescents aged 12-15 years: PROTECT Cohort, July 2021-February 2022.MMWR Morb Mortal Wkly Rep. 2022; 71: 422-428Crossref PubMed Scopus (84) Google Scholar,5Bergwerk M. Gonen T. Lustig Y. et al.Covid-19 breakthrough infections in vaccinated health care workers.N Engl J Med. 2021; 385: 1474-1484Crossref PubMed Scopus (794) Google Scholar The role of SARS-CoV-2 infection in the pathogenesis of extrapulmonary manifestations of COVID-19 is not fully understood.6Boyton R.J. Altmann D.M. The immunology of asymptomatic SARS-CoV-2 infection: what are the key questions?.Nat Rev Immunol. 2021; 21: 762-768Crossref PubMed Scopus (42) Google Scholar, 7Al-Kuraishy H.M. Al-Gareeb A.I. Alblihed M. Guerreiro S.G. Cruz-Martins N. Batiha G.E. COVID-19 in relation to hyperglycemia and diabetes mellitus.Front Cardiovasc Med. 2021; 8644095Crossref Google Scholar, 8Gupta A. Madhavan M.V. Sehgal K. et al.Extrapulmonary manifestations of COVID-19.Nat Med. 2020; 26: 1017-1032Crossref PubMed Scopus (1654) Google Scholar Our results suggest that SARS-CoV-2 infection is not an independent risk factor for VTE in critically ill patients with nonrespiratory presentations of COVID-19 regardless of vaccination status. In contrast, respiratory presentations of COVID-19 were associated with an increased risk of 90-day VTE in both vaccinated and unvaccinated ICU patients. Although the risk of VTE appears to be attenuated in vaccinated COVID-19 patients, receipt of a vaccine booster did not further reduce this risk in patients requiring ICU admission. Multiple studies have shown a significant decrease in risk of hospitalization and death among vaccinated individuals with COVID-19.9Andrews N. Stowe J. Kirsebom F. et al.Covid-19 vaccine effectiveness against the omicron (B.1.1.529) variant.N Engl J Med. 2022; 386: 1532-1546Crossref PubMed Scopus (922) Google Scholar,10Tartof S.Y. Slezak J.M. Fischer H. et al.Effectiveness of mRNA BNT162b2 COVID-19 vaccine up to 6 months in a large integrated health system in the USA: a retrospective cohort study.Lancet. 2021; 398: 1407-1416Abstract Full Text Full Text PDF PubMed Google Scholar However, clinicians should be aware that the risk of VTE and mortality remains increased in vaccinated ICU patients with respiratory manifestations of COVID-19, including those with SARS-CoV-2 Omicron variant infections. Our data support continued evaluation of the risk of VTE with exposures to evolving SARS-CoV-2 variants and vaccines. This study has several limitations. The exclusion of patients with a history of VTE or prior anticoagulation potentially reduced the overall VTE incidence. Diagnostic testing patterns for VTE may have differed based on SARS-CoV-2 positivity, clinical presentation, or vaccination status. Finally, we were unable to quantify the impact of SARS-CoV-2 infection in nonrespiratory presentations of COVID-19; however, the lack of increased risk for VTE in these cases is nonetheless reassuring. In conclusion, SARS-CoV-2 infection was not associated with increased incidence of 90-day VTE in vaccinated and unvaccinated COVID-19 ICU patients with nonrespiratory diagnoses. In contrast, the risk of VTE remained increased, regardless of vaccination status, in critically ill patients with respiratory presentations of COVID-19. Funding for this project was provided by the National Heart, Lung, and Blood Institute (R01HL126130).