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COVID-19–associated coagulopathy
Coronavirus disease 2019 (COVID-19) is a viral illness caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), currently causing a pandemic affecting many countries around the world, beginning in December 2019 and spreading rapidly on a global scale since. Globally, its burden has been increasing rapidly, with more than 1.2 million people testing positive for the illness and 123,000 people losing their lives, as per April 15th’s WHO COVID-19 Situation Report.1 These numbers are increasing with each passing day. Clinically, SARS-CoV-2 has a highly variable course, ranging from mild disease manifested as a self-limited illness (seen in younger and healthier patients) to severe pneumonia/ARDS and multiorgan failure with intravascular coagulopathy.2
In this article, we intend to investigate and establish a comprehensive review of COVID-19–associated coagulopathy mechanisms, laboratory findings, and current management guidelines put forth by various societies globally.
Mechanism of coagulopathy
COVID-19–associated coagulopathy has been shown to predispose to both arterial and venous thrombosis through excessive inflammation and hypoxia, leading to activation of the coagulation cascade and consumption of coagulation factors, resulting in microvascular thrombosis.3 Though the exact pathophysiology for the activation of this cascade is not known, the proposed mechanism has been: endothelial damage triggering platelet activation within the lung, leading to aggregation, thrombosis, and consumption of platelets in the lung.2,5,6
Fox et al. noted similar coagulopathy findings of four deceased COVID-19 patients. Autopsy results concluded that the dominant process was diffuse alveolar damage, notable CD4+ aggregates around thrombosed small vessels, significant associated hemorrhage, and thrombotic microangiopathy restricted to the lungs. The proposed mechanism was the activation of megakaryocytes, possibly native to the lung, with platelet aggregation, formation of platelet-rich clots, and fibrin deposition playing a major role.4
It has been noted that diabetic patients are at an increased risk of vascular events and hypercoagulability with COVID-19.7 COVID-19 can also cause livedo reticularis and acrocyanosis because of the microthrombosis in the cutaneous vasculature secondary to underlying coagulopathy, as reported in a case report of two U.S. patients with COVID-19.8
Clinical and laboratory abnormalities
A recent study reported from Netherlands by Klok et al. analyzed 184 ICU patients with COVID-19 pneumonia and concluded that the cumulative incidence of acute pulmonary embolism (PE), deep vein thrombosis (DVT), ischemic stroke, MI, or systemic arterial embolism was 31% (95% confidence interval, 20%-41%). PE was the most frequent thrombotic complication and was noted in 81% of patients. Coagulopathy, defined as spontaneous prolongation of prothrombin time (PT) > 3s or activated partial thromboplastin time (aPTT) > 5s, was reported as an independent predictor of thrombotic complications.3
Hematologic abnormalities that were noted in COVID-19 coagulopathy include: decreased platelet counts, decreased fibrinogen levels, elevated PT/INR, elevated partial thromboplastin time (PTT), and elevated d-dimer.9,10 In a retrospective analysis9 by Tang et al., 71.4% of nonsurvivors and 0.6% of survivors had met the criteria of disseminated intravascular coagulation (DIC) during their hospital stay. Nonsurvivors of COVID-19 had statistically significant elevation of d-dimer levels, FDP levels, PT, and aPTT, when compared to survivors (P < .05). The overall mortality in this study was reported as 11.5%.9 In addition, elevated d-dimer, fibrin and fibrinogen degradation product (FDP) levels and longer PT and aPTT were associated with poor prognosis.
Thus, d-dimer, PT, and platelet count should be measured in all patients who present with COVID-19 infection. We can also suggest that in patients with markedly elevated d-dimer (three- to fourfold increase), admission to hospital should be considered even in the absence of severe clinical symptoms.11
COVID-19 coagulopathy management
In a retrospective study9 of 449 patients with severe COVID-19 from Wuhan, China, by Tang et al., 99 patients mainly received low-weight molecular heparin (LMWH) for 7 days or longer. No difference in 28-day mortality was noted between heparin users and nonusers (30.3% vs. 29.7%; P = .910). A lower 28-day mortality rate was noted in heparin patients with sepsis-induced coagulopathy score of ≥4.0 (40.0% vs. 64.2%; P = .029) or a d-dimer level greater than sixfold of upper limit of normal, compared with nonusers of heparin.12
Another small study of seven COVID-19 patients with acroischemia in China demonstrated that administering LMWH was successful at decreasing the d-dimer and fibrinogen degradation product levels but noted no significant improvement in clinical symptoms.13
Recently, the International Society of Thrombosis and Hemostasis and American Society of Hematology published recommendations and guidelines regarding the recognition and management of coagulopathy in COVID-19.11 Prophylactic anticoagulation therapy with LMWH was recommended in all hospitalized patients with COVID-19, provided there was an absence of any contraindications (active bleeding, platelet count less than 25 x 109/L and fibrinogen less than 0.5 g/dL). Anticoagulation with LMWH was associated with better prognosis in severe COVID-19 patients and in COVID-19 patients with markedly elevated d-dimer, as it also has anti-inflammatory effects.12 This anti-inflammatory property of heparin has been documented in previous studies but the underlying mechanism is unknown and more research is required.14,15
Despite coagulopathy being noticed with cases of COVID-19, bleeding has been a rare finding in COVID-19 infections. If bleeding is noted, recommendations were made to keep platelet levels greater than 50 x109/L, fibrinogen less than 2.0 g/L, and INR [international normalized ratio] greater than 1.5.11 Mechanical thromboprophylaxis should be used when pharmacologic thromboprophylaxis is contraindicated.16
COVID-19 patients with new diagnoses of venous thromboembolism (VTE) or atrial fibrillation should be prescribed therapeutic anticoagulation. Patients who are already on anticoagulation for VTE or atrial fibrillation should continue their therapy unless the platelet count is less than 30-50x109/L or if the fibrinogen is less than 1.0 g/L.16
Conclusion
Coagulopathies associated with COVID-19 infections have been documented in several studies around the world, and it has been shown to be fatal in some cases. Despite documentation, the mechanism behind this coagulopathy is not well understood. Because of the potentially lethal complications associated with coagulopathies, early recognition and anticoagulation is imperative to improve clinical outcomes. These results are very preliminary: More studies are required to understand the role of anticoagulation and its effect on the morbidity and mortality associated with COVID-19–associated coagulopathy.
Dr. Yeruva is a board-certified hematologist/medical oncologist with WellSpan Health and clinical assistant professor of internal medicine, Penn State University, Hershey. Mr. Henderson is a third-year graduate-entry medical student at the Royal College of Surgeons in Ireland with interests in family medicine, dermatology, and tropical diseases. Dr. Al-Tawfiq is a consultant of internal medicine & infectious diseases, and the director of quality at Johns Hopkins Aramco Healthcare in Dhahran, Saudi Arabia, an adjunct associate professor of infectious diseases, molecular medicine and clinical pharmacology at Johns Hopkins University School of Medicine, and adjunct associate professor at Indiana University School of Medicine, Indianapolis. Dr. Tirupathi is the medical director of Keystone Infectious Diseases/HIV in Chambersburg, Pa., and currently chair of infection prevention at Wellspan Chambersburg and Waynesboro (Pa.) Hospitals. He also is the lead physician for antibiotic stewardship at these hospitals.
References
1. World Health Organization. Coronavirus disease (COVID-2019) situation reports.
2. Lippi G et al. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis. Clin Chim Acta. 2020 Mar 13. 506:145-8. doi: 10.1016/j.cca.2020.03.022.
3. Klok FA et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Throm Res. 2020;18(4):844-7. doi: 10.1016/j.thromres.2020.04.013.
4. Fox S et al. Pulmonary and cardiac pathology in Covid-19: The first autopsy series from New Orleans. MedRxiv. 2020 Apr 10. doi: 10.1101/2020.04.06.20050575.
5. Yang M et al. Thrombocytopenia in patients with severe acute respiratory syndrome (review). Hematology 2013 Sep 4. doi: 10.1080/1024533040002617.
6. Giannis D et al. Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past. J Clin Virol. 2020 June. doi: 10.1016/j.jcv.2020.104362.
7. Guo W et al. Diabetes is a risk factor for the progression and prognosis of COVID-19. Diabetes Metab Res Rev. 2020 Mar 31. doi: 10.1002/dmrr.3319.
8. Manalo IF et al. A dermatologic manifestation of COVID-19: Transient livedo reticularis. J Am Acad Dermat. 2020 Apr. doi: 10.1016/j.jaad.2020.04.018.
9. Tang N et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020 Feb 19. doi: 10.1111/jth.14768, 18: 844-847.
10. Huang C et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020 Jan 24. doi: 10.1016/S0140-6736(20)30183-5.
11. Thachil J et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020 Mar 25. doi: 10.1111/JTH.14810.
12. Tang N et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020 Mar 27. doi: 10.1111/JTH.14817.
13. Zhang Y et al. Clinical and coagulation characteristics of 7 patients with critical COVID-2019 pneumonia and acro-ischemia. Zhonghua Xue Ye Xue Za Zhi. 2020 Mar 28. doi: 10.3760/cma.j.issn.0253-2727.2020.0006.
14. Poterucha TJ et al. More than an anticoagulant: Do heparins have direct anti-inflammatory effects? Thromb Haemost. 2017. doi: 10.1160/TH16-08-0620.
15. Mousavi S et al. Anti-inflammatory effects of heparin and its derivatives: A systematic review. Adv Pharmacol Pharm Sci. 2015 May 12. doi: 10.1155/2015/507151.
16. Kreuziger L et al. COVID-19 and VTE/anticoagulation: Frequently asked questions. American Society of Hematology. 2020 Apr 17.
Coronavirus disease 2019 (COVID-19) is a viral illness caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), currently causing a pandemic affecting many countries around the world, beginning in December 2019 and spreading rapidly on a global scale since. Globally, its burden has been increasing rapidly, with more than 1.2 million people testing positive for the illness and 123,000 people losing their lives, as per April 15th’s WHO COVID-19 Situation Report.1 These numbers are increasing with each passing day. Clinically, SARS-CoV-2 has a highly variable course, ranging from mild disease manifested as a self-limited illness (seen in younger and healthier patients) to severe pneumonia/ARDS and multiorgan failure with intravascular coagulopathy.2
In this article, we intend to investigate and establish a comprehensive review of COVID-19–associated coagulopathy mechanisms, laboratory findings, and current management guidelines put forth by various societies globally.
Mechanism of coagulopathy
COVID-19–associated coagulopathy has been shown to predispose to both arterial and venous thrombosis through excessive inflammation and hypoxia, leading to activation of the coagulation cascade and consumption of coagulation factors, resulting in microvascular thrombosis.3 Though the exact pathophysiology for the activation of this cascade is not known, the proposed mechanism has been: endothelial damage triggering platelet activation within the lung, leading to aggregation, thrombosis, and consumption of platelets in the lung.2,5,6
Fox et al. noted similar coagulopathy findings of four deceased COVID-19 patients. Autopsy results concluded that the dominant process was diffuse alveolar damage, notable CD4+ aggregates around thrombosed small vessels, significant associated hemorrhage, and thrombotic microangiopathy restricted to the lungs. The proposed mechanism was the activation of megakaryocytes, possibly native to the lung, with platelet aggregation, formation of platelet-rich clots, and fibrin deposition playing a major role.4
It has been noted that diabetic patients are at an increased risk of vascular events and hypercoagulability with COVID-19.7 COVID-19 can also cause livedo reticularis and acrocyanosis because of the microthrombosis in the cutaneous vasculature secondary to underlying coagulopathy, as reported in a case report of two U.S. patients with COVID-19.8
Clinical and laboratory abnormalities
A recent study reported from Netherlands by Klok et al. analyzed 184 ICU patients with COVID-19 pneumonia and concluded that the cumulative incidence of acute pulmonary embolism (PE), deep vein thrombosis (DVT), ischemic stroke, MI, or systemic arterial embolism was 31% (95% confidence interval, 20%-41%). PE was the most frequent thrombotic complication and was noted in 81% of patients. Coagulopathy, defined as spontaneous prolongation of prothrombin time (PT) > 3s or activated partial thromboplastin time (aPTT) > 5s, was reported as an independent predictor of thrombotic complications.3
Hematologic abnormalities that were noted in COVID-19 coagulopathy include: decreased platelet counts, decreased fibrinogen levels, elevated PT/INR, elevated partial thromboplastin time (PTT), and elevated d-dimer.9,10 In a retrospective analysis9 by Tang et al., 71.4% of nonsurvivors and 0.6% of survivors had met the criteria of disseminated intravascular coagulation (DIC) during their hospital stay. Nonsurvivors of COVID-19 had statistically significant elevation of d-dimer levels, FDP levels, PT, and aPTT, when compared to survivors (P < .05). The overall mortality in this study was reported as 11.5%.9 In addition, elevated d-dimer, fibrin and fibrinogen degradation product (FDP) levels and longer PT and aPTT were associated with poor prognosis.
Thus, d-dimer, PT, and platelet count should be measured in all patients who present with COVID-19 infection. We can also suggest that in patients with markedly elevated d-dimer (three- to fourfold increase), admission to hospital should be considered even in the absence of severe clinical symptoms.11
COVID-19 coagulopathy management
In a retrospective study9 of 449 patients with severe COVID-19 from Wuhan, China, by Tang et al., 99 patients mainly received low-weight molecular heparin (LMWH) for 7 days or longer. No difference in 28-day mortality was noted between heparin users and nonusers (30.3% vs. 29.7%; P = .910). A lower 28-day mortality rate was noted in heparin patients with sepsis-induced coagulopathy score of ≥4.0 (40.0% vs. 64.2%; P = .029) or a d-dimer level greater than sixfold of upper limit of normal, compared with nonusers of heparin.12
Another small study of seven COVID-19 patients with acroischemia in China demonstrated that administering LMWH was successful at decreasing the d-dimer and fibrinogen degradation product levels but noted no significant improvement in clinical symptoms.13
Recently, the International Society of Thrombosis and Hemostasis and American Society of Hematology published recommendations and guidelines regarding the recognition and management of coagulopathy in COVID-19.11 Prophylactic anticoagulation therapy with LMWH was recommended in all hospitalized patients with COVID-19, provided there was an absence of any contraindications (active bleeding, platelet count less than 25 x 109/L and fibrinogen less than 0.5 g/dL). Anticoagulation with LMWH was associated with better prognosis in severe COVID-19 patients and in COVID-19 patients with markedly elevated d-dimer, as it also has anti-inflammatory effects.12 This anti-inflammatory property of heparin has been documented in previous studies but the underlying mechanism is unknown and more research is required.14,15
Despite coagulopathy being noticed with cases of COVID-19, bleeding has been a rare finding in COVID-19 infections. If bleeding is noted, recommendations were made to keep platelet levels greater than 50 x109/L, fibrinogen less than 2.0 g/L, and INR [international normalized ratio] greater than 1.5.11 Mechanical thromboprophylaxis should be used when pharmacologic thromboprophylaxis is contraindicated.16
COVID-19 patients with new diagnoses of venous thromboembolism (VTE) or atrial fibrillation should be prescribed therapeutic anticoagulation. Patients who are already on anticoagulation for VTE or atrial fibrillation should continue their therapy unless the platelet count is less than 30-50x109/L or if the fibrinogen is less than 1.0 g/L.16
Conclusion
Coagulopathies associated with COVID-19 infections have been documented in several studies around the world, and it has been shown to be fatal in some cases. Despite documentation, the mechanism behind this coagulopathy is not well understood. Because of the potentially lethal complications associated with coagulopathies, early recognition and anticoagulation is imperative to improve clinical outcomes. These results are very preliminary: More studies are required to understand the role of anticoagulation and its effect on the morbidity and mortality associated with COVID-19–associated coagulopathy.
Dr. Yeruva is a board-certified hematologist/medical oncologist with WellSpan Health and clinical assistant professor of internal medicine, Penn State University, Hershey. Mr. Henderson is a third-year graduate-entry medical student at the Royal College of Surgeons in Ireland with interests in family medicine, dermatology, and tropical diseases. Dr. Al-Tawfiq is a consultant of internal medicine & infectious diseases, and the director of quality at Johns Hopkins Aramco Healthcare in Dhahran, Saudi Arabia, an adjunct associate professor of infectious diseases, molecular medicine and clinical pharmacology at Johns Hopkins University School of Medicine, and adjunct associate professor at Indiana University School of Medicine, Indianapolis. Dr. Tirupathi is the medical director of Keystone Infectious Diseases/HIV in Chambersburg, Pa., and currently chair of infection prevention at Wellspan Chambersburg and Waynesboro (Pa.) Hospitals. He also is the lead physician for antibiotic stewardship at these hospitals.
References
1. World Health Organization. Coronavirus disease (COVID-2019) situation reports.
2. Lippi G et al. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis. Clin Chim Acta. 2020 Mar 13. 506:145-8. doi: 10.1016/j.cca.2020.03.022.
3. Klok FA et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Throm Res. 2020;18(4):844-7. doi: 10.1016/j.thromres.2020.04.013.
4. Fox S et al. Pulmonary and cardiac pathology in Covid-19: The first autopsy series from New Orleans. MedRxiv. 2020 Apr 10. doi: 10.1101/2020.04.06.20050575.
5. Yang M et al. Thrombocytopenia in patients with severe acute respiratory syndrome (review). Hematology 2013 Sep 4. doi: 10.1080/1024533040002617.
6. Giannis D et al. Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past. J Clin Virol. 2020 June. doi: 10.1016/j.jcv.2020.104362.
7. Guo W et al. Diabetes is a risk factor for the progression and prognosis of COVID-19. Diabetes Metab Res Rev. 2020 Mar 31. doi: 10.1002/dmrr.3319.
8. Manalo IF et al. A dermatologic manifestation of COVID-19: Transient livedo reticularis. J Am Acad Dermat. 2020 Apr. doi: 10.1016/j.jaad.2020.04.018.
9. Tang N et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020 Feb 19. doi: 10.1111/jth.14768, 18: 844-847.
10. Huang C et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020 Jan 24. doi: 10.1016/S0140-6736(20)30183-5.
11. Thachil J et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020 Mar 25. doi: 10.1111/JTH.14810.
12. Tang N et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020 Mar 27. doi: 10.1111/JTH.14817.
13. Zhang Y et al. Clinical and coagulation characteristics of 7 patients with critical COVID-2019 pneumonia and acro-ischemia. Zhonghua Xue Ye Xue Za Zhi. 2020 Mar 28. doi: 10.3760/cma.j.issn.0253-2727.2020.0006.
14. Poterucha TJ et al. More than an anticoagulant: Do heparins have direct anti-inflammatory effects? Thromb Haemost. 2017. doi: 10.1160/TH16-08-0620.
15. Mousavi S et al. Anti-inflammatory effects of heparin and its derivatives: A systematic review. Adv Pharmacol Pharm Sci. 2015 May 12. doi: 10.1155/2015/507151.
16. Kreuziger L et al. COVID-19 and VTE/anticoagulation: Frequently asked questions. American Society of Hematology. 2020 Apr 17.
Coronavirus disease 2019 (COVID-19) is a viral illness caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), currently causing a pandemic affecting many countries around the world, beginning in December 2019 and spreading rapidly on a global scale since. Globally, its burden has been increasing rapidly, with more than 1.2 million people testing positive for the illness and 123,000 people losing their lives, as per April 15th’s WHO COVID-19 Situation Report.1 These numbers are increasing with each passing day. Clinically, SARS-CoV-2 has a highly variable course, ranging from mild disease manifested as a self-limited illness (seen in younger and healthier patients) to severe pneumonia/ARDS and multiorgan failure with intravascular coagulopathy.2
In this article, we intend to investigate and establish a comprehensive review of COVID-19–associated coagulopathy mechanisms, laboratory findings, and current management guidelines put forth by various societies globally.
Mechanism of coagulopathy
COVID-19–associated coagulopathy has been shown to predispose to both arterial and venous thrombosis through excessive inflammation and hypoxia, leading to activation of the coagulation cascade and consumption of coagulation factors, resulting in microvascular thrombosis.3 Though the exact pathophysiology for the activation of this cascade is not known, the proposed mechanism has been: endothelial damage triggering platelet activation within the lung, leading to aggregation, thrombosis, and consumption of platelets in the lung.2,5,6
Fox et al. noted similar coagulopathy findings of four deceased COVID-19 patients. Autopsy results concluded that the dominant process was diffuse alveolar damage, notable CD4+ aggregates around thrombosed small vessels, significant associated hemorrhage, and thrombotic microangiopathy restricted to the lungs. The proposed mechanism was the activation of megakaryocytes, possibly native to the lung, with platelet aggregation, formation of platelet-rich clots, and fibrin deposition playing a major role.4
It has been noted that diabetic patients are at an increased risk of vascular events and hypercoagulability with COVID-19.7 COVID-19 can also cause livedo reticularis and acrocyanosis because of the microthrombosis in the cutaneous vasculature secondary to underlying coagulopathy, as reported in a case report of two U.S. patients with COVID-19.8
Clinical and laboratory abnormalities
A recent study reported from Netherlands by Klok et al. analyzed 184 ICU patients with COVID-19 pneumonia and concluded that the cumulative incidence of acute pulmonary embolism (PE), deep vein thrombosis (DVT), ischemic stroke, MI, or systemic arterial embolism was 31% (95% confidence interval, 20%-41%). PE was the most frequent thrombotic complication and was noted in 81% of patients. Coagulopathy, defined as spontaneous prolongation of prothrombin time (PT) > 3s or activated partial thromboplastin time (aPTT) > 5s, was reported as an independent predictor of thrombotic complications.3
Hematologic abnormalities that were noted in COVID-19 coagulopathy include: decreased platelet counts, decreased fibrinogen levels, elevated PT/INR, elevated partial thromboplastin time (PTT), and elevated d-dimer.9,10 In a retrospective analysis9 by Tang et al., 71.4% of nonsurvivors and 0.6% of survivors had met the criteria of disseminated intravascular coagulation (DIC) during their hospital stay. Nonsurvivors of COVID-19 had statistically significant elevation of d-dimer levels, FDP levels, PT, and aPTT, when compared to survivors (P < .05). The overall mortality in this study was reported as 11.5%.9 In addition, elevated d-dimer, fibrin and fibrinogen degradation product (FDP) levels and longer PT and aPTT were associated with poor prognosis.
Thus, d-dimer, PT, and platelet count should be measured in all patients who present with COVID-19 infection. We can also suggest that in patients with markedly elevated d-dimer (three- to fourfold increase), admission to hospital should be considered even in the absence of severe clinical symptoms.11
COVID-19 coagulopathy management
In a retrospective study9 of 449 patients with severe COVID-19 from Wuhan, China, by Tang et al., 99 patients mainly received low-weight molecular heparin (LMWH) for 7 days or longer. No difference in 28-day mortality was noted between heparin users and nonusers (30.3% vs. 29.7%; P = .910). A lower 28-day mortality rate was noted in heparin patients with sepsis-induced coagulopathy score of ≥4.0 (40.0% vs. 64.2%; P = .029) or a d-dimer level greater than sixfold of upper limit of normal, compared with nonusers of heparin.12
Another small study of seven COVID-19 patients with acroischemia in China demonstrated that administering LMWH was successful at decreasing the d-dimer and fibrinogen degradation product levels but noted no significant improvement in clinical symptoms.13
Recently, the International Society of Thrombosis and Hemostasis and American Society of Hematology published recommendations and guidelines regarding the recognition and management of coagulopathy in COVID-19.11 Prophylactic anticoagulation therapy with LMWH was recommended in all hospitalized patients with COVID-19, provided there was an absence of any contraindications (active bleeding, platelet count less than 25 x 109/L and fibrinogen less than 0.5 g/dL). Anticoagulation with LMWH was associated with better prognosis in severe COVID-19 patients and in COVID-19 patients with markedly elevated d-dimer, as it also has anti-inflammatory effects.12 This anti-inflammatory property of heparin has been documented in previous studies but the underlying mechanism is unknown and more research is required.14,15
Despite coagulopathy being noticed with cases of COVID-19, bleeding has been a rare finding in COVID-19 infections. If bleeding is noted, recommendations were made to keep platelet levels greater than 50 x109/L, fibrinogen less than 2.0 g/L, and INR [international normalized ratio] greater than 1.5.11 Mechanical thromboprophylaxis should be used when pharmacologic thromboprophylaxis is contraindicated.16
COVID-19 patients with new diagnoses of venous thromboembolism (VTE) or atrial fibrillation should be prescribed therapeutic anticoagulation. Patients who are already on anticoagulation for VTE or atrial fibrillation should continue their therapy unless the platelet count is less than 30-50x109/L or if the fibrinogen is less than 1.0 g/L.16
Conclusion
Coagulopathies associated with COVID-19 infections have been documented in several studies around the world, and it has been shown to be fatal in some cases. Despite documentation, the mechanism behind this coagulopathy is not well understood. Because of the potentially lethal complications associated with coagulopathies, early recognition and anticoagulation is imperative to improve clinical outcomes. These results are very preliminary: More studies are required to understand the role of anticoagulation and its effect on the morbidity and mortality associated with COVID-19–associated coagulopathy.
Dr. Yeruva is a board-certified hematologist/medical oncologist with WellSpan Health and clinical assistant professor of internal medicine, Penn State University, Hershey. Mr. Henderson is a third-year graduate-entry medical student at the Royal College of Surgeons in Ireland with interests in family medicine, dermatology, and tropical diseases. Dr. Al-Tawfiq is a consultant of internal medicine & infectious diseases, and the director of quality at Johns Hopkins Aramco Healthcare in Dhahran, Saudi Arabia, an adjunct associate professor of infectious diseases, molecular medicine and clinical pharmacology at Johns Hopkins University School of Medicine, and adjunct associate professor at Indiana University School of Medicine, Indianapolis. Dr. Tirupathi is the medical director of Keystone Infectious Diseases/HIV in Chambersburg, Pa., and currently chair of infection prevention at Wellspan Chambersburg and Waynesboro (Pa.) Hospitals. He also is the lead physician for antibiotic stewardship at these hospitals.
References
1. World Health Organization. Coronavirus disease (COVID-2019) situation reports.
2. Lippi G et al. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis. Clin Chim Acta. 2020 Mar 13. 506:145-8. doi: 10.1016/j.cca.2020.03.022.
3. Klok FA et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Throm Res. 2020;18(4):844-7. doi: 10.1016/j.thromres.2020.04.013.
4. Fox S et al. Pulmonary and cardiac pathology in Covid-19: The first autopsy series from New Orleans. MedRxiv. 2020 Apr 10. doi: 10.1101/2020.04.06.20050575.
5. Yang M et al. Thrombocytopenia in patients with severe acute respiratory syndrome (review). Hematology 2013 Sep 4. doi: 10.1080/1024533040002617.
6. Giannis D et al. Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past. J Clin Virol. 2020 June. doi: 10.1016/j.jcv.2020.104362.
7. Guo W et al. Diabetes is a risk factor for the progression and prognosis of COVID-19. Diabetes Metab Res Rev. 2020 Mar 31. doi: 10.1002/dmrr.3319.
8. Manalo IF et al. A dermatologic manifestation of COVID-19: Transient livedo reticularis. J Am Acad Dermat. 2020 Apr. doi: 10.1016/j.jaad.2020.04.018.
9. Tang N et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020 Feb 19. doi: 10.1111/jth.14768, 18: 844-847.
10. Huang C et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020 Jan 24. doi: 10.1016/S0140-6736(20)30183-5.
11. Thachil J et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020 Mar 25. doi: 10.1111/JTH.14810.
12. Tang N et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020 Mar 27. doi: 10.1111/JTH.14817.
13. Zhang Y et al. Clinical and coagulation characteristics of 7 patients with critical COVID-2019 pneumonia and acro-ischemia. Zhonghua Xue Ye Xue Za Zhi. 2020 Mar 28. doi: 10.3760/cma.j.issn.0253-2727.2020.0006.
14. Poterucha TJ et al. More than an anticoagulant: Do heparins have direct anti-inflammatory effects? Thromb Haemost. 2017. doi: 10.1160/TH16-08-0620.
15. Mousavi S et al. Anti-inflammatory effects of heparin and its derivatives: A systematic review. Adv Pharmacol Pharm Sci. 2015 May 12. doi: 10.1155/2015/507151.
16. Kreuziger L et al. COVID-19 and VTE/anticoagulation: Frequently asked questions. American Society of Hematology. 2020 Apr 17.
IV-to-oral antibiotics can benefit patients with MRSA bloodstream infection
Background: Methicillin-resistant Staphylococcus aureus bloodstream infections carry a high risk of morbidity and relapse with most published guidelines recommending prolonged courses of IV antibiotics to ensure complete clearance of the infection. However, long-term IV antibiotic therapy may also be costly and is not without its own complications. An equally effective IV-to-oral antibiotic therapy would be welcome.
Study design: Retrospective cohort study.
Setting: A single academic center in the United States.
Synopsis: The investigators reviewed data from 492 adults with at least one positive blood culture for MRSA who had not yet completed their antibiotic course at the time of discharge during the index hospitalization but were sufficiently stable to complete outpatient antibiotic treatment. Of this cohort, 70 patients were switched to oral antibiotic therapy on discharge, while the rest received OPAT. The primary outcome was clinical failure, a 90-day composite measure of MRSA bloodstream infection recurrence, deep MRSA infection, or all-cause mortality. The most commonly used oral antibiotics were linezolid, trimethoprim/sulfamethoxazole, and clindamycin, all with high bioavailability. Endovascular infection was present in 21.5% of the study population. After propensity score adjustment for covariates, patients who received oral antibiotics had a nonsignificant reduction in the rate of clinical failure (hazard ratio, 0.379; 95% CI, 0.131-1.101).
Limitations of the study included its observational design with potential for significant residual confounding despite the propensity score–adjusted analysis, its single-center setting, the low frequency of endovascular infections, and the uncertainty in how the loss of patients to follow-up might have affected the results.
Bottom line: Selected patients with MRSA BSI may be successfully treated with sequential IV-to-oral antibiotic therapy.
Citation: Jorgensen SCJ et al. Sequential intravenous-to-oral outpatient antibiotic therapy for MRSA bacteraemia: One step closer. J Antimicrob Chemother. 2019 Feb;74(2):489-98.
Dr. Torres is a hospitalist at Massachusetts General Hospital.
Background: Methicillin-resistant Staphylococcus aureus bloodstream infections carry a high risk of morbidity and relapse with most published guidelines recommending prolonged courses of IV antibiotics to ensure complete clearance of the infection. However, long-term IV antibiotic therapy may also be costly and is not without its own complications. An equally effective IV-to-oral antibiotic therapy would be welcome.
Study design: Retrospective cohort study.
Setting: A single academic center in the United States.
Synopsis: The investigators reviewed data from 492 adults with at least one positive blood culture for MRSA who had not yet completed their antibiotic course at the time of discharge during the index hospitalization but were sufficiently stable to complete outpatient antibiotic treatment. Of this cohort, 70 patients were switched to oral antibiotic therapy on discharge, while the rest received OPAT. The primary outcome was clinical failure, a 90-day composite measure of MRSA bloodstream infection recurrence, deep MRSA infection, or all-cause mortality. The most commonly used oral antibiotics were linezolid, trimethoprim/sulfamethoxazole, and clindamycin, all with high bioavailability. Endovascular infection was present in 21.5% of the study population. After propensity score adjustment for covariates, patients who received oral antibiotics had a nonsignificant reduction in the rate of clinical failure (hazard ratio, 0.379; 95% CI, 0.131-1.101).
Limitations of the study included its observational design with potential for significant residual confounding despite the propensity score–adjusted analysis, its single-center setting, the low frequency of endovascular infections, and the uncertainty in how the loss of patients to follow-up might have affected the results.
Bottom line: Selected patients with MRSA BSI may be successfully treated with sequential IV-to-oral antibiotic therapy.
Citation: Jorgensen SCJ et al. Sequential intravenous-to-oral outpatient antibiotic therapy for MRSA bacteraemia: One step closer. J Antimicrob Chemother. 2019 Feb;74(2):489-98.
Dr. Torres is a hospitalist at Massachusetts General Hospital.
Background: Methicillin-resistant Staphylococcus aureus bloodstream infections carry a high risk of morbidity and relapse with most published guidelines recommending prolonged courses of IV antibiotics to ensure complete clearance of the infection. However, long-term IV antibiotic therapy may also be costly and is not without its own complications. An equally effective IV-to-oral antibiotic therapy would be welcome.
Study design: Retrospective cohort study.
Setting: A single academic center in the United States.
Synopsis: The investigators reviewed data from 492 adults with at least one positive blood culture for MRSA who had not yet completed their antibiotic course at the time of discharge during the index hospitalization but were sufficiently stable to complete outpatient antibiotic treatment. Of this cohort, 70 patients were switched to oral antibiotic therapy on discharge, while the rest received OPAT. The primary outcome was clinical failure, a 90-day composite measure of MRSA bloodstream infection recurrence, deep MRSA infection, or all-cause mortality. The most commonly used oral antibiotics were linezolid, trimethoprim/sulfamethoxazole, and clindamycin, all with high bioavailability. Endovascular infection was present in 21.5% of the study population. After propensity score adjustment for covariates, patients who received oral antibiotics had a nonsignificant reduction in the rate of clinical failure (hazard ratio, 0.379; 95% CI, 0.131-1.101).
Limitations of the study included its observational design with potential for significant residual confounding despite the propensity score–adjusted analysis, its single-center setting, the low frequency of endovascular infections, and the uncertainty in how the loss of patients to follow-up might have affected the results.
Bottom line: Selected patients with MRSA BSI may be successfully treated with sequential IV-to-oral antibiotic therapy.
Citation: Jorgensen SCJ et al. Sequential intravenous-to-oral outpatient antibiotic therapy for MRSA bacteraemia: One step closer. J Antimicrob Chemother. 2019 Feb;74(2):489-98.
Dr. Torres is a hospitalist at Massachusetts General Hospital.
COVID-19 pulmonary severity ascribed to coagulation differences
Differences in COVID-19-related death rates between people of white and Asian ancestry may be partly explained by documented ethnic/racial differences in risk for blood clotting and pulmonary thrombotic events, investigators propose.
“Our novel findings demonstrate that COVID-19 is associated with a unique type of blood clotting disorder that is primarily focused within the lungs and which undoubtedly contributes to the high levels of mortality being seen in patients with COVID-19,” said James O’Donnell, MB, PhD, director of the Irish Centre for Vascular Biology at the Royal College of Surgeons in Ireland.
Dr. O’Donnell and colleagues studied pulmonary effects and outcomes of 83 patients admitted to St. James Hospital in Dublin, and found evidence to suggest that the diffuse, bilateral pulmonary inflammation seen in many patients with severe COVID-19 infections may be caused by a pulmonary-specific vasculopathy they label “pulmonary intravascular coagulopathy” (PIC), an entity distinct from disseminated intravascular coagulopathy (DIC).
“Given that thrombotic risk is significantly impacted by race, coupled with the accumulating evidence that coagulopathy is important in COVID-19 pathogenesis, our findings raise the intriguing possibility that pulmonary vasculopathy may contribute to the unexplained differences that are beginning to emerge highlighting racial susceptibility to COVID-19 mortality,” they wrote in a study published online in the British Journal of Haematology.
Study flaws harm conclusions
But critical care specialists who agreed to review and comment on the study for MDedge News said that it has significant flaws that affect the ability to interpret the findings and “undermine the conclusions reached by the authors.”
“The underlying premise of the study is that there are racial and ethnic differences in the development of venous thromboembolism that may explain the racial and ethnic differences in outcomes from COVID-19,” J. Daryl Thornton, MD, MPH, a fellow of the American Thoracic Society and associate professor of pulmonary, critical care, and sleep medicine at Case Western Reserve University, Cleveland, said in an interview. “This is an interesting hypothesis and one that could be easily tested in a well-designed study with sufficient representation from the relevant racial and ethnic groups. However, this study is neither well designed nor does it have sufficient racial and ethnic representation.”
Elliott R. Haut, MD, PhD, associate professor of surgery, anesthesiology and critical care medicine at Johns Hopkins Medicine, Baltimore, said in an interview that the study is “mediocre” and has the feel of a paper rushed to press.
“It talks about their theory that race, ethnicity, have an effect on venous thromboembolism, and that’s a pretty well-known fact. No one’s a hundred percent sure why that is, but certainly there are tons and tons of papers that show that there are groups that are at higher risk than others,” he said. “Their idea that this is caused by this pulmonary inflammation, that is totally a guess; there is no data in this paper to support that.”
Dr. Thornton and Dr. Haut both noted that the authors don’t define how race and ethnicity were determined and whether patients were asked to provide it, and although they mention the racial/ethnic breakdown once, subsequent references are to entire cohort are as “Caucasian.”
They also called into question the value of comparing laboratory data across continents in centers with different testing methods and parameters, especially in a time when the clinical picture changes so rapidly.
Coagulation differences
Dr. O’Donnell and colleagues noted that most studies of COVID-19-associated coagulopathy published to date have been with Chinese patients.
“This is important because race and ethnicity have major effects upon thrombotic risk. In particular, epidemiological studies have shown that the incidence of venous thromboembolism (VTE) is approximately three to fourfold lower in Chinese compared to Caucasian individuals. Conversely, VTE risk is significantly higher in African-Americans compared to Caucasians,” they wrote.
Because of the lower risk of VTE in the Chinese population, thromboprophylaxis with low-molecular-weight heparin (LMWH) or other agents is less frequently used in Chinese hospitals than in hospitals with predominantly non-Asian patients, they noted.
To see whether the were differences in coagulopathy between Chinese and white patients, the researchers enrolled 55 men and 28 women, median age 64, who were admitted to St. James Hospital with COVID-19 infections from March 13 through April 10, 2020. The cohort included 67 patients of white background, 10 of Asian ancestry, 5 of African ethnicity, and 1 of Latino/Hispanic ancestry.
Of the 83 patients, 67 had comorbidities at admission. At the time of the report, 50 patients had fully recovered and were discharged, 20 remained in the hospital, and 13 had died. In all, 50 patients were discharged without needing ICU care, 23 were admitted to the ICU, and 10 required ICU but were deemed “clinically unsuitable” for ICU admission.
Although the patients had normal prothrombin time (PT) and normal activated partial thromboplastin time (APTT), plasma d-dimer levels were significantly elevated and were above the range of normal in two-thirds of patients on admission.
Despite the increased d-dimer levels, however, there was no evidence of DIC as defined by the International Society of Thrombosis and Hemostasis Scientific and Standardization committee (ISTH SSC) guidelines. Platelet counts were in the normal range in 83.1% of patients, and only five had counts less than 100 x 109/L at admission. Fibrinogen levels were also elevated, as were C-reactive protein levels, both likely indicating an acute phase response.
“Thus, despite the fact that thrombotic risk is much higher in Caucasian patients and the significant elevated levels of d-dimers observed, overt DIC as defined according to the ISTH SSC DIC score was present in none of our COVID-19 patients at time of admission. Nevertheless, our data confirm that severe COVID-19 infection is associated with a significant coagulopathy in Caucasian patients that appears to be similar in magnitude to that previously reported in the original Chinese cohorts,” they wrote.
When they compared patients who required ICU admission for ventilator support and those who died with patients who were discharged without needing ICU support, they found that survivors were younger (median age 60.2 vs. 75.2 years), and that more critically ill patients were more likely to have comorbidities.
They also found that patients with abnormal coagulation parameters on admission were significantly more likely to have poor prognosis (P = .018), and that patients in the adverse outcomes group had significantly higher fibrinogen and CRP levels (P = .045 and .0005, respectively).
There was no significant difference in PT between the prognosis groups at admission, but by day 4 and beyond PT was a median of 13.1 vs. 12.5 seconds in the favorable outcomes groups (P = .007), and patients with poor prognosis continued to have significantly higher d-dimer levels. (P = .003)
“Cumulatively, these data support the hypothesis that COVID-19–associated coagulopathy probably contributes to the underlying pulmonary pathogenesis,” the researchers wrote.
They noted that the angiotensin converting enzyme 2 (ACE-2) receptor that COVID-19 uses to enter cells is expressed on both type II pneumocytes and vascular endothelial cells within the lung, suggesting that the coagulopathy may be related to direct pulmonary endothelial cell infection , activation, and/or damage, and to the documented cytokine storm that can affect thrombin generation and fibrin deposition within the lungs.
“In the context of this lung-centric vasculopathy, we hypothesize that the refractory acute respiratory distress syndrome phenotype observed in severe COVID-19 is due to concurrent ‘double-hit’ pathologies targeting both ventilation (V) and perfusion (Q) within the lungs where alveoli and pulmonary microvasculature exist in close anatomical juxtaposition,” they wrote.
The investigators noted that larger randomized trials will be needed to determine whether more aggressive anti-coagulation and/or targeted anti-inflammatory therapies could effectively treated PIC in patients with severe COVID-19.
The study was supported by the Wellcome Trust and the Health Research Board Health Service and the Research and Development Division, Northern Ireland. Dr. O’Donnell disclosed speakers bureau activities, advisory board participation, and research grants from multiple companies. The other doctors had no relevant conflicts of interest to disclose.
SOURCE: Fogarty H et al. Br J Haematol. 2020 Apr 24. doi: 10.1111/bjh.16749.
Differences in COVID-19-related death rates between people of white and Asian ancestry may be partly explained by documented ethnic/racial differences in risk for blood clotting and pulmonary thrombotic events, investigators propose.
“Our novel findings demonstrate that COVID-19 is associated with a unique type of blood clotting disorder that is primarily focused within the lungs and which undoubtedly contributes to the high levels of mortality being seen in patients with COVID-19,” said James O’Donnell, MB, PhD, director of the Irish Centre for Vascular Biology at the Royal College of Surgeons in Ireland.
Dr. O’Donnell and colleagues studied pulmonary effects and outcomes of 83 patients admitted to St. James Hospital in Dublin, and found evidence to suggest that the diffuse, bilateral pulmonary inflammation seen in many patients with severe COVID-19 infections may be caused by a pulmonary-specific vasculopathy they label “pulmonary intravascular coagulopathy” (PIC), an entity distinct from disseminated intravascular coagulopathy (DIC).
“Given that thrombotic risk is significantly impacted by race, coupled with the accumulating evidence that coagulopathy is important in COVID-19 pathogenesis, our findings raise the intriguing possibility that pulmonary vasculopathy may contribute to the unexplained differences that are beginning to emerge highlighting racial susceptibility to COVID-19 mortality,” they wrote in a study published online in the British Journal of Haematology.
Study flaws harm conclusions
But critical care specialists who agreed to review and comment on the study for MDedge News said that it has significant flaws that affect the ability to interpret the findings and “undermine the conclusions reached by the authors.”
“The underlying premise of the study is that there are racial and ethnic differences in the development of venous thromboembolism that may explain the racial and ethnic differences in outcomes from COVID-19,” J. Daryl Thornton, MD, MPH, a fellow of the American Thoracic Society and associate professor of pulmonary, critical care, and sleep medicine at Case Western Reserve University, Cleveland, said in an interview. “This is an interesting hypothesis and one that could be easily tested in a well-designed study with sufficient representation from the relevant racial and ethnic groups. However, this study is neither well designed nor does it have sufficient racial and ethnic representation.”
Elliott R. Haut, MD, PhD, associate professor of surgery, anesthesiology and critical care medicine at Johns Hopkins Medicine, Baltimore, said in an interview that the study is “mediocre” and has the feel of a paper rushed to press.
“It talks about their theory that race, ethnicity, have an effect on venous thromboembolism, and that’s a pretty well-known fact. No one’s a hundred percent sure why that is, but certainly there are tons and tons of papers that show that there are groups that are at higher risk than others,” he said. “Their idea that this is caused by this pulmonary inflammation, that is totally a guess; there is no data in this paper to support that.”
Dr. Thornton and Dr. Haut both noted that the authors don’t define how race and ethnicity were determined and whether patients were asked to provide it, and although they mention the racial/ethnic breakdown once, subsequent references are to entire cohort are as “Caucasian.”
They also called into question the value of comparing laboratory data across continents in centers with different testing methods and parameters, especially in a time when the clinical picture changes so rapidly.
Coagulation differences
Dr. O’Donnell and colleagues noted that most studies of COVID-19-associated coagulopathy published to date have been with Chinese patients.
“This is important because race and ethnicity have major effects upon thrombotic risk. In particular, epidemiological studies have shown that the incidence of venous thromboembolism (VTE) is approximately three to fourfold lower in Chinese compared to Caucasian individuals. Conversely, VTE risk is significantly higher in African-Americans compared to Caucasians,” they wrote.
Because of the lower risk of VTE in the Chinese population, thromboprophylaxis with low-molecular-weight heparin (LMWH) or other agents is less frequently used in Chinese hospitals than in hospitals with predominantly non-Asian patients, they noted.
To see whether the were differences in coagulopathy between Chinese and white patients, the researchers enrolled 55 men and 28 women, median age 64, who were admitted to St. James Hospital with COVID-19 infections from March 13 through April 10, 2020. The cohort included 67 patients of white background, 10 of Asian ancestry, 5 of African ethnicity, and 1 of Latino/Hispanic ancestry.
Of the 83 patients, 67 had comorbidities at admission. At the time of the report, 50 patients had fully recovered and were discharged, 20 remained in the hospital, and 13 had died. In all, 50 patients were discharged without needing ICU care, 23 were admitted to the ICU, and 10 required ICU but were deemed “clinically unsuitable” for ICU admission.
Although the patients had normal prothrombin time (PT) and normal activated partial thromboplastin time (APTT), plasma d-dimer levels were significantly elevated and were above the range of normal in two-thirds of patients on admission.
Despite the increased d-dimer levels, however, there was no evidence of DIC as defined by the International Society of Thrombosis and Hemostasis Scientific and Standardization committee (ISTH SSC) guidelines. Platelet counts were in the normal range in 83.1% of patients, and only five had counts less than 100 x 109/L at admission. Fibrinogen levels were also elevated, as were C-reactive protein levels, both likely indicating an acute phase response.
“Thus, despite the fact that thrombotic risk is much higher in Caucasian patients and the significant elevated levels of d-dimers observed, overt DIC as defined according to the ISTH SSC DIC score was present in none of our COVID-19 patients at time of admission. Nevertheless, our data confirm that severe COVID-19 infection is associated with a significant coagulopathy in Caucasian patients that appears to be similar in magnitude to that previously reported in the original Chinese cohorts,” they wrote.
When they compared patients who required ICU admission for ventilator support and those who died with patients who were discharged without needing ICU support, they found that survivors were younger (median age 60.2 vs. 75.2 years), and that more critically ill patients were more likely to have comorbidities.
They also found that patients with abnormal coagulation parameters on admission were significantly more likely to have poor prognosis (P = .018), and that patients in the adverse outcomes group had significantly higher fibrinogen and CRP levels (P = .045 and .0005, respectively).
There was no significant difference in PT between the prognosis groups at admission, but by day 4 and beyond PT was a median of 13.1 vs. 12.5 seconds in the favorable outcomes groups (P = .007), and patients with poor prognosis continued to have significantly higher d-dimer levels. (P = .003)
“Cumulatively, these data support the hypothesis that COVID-19–associated coagulopathy probably contributes to the underlying pulmonary pathogenesis,” the researchers wrote.
They noted that the angiotensin converting enzyme 2 (ACE-2) receptor that COVID-19 uses to enter cells is expressed on both type II pneumocytes and vascular endothelial cells within the lung, suggesting that the coagulopathy may be related to direct pulmonary endothelial cell infection , activation, and/or damage, and to the documented cytokine storm that can affect thrombin generation and fibrin deposition within the lungs.
“In the context of this lung-centric vasculopathy, we hypothesize that the refractory acute respiratory distress syndrome phenotype observed in severe COVID-19 is due to concurrent ‘double-hit’ pathologies targeting both ventilation (V) and perfusion (Q) within the lungs where alveoli and pulmonary microvasculature exist in close anatomical juxtaposition,” they wrote.
The investigators noted that larger randomized trials will be needed to determine whether more aggressive anti-coagulation and/or targeted anti-inflammatory therapies could effectively treated PIC in patients with severe COVID-19.
The study was supported by the Wellcome Trust and the Health Research Board Health Service and the Research and Development Division, Northern Ireland. Dr. O’Donnell disclosed speakers bureau activities, advisory board participation, and research grants from multiple companies. The other doctors had no relevant conflicts of interest to disclose.
SOURCE: Fogarty H et al. Br J Haematol. 2020 Apr 24. doi: 10.1111/bjh.16749.
Differences in COVID-19-related death rates between people of white and Asian ancestry may be partly explained by documented ethnic/racial differences in risk for blood clotting and pulmonary thrombotic events, investigators propose.
“Our novel findings demonstrate that COVID-19 is associated with a unique type of blood clotting disorder that is primarily focused within the lungs and which undoubtedly contributes to the high levels of mortality being seen in patients with COVID-19,” said James O’Donnell, MB, PhD, director of the Irish Centre for Vascular Biology at the Royal College of Surgeons in Ireland.
Dr. O’Donnell and colleagues studied pulmonary effects and outcomes of 83 patients admitted to St. James Hospital in Dublin, and found evidence to suggest that the diffuse, bilateral pulmonary inflammation seen in many patients with severe COVID-19 infections may be caused by a pulmonary-specific vasculopathy they label “pulmonary intravascular coagulopathy” (PIC), an entity distinct from disseminated intravascular coagulopathy (DIC).
“Given that thrombotic risk is significantly impacted by race, coupled with the accumulating evidence that coagulopathy is important in COVID-19 pathogenesis, our findings raise the intriguing possibility that pulmonary vasculopathy may contribute to the unexplained differences that are beginning to emerge highlighting racial susceptibility to COVID-19 mortality,” they wrote in a study published online in the British Journal of Haematology.
Study flaws harm conclusions
But critical care specialists who agreed to review and comment on the study for MDedge News said that it has significant flaws that affect the ability to interpret the findings and “undermine the conclusions reached by the authors.”
“The underlying premise of the study is that there are racial and ethnic differences in the development of venous thromboembolism that may explain the racial and ethnic differences in outcomes from COVID-19,” J. Daryl Thornton, MD, MPH, a fellow of the American Thoracic Society and associate professor of pulmonary, critical care, and sleep medicine at Case Western Reserve University, Cleveland, said in an interview. “This is an interesting hypothesis and one that could be easily tested in a well-designed study with sufficient representation from the relevant racial and ethnic groups. However, this study is neither well designed nor does it have sufficient racial and ethnic representation.”
Elliott R. Haut, MD, PhD, associate professor of surgery, anesthesiology and critical care medicine at Johns Hopkins Medicine, Baltimore, said in an interview that the study is “mediocre” and has the feel of a paper rushed to press.
“It talks about their theory that race, ethnicity, have an effect on venous thromboembolism, and that’s a pretty well-known fact. No one’s a hundred percent sure why that is, but certainly there are tons and tons of papers that show that there are groups that are at higher risk than others,” he said. “Their idea that this is caused by this pulmonary inflammation, that is totally a guess; there is no data in this paper to support that.”
Dr. Thornton and Dr. Haut both noted that the authors don’t define how race and ethnicity were determined and whether patients were asked to provide it, and although they mention the racial/ethnic breakdown once, subsequent references are to entire cohort are as “Caucasian.”
They also called into question the value of comparing laboratory data across continents in centers with different testing methods and parameters, especially in a time when the clinical picture changes so rapidly.
Coagulation differences
Dr. O’Donnell and colleagues noted that most studies of COVID-19-associated coagulopathy published to date have been with Chinese patients.
“This is important because race and ethnicity have major effects upon thrombotic risk. In particular, epidemiological studies have shown that the incidence of venous thromboembolism (VTE) is approximately three to fourfold lower in Chinese compared to Caucasian individuals. Conversely, VTE risk is significantly higher in African-Americans compared to Caucasians,” they wrote.
Because of the lower risk of VTE in the Chinese population, thromboprophylaxis with low-molecular-weight heparin (LMWH) or other agents is less frequently used in Chinese hospitals than in hospitals with predominantly non-Asian patients, they noted.
To see whether the were differences in coagulopathy between Chinese and white patients, the researchers enrolled 55 men and 28 women, median age 64, who were admitted to St. James Hospital with COVID-19 infections from March 13 through April 10, 2020. The cohort included 67 patients of white background, 10 of Asian ancestry, 5 of African ethnicity, and 1 of Latino/Hispanic ancestry.
Of the 83 patients, 67 had comorbidities at admission. At the time of the report, 50 patients had fully recovered and were discharged, 20 remained in the hospital, and 13 had died. In all, 50 patients were discharged without needing ICU care, 23 were admitted to the ICU, and 10 required ICU but were deemed “clinically unsuitable” for ICU admission.
Although the patients had normal prothrombin time (PT) and normal activated partial thromboplastin time (APTT), plasma d-dimer levels were significantly elevated and were above the range of normal in two-thirds of patients on admission.
Despite the increased d-dimer levels, however, there was no evidence of DIC as defined by the International Society of Thrombosis and Hemostasis Scientific and Standardization committee (ISTH SSC) guidelines. Platelet counts were in the normal range in 83.1% of patients, and only five had counts less than 100 x 109/L at admission. Fibrinogen levels were also elevated, as were C-reactive protein levels, both likely indicating an acute phase response.
“Thus, despite the fact that thrombotic risk is much higher in Caucasian patients and the significant elevated levels of d-dimers observed, overt DIC as defined according to the ISTH SSC DIC score was present in none of our COVID-19 patients at time of admission. Nevertheless, our data confirm that severe COVID-19 infection is associated with a significant coagulopathy in Caucasian patients that appears to be similar in magnitude to that previously reported in the original Chinese cohorts,” they wrote.
When they compared patients who required ICU admission for ventilator support and those who died with patients who were discharged without needing ICU support, they found that survivors were younger (median age 60.2 vs. 75.2 years), and that more critically ill patients were more likely to have comorbidities.
They also found that patients with abnormal coagulation parameters on admission were significantly more likely to have poor prognosis (P = .018), and that patients in the adverse outcomes group had significantly higher fibrinogen and CRP levels (P = .045 and .0005, respectively).
There was no significant difference in PT between the prognosis groups at admission, but by day 4 and beyond PT was a median of 13.1 vs. 12.5 seconds in the favorable outcomes groups (P = .007), and patients with poor prognosis continued to have significantly higher d-dimer levels. (P = .003)
“Cumulatively, these data support the hypothesis that COVID-19–associated coagulopathy probably contributes to the underlying pulmonary pathogenesis,” the researchers wrote.
They noted that the angiotensin converting enzyme 2 (ACE-2) receptor that COVID-19 uses to enter cells is expressed on both type II pneumocytes and vascular endothelial cells within the lung, suggesting that the coagulopathy may be related to direct pulmonary endothelial cell infection , activation, and/or damage, and to the documented cytokine storm that can affect thrombin generation and fibrin deposition within the lungs.
“In the context of this lung-centric vasculopathy, we hypothesize that the refractory acute respiratory distress syndrome phenotype observed in severe COVID-19 is due to concurrent ‘double-hit’ pathologies targeting both ventilation (V) and perfusion (Q) within the lungs where alveoli and pulmonary microvasculature exist in close anatomical juxtaposition,” they wrote.
The investigators noted that larger randomized trials will be needed to determine whether more aggressive anti-coagulation and/or targeted anti-inflammatory therapies could effectively treated PIC in patients with severe COVID-19.
The study was supported by the Wellcome Trust and the Health Research Board Health Service and the Research and Development Division, Northern Ireland. Dr. O’Donnell disclosed speakers bureau activities, advisory board participation, and research grants from multiple companies. The other doctors had no relevant conflicts of interest to disclose.
SOURCE: Fogarty H et al. Br J Haematol. 2020 Apr 24. doi: 10.1111/bjh.16749.
FROM THE BRITISH JOURNAL OF HEMATOLOGY
New angiotensin studies in COVID-19 give more reassurance
Four more studies of the relationship of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) with COVID-19 have been published in the past few days in top-tier peer-reviewed journals, and on the whole, the data are reassuring.
Three of the new studies were published in the New England Journal of Medicine on May 1, and one study was published in JAMA Cardiology on May 5.
Although all the studies are observational in design and have some confounding factors, overall, However, there are some contradictory findings in secondary analyses regarding possible differences in the effects of the two drug classes.
Providing commentary, John McMurray, MD, professor of medical cardiology at the University of Glasgow, said: “The overall picture seems to suggest no increase in risk of adverse outcomes in patients taking renin-angiotensin system [RAS] blockers ― but with lots of caveats: These are all observational rather than randomized studies, and there may be residual or unmeasured confounding.”
Was it ‘Much ado about nothing’?
Franz Messerli, MD, professor of medicine at the University of Bern (Switzerland), added: “Given this state of the art, I am inclined to consider RAS blockade and COVID-19 – despite all the hype in the news media – as much ado about nothing.”
But both Dr. McMurray and Dr. Messerli said they were intrigued about possible differences in the effects of ACE inhibitors and ARBs that some of the new results suggest.
In one study, a team led by Mandeep Mehra, MD, of Brigham and Women’s Hospital Heart and Vascular Center, Boston, analyzed data from 8,910 patients with COVID-19 admitted to 169 hospitals in Asia, Europe, and North America who had either died in the hospital (5.8%) or survived to hospital discharge (94.2%).
In multivariate logistic-regression analysis, age greater than 65 years, coronary artery disease, congestive heart failure, history of cardiac arrhythmia, chronic obstructive pulmonary disease, and current smoking were associated with an increased risk for in-hospital death. Female sex was associated with a decreased risk. Neither ACE inhibitors nor ARBs were associated with an increased risk for in-hospital death.
In fact, ACE inhibitors were associated with a significant reduction in mortality (odds ratio, 0.33), as were statins (OR, 0.35).
The authors, however, stressed that these observations about reduced mortality with ACE inhibitors and statins “should be considered with extreme caution.”
“Because our study was not a randomized, controlled trial, we cannot exclude the possibility of confounding. In addition, we examined relationships between many variables and in-hospital death, and no primary hypothesis was prespecified; these factors increased the probability of chance associations being found. Therefore, a cause-and-effect relationship between drug therapy and survival should not be inferred,” they wrote.
A secondary analysis that was restricted to patients with hypertension (those for whom an ACE inhibitor or an ARB would be indicated) also did not show harm.
A second study published in the New England Journal of Medicine had a case-control design. The authors, led by Giuseppe Mancia, MD, of the University of Milano-Bicocca (Italy), compared 6,272 patients with confirmed COVID-19 (case patients) with 30,759 control persons who were matched according to age, sex, and municipality of residence.
In a conditional logistic-regression multivariate analysis, neither ACE inhibitors nor ARBs were associated with the likelihood of SARS-CoV-2 infection.
“Thus, our results do not provide evidence of an independent relationship between renin angiotensin aldosterone blockers and the susceptibility to COVID-19 in humans,” the authors concluded.
In addition, a second analysis that compared patients who had severe or fatal infections with matched control persons did not show an association between ACE inhibitors or ARBs and severe disease.
In the third study published in the New England Journal of Medicine, a group led by Harmony R. Reynolds, MD, of New York University, analyzed data from the health records of 12,594 patients in the NYU Langone Health system who had been tested for COVID-19. They found 5,894 patients whose test results were positive. Of these patients, 1,002 had severe illness, which was defined as illness requiring admission to the ICU, need for mechanical ventilation, or death.
Using Bayesian analysis and propensity score matching, the researchers assessed the relation between previous treatment with five different classes of antihypertensive drugs (ACE inhibitors, ARBs, beta blockers, calcium blockers, and thiazide diuretics) and the likelihood of a positive or negative result on COVID-19 testing, as well as the likelihood of severe illness among patients who tested positive.
Results showed no positive association between any of the analyzed drug classes and either a positive test result or severe illness.
In an accompanying editorial, a group led by John A. Jarcho, MD, of Harvard Medical School, Boston, and deputy editor of the New England Journal of Medicine, wrote: “Taken together, these three studies do not provide evidence to support the hypothesis that ACE inhibitor or ARB use is associated with the risk of SARS-CoV-2 infection, the risk of severe COVID-19 among those infected, or the risk of in-hospital death among those with a positive test.
“Each of these studies has weaknesses inherent in observational data, but we find it reassuring that three studies in different populations and with different designs arrive at the consistent message that the continued use of ACE inhibitors and ARBs is unlikely to be harmful in patients with COVID-19. Several other smaller studies from China and the United Kingdom have come to the same conclusion,” the authors of the editorial stated.
In the study published in JAMA Cardiology, a group led by Neil Mehta, MBBS, of the Cleveland Clinic, Ohio, analyzed data on 18,472 patients who had been tested for COVID-19 between March 8 and April 12 in the Cleveland Clinic Health System in Ohio and Florida. Of these patients, 9.4% tested positive.
After overlap propensity score weighting for both ACE inhibitors and ARBs to take into account relevant comorbidities, there was no difference in risk for testing positive among patients taking an ACE inhibitor or an ARB in comparison with those not taking such medication.
Are there different effects between ACE inhibitors and ARBs?
A secondary exploratory analysis showed a higher likelihood of hospital admission among patients who tested positive and who were taking either ACE inhibitors (OR, 1.84) or ARBs (OR, 1.61), and there was a higher likelihood of ICU admission among patients who tested positive and who were taking an ACE inhibitor (OR 1.77), but no such difference was observed among those taking ARBs.
Coauthor Ankur Kalra, MD, of the Cleveland Clinic, said in an interview that results of the exploratory analysis fit with the hypothesis that the two drugs classes may have different effects in patients with COVID-19.
“Angiotensin II promotes vasoconstriction, inflammation, and fibrosis in the lungs, and ARBs block the effects of angiotensin II more effectively than ACE inhibitors. In addition, ACE inhibitors (but not ARBs) increase levels of bradykinin, which may be one factor leading to acute respiratory distress syndrome,” he noted.
“However, these results should only be considered exploratory, as there is inherent bias in observational data,” Dr. Kalra stressed.
In an accompanying editorial in JAMA Cardiology, a group led by Laine E. Thomas, PhD, of Duke Clinical Research Institute, Durham, North Carolina, said that the results of this secondary exploratory analysis are limited by a small number of patients and “are likely explained by confounding and should not be inferred as causal.”
The New England Journal of Medicine editorialists reached a similar conclusion regarding the lower mortality in COVID-19 patients who took ACE inhibitors in the study by Dr. Mehra and colleagues. They say this unexpected result “may be due to unmeasured confounding and, in the absence of a randomized trial, should not be regarded as evidence to prescribe these drugs in patients with COVID-19.”
Providing further comment, Dr. McMurray said: “Normally, I would not read too much into the different effects of ACE inhibitors and ARBs suggested in the Cleveland study because of the small numbers (about 28 ACE inhibitor–treated patients admitted to ICU) and the limited information about matching and/or adjustment for potential differences between groups.
“I could also argue that the comparison that would best answer the question about risk related to type of RAS blocker would be the direct comparison of people taking an ACE inhibitor with those taking an ARB (and that doesn’t look very different). The only thing that makes me a little cautious about completely dismissing the possibility of a difference between ACE inhibitor and ARB here is the suggestion of a similar trend in another large study from the VA [Veterans Affairs] system,” he added.
He also noted that speculation about there being mechanisms that involve different effects of the two drug classes on bradykinin and angiotensin II was “plausible but unproven.”
Dr. Messerli added: “Before turning the page, I would like to see an analysis comparing ACE inhibitors and ARBs, since experimentally, their effect on ACE2 (the receptor to which the virus binds) seems to differ. The study of Mehta et al in JAMA Cardiology may be the first clinical hint indicating that ARBs are more protective than ACEIs. However even here, the looming possibility of confounding cannot be excluded.”
Dr. Messerli also pointed to a hypothesis that suggests that direct viral infection of endothelial cells expressing ACE2 receptors may explain worse outcomes in patients with cardiovascular comorbidities, which provides a rationale for therapies to stabilize the endothelium, particularly with anti-inflammatory anticytokine drugs, ACE inhibitors, and statins.
A version of this article originally appeared on Medscape.com.
Four more studies of the relationship of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) with COVID-19 have been published in the past few days in top-tier peer-reviewed journals, and on the whole, the data are reassuring.
Three of the new studies were published in the New England Journal of Medicine on May 1, and one study was published in JAMA Cardiology on May 5.
Although all the studies are observational in design and have some confounding factors, overall, However, there are some contradictory findings in secondary analyses regarding possible differences in the effects of the two drug classes.
Providing commentary, John McMurray, MD, professor of medical cardiology at the University of Glasgow, said: “The overall picture seems to suggest no increase in risk of adverse outcomes in patients taking renin-angiotensin system [RAS] blockers ― but with lots of caveats: These are all observational rather than randomized studies, and there may be residual or unmeasured confounding.”
Was it ‘Much ado about nothing’?
Franz Messerli, MD, professor of medicine at the University of Bern (Switzerland), added: “Given this state of the art, I am inclined to consider RAS blockade and COVID-19 – despite all the hype in the news media – as much ado about nothing.”
But both Dr. McMurray and Dr. Messerli said they were intrigued about possible differences in the effects of ACE inhibitors and ARBs that some of the new results suggest.
In one study, a team led by Mandeep Mehra, MD, of Brigham and Women’s Hospital Heart and Vascular Center, Boston, analyzed data from 8,910 patients with COVID-19 admitted to 169 hospitals in Asia, Europe, and North America who had either died in the hospital (5.8%) or survived to hospital discharge (94.2%).
In multivariate logistic-regression analysis, age greater than 65 years, coronary artery disease, congestive heart failure, history of cardiac arrhythmia, chronic obstructive pulmonary disease, and current smoking were associated with an increased risk for in-hospital death. Female sex was associated with a decreased risk. Neither ACE inhibitors nor ARBs were associated with an increased risk for in-hospital death.
In fact, ACE inhibitors were associated with a significant reduction in mortality (odds ratio, 0.33), as were statins (OR, 0.35).
The authors, however, stressed that these observations about reduced mortality with ACE inhibitors and statins “should be considered with extreme caution.”
“Because our study was not a randomized, controlled trial, we cannot exclude the possibility of confounding. In addition, we examined relationships between many variables and in-hospital death, and no primary hypothesis was prespecified; these factors increased the probability of chance associations being found. Therefore, a cause-and-effect relationship between drug therapy and survival should not be inferred,” they wrote.
A secondary analysis that was restricted to patients with hypertension (those for whom an ACE inhibitor or an ARB would be indicated) also did not show harm.
A second study published in the New England Journal of Medicine had a case-control design. The authors, led by Giuseppe Mancia, MD, of the University of Milano-Bicocca (Italy), compared 6,272 patients with confirmed COVID-19 (case patients) with 30,759 control persons who were matched according to age, sex, and municipality of residence.
In a conditional logistic-regression multivariate analysis, neither ACE inhibitors nor ARBs were associated with the likelihood of SARS-CoV-2 infection.
“Thus, our results do not provide evidence of an independent relationship between renin angiotensin aldosterone blockers and the susceptibility to COVID-19 in humans,” the authors concluded.
In addition, a second analysis that compared patients who had severe or fatal infections with matched control persons did not show an association between ACE inhibitors or ARBs and severe disease.
In the third study published in the New England Journal of Medicine, a group led by Harmony R. Reynolds, MD, of New York University, analyzed data from the health records of 12,594 patients in the NYU Langone Health system who had been tested for COVID-19. They found 5,894 patients whose test results were positive. Of these patients, 1,002 had severe illness, which was defined as illness requiring admission to the ICU, need for mechanical ventilation, or death.
Using Bayesian analysis and propensity score matching, the researchers assessed the relation between previous treatment with five different classes of antihypertensive drugs (ACE inhibitors, ARBs, beta blockers, calcium blockers, and thiazide diuretics) and the likelihood of a positive or negative result on COVID-19 testing, as well as the likelihood of severe illness among patients who tested positive.
Results showed no positive association between any of the analyzed drug classes and either a positive test result or severe illness.
In an accompanying editorial, a group led by John A. Jarcho, MD, of Harvard Medical School, Boston, and deputy editor of the New England Journal of Medicine, wrote: “Taken together, these three studies do not provide evidence to support the hypothesis that ACE inhibitor or ARB use is associated with the risk of SARS-CoV-2 infection, the risk of severe COVID-19 among those infected, or the risk of in-hospital death among those with a positive test.
“Each of these studies has weaknesses inherent in observational data, but we find it reassuring that three studies in different populations and with different designs arrive at the consistent message that the continued use of ACE inhibitors and ARBs is unlikely to be harmful in patients with COVID-19. Several other smaller studies from China and the United Kingdom have come to the same conclusion,” the authors of the editorial stated.
In the study published in JAMA Cardiology, a group led by Neil Mehta, MBBS, of the Cleveland Clinic, Ohio, analyzed data on 18,472 patients who had been tested for COVID-19 between March 8 and April 12 in the Cleveland Clinic Health System in Ohio and Florida. Of these patients, 9.4% tested positive.
After overlap propensity score weighting for both ACE inhibitors and ARBs to take into account relevant comorbidities, there was no difference in risk for testing positive among patients taking an ACE inhibitor or an ARB in comparison with those not taking such medication.
Are there different effects between ACE inhibitors and ARBs?
A secondary exploratory analysis showed a higher likelihood of hospital admission among patients who tested positive and who were taking either ACE inhibitors (OR, 1.84) or ARBs (OR, 1.61), and there was a higher likelihood of ICU admission among patients who tested positive and who were taking an ACE inhibitor (OR 1.77), but no such difference was observed among those taking ARBs.
Coauthor Ankur Kalra, MD, of the Cleveland Clinic, said in an interview that results of the exploratory analysis fit with the hypothesis that the two drugs classes may have different effects in patients with COVID-19.
“Angiotensin II promotes vasoconstriction, inflammation, and fibrosis in the lungs, and ARBs block the effects of angiotensin II more effectively than ACE inhibitors. In addition, ACE inhibitors (but not ARBs) increase levels of bradykinin, which may be one factor leading to acute respiratory distress syndrome,” he noted.
“However, these results should only be considered exploratory, as there is inherent bias in observational data,” Dr. Kalra stressed.
In an accompanying editorial in JAMA Cardiology, a group led by Laine E. Thomas, PhD, of Duke Clinical Research Institute, Durham, North Carolina, said that the results of this secondary exploratory analysis are limited by a small number of patients and “are likely explained by confounding and should not be inferred as causal.”
The New England Journal of Medicine editorialists reached a similar conclusion regarding the lower mortality in COVID-19 patients who took ACE inhibitors in the study by Dr. Mehra and colleagues. They say this unexpected result “may be due to unmeasured confounding and, in the absence of a randomized trial, should not be regarded as evidence to prescribe these drugs in patients with COVID-19.”
Providing further comment, Dr. McMurray said: “Normally, I would not read too much into the different effects of ACE inhibitors and ARBs suggested in the Cleveland study because of the small numbers (about 28 ACE inhibitor–treated patients admitted to ICU) and the limited information about matching and/or adjustment for potential differences between groups.
“I could also argue that the comparison that would best answer the question about risk related to type of RAS blocker would be the direct comparison of people taking an ACE inhibitor with those taking an ARB (and that doesn’t look very different). The only thing that makes me a little cautious about completely dismissing the possibility of a difference between ACE inhibitor and ARB here is the suggestion of a similar trend in another large study from the VA [Veterans Affairs] system,” he added.
He also noted that speculation about there being mechanisms that involve different effects of the two drug classes on bradykinin and angiotensin II was “plausible but unproven.”
Dr. Messerli added: “Before turning the page, I would like to see an analysis comparing ACE inhibitors and ARBs, since experimentally, their effect on ACE2 (the receptor to which the virus binds) seems to differ. The study of Mehta et al in JAMA Cardiology may be the first clinical hint indicating that ARBs are more protective than ACEIs. However even here, the looming possibility of confounding cannot be excluded.”
Dr. Messerli also pointed to a hypothesis that suggests that direct viral infection of endothelial cells expressing ACE2 receptors may explain worse outcomes in patients with cardiovascular comorbidities, which provides a rationale for therapies to stabilize the endothelium, particularly with anti-inflammatory anticytokine drugs, ACE inhibitors, and statins.
A version of this article originally appeared on Medscape.com.
Four more studies of the relationship of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) with COVID-19 have been published in the past few days in top-tier peer-reviewed journals, and on the whole, the data are reassuring.
Three of the new studies were published in the New England Journal of Medicine on May 1, and one study was published in JAMA Cardiology on May 5.
Although all the studies are observational in design and have some confounding factors, overall, However, there are some contradictory findings in secondary analyses regarding possible differences in the effects of the two drug classes.
Providing commentary, John McMurray, MD, professor of medical cardiology at the University of Glasgow, said: “The overall picture seems to suggest no increase in risk of adverse outcomes in patients taking renin-angiotensin system [RAS] blockers ― but with lots of caveats: These are all observational rather than randomized studies, and there may be residual or unmeasured confounding.”
Was it ‘Much ado about nothing’?
Franz Messerli, MD, professor of medicine at the University of Bern (Switzerland), added: “Given this state of the art, I am inclined to consider RAS blockade and COVID-19 – despite all the hype in the news media – as much ado about nothing.”
But both Dr. McMurray and Dr. Messerli said they were intrigued about possible differences in the effects of ACE inhibitors and ARBs that some of the new results suggest.
In one study, a team led by Mandeep Mehra, MD, of Brigham and Women’s Hospital Heart and Vascular Center, Boston, analyzed data from 8,910 patients with COVID-19 admitted to 169 hospitals in Asia, Europe, and North America who had either died in the hospital (5.8%) or survived to hospital discharge (94.2%).
In multivariate logistic-regression analysis, age greater than 65 years, coronary artery disease, congestive heart failure, history of cardiac arrhythmia, chronic obstructive pulmonary disease, and current smoking were associated with an increased risk for in-hospital death. Female sex was associated with a decreased risk. Neither ACE inhibitors nor ARBs were associated with an increased risk for in-hospital death.
In fact, ACE inhibitors were associated with a significant reduction in mortality (odds ratio, 0.33), as were statins (OR, 0.35).
The authors, however, stressed that these observations about reduced mortality with ACE inhibitors and statins “should be considered with extreme caution.”
“Because our study was not a randomized, controlled trial, we cannot exclude the possibility of confounding. In addition, we examined relationships between many variables and in-hospital death, and no primary hypothesis was prespecified; these factors increased the probability of chance associations being found. Therefore, a cause-and-effect relationship between drug therapy and survival should not be inferred,” they wrote.
A secondary analysis that was restricted to patients with hypertension (those for whom an ACE inhibitor or an ARB would be indicated) also did not show harm.
A second study published in the New England Journal of Medicine had a case-control design. The authors, led by Giuseppe Mancia, MD, of the University of Milano-Bicocca (Italy), compared 6,272 patients with confirmed COVID-19 (case patients) with 30,759 control persons who were matched according to age, sex, and municipality of residence.
In a conditional logistic-regression multivariate analysis, neither ACE inhibitors nor ARBs were associated with the likelihood of SARS-CoV-2 infection.
“Thus, our results do not provide evidence of an independent relationship between renin angiotensin aldosterone blockers and the susceptibility to COVID-19 in humans,” the authors concluded.
In addition, a second analysis that compared patients who had severe or fatal infections with matched control persons did not show an association between ACE inhibitors or ARBs and severe disease.
In the third study published in the New England Journal of Medicine, a group led by Harmony R. Reynolds, MD, of New York University, analyzed data from the health records of 12,594 patients in the NYU Langone Health system who had been tested for COVID-19. They found 5,894 patients whose test results were positive. Of these patients, 1,002 had severe illness, which was defined as illness requiring admission to the ICU, need for mechanical ventilation, or death.
Using Bayesian analysis and propensity score matching, the researchers assessed the relation between previous treatment with five different classes of antihypertensive drugs (ACE inhibitors, ARBs, beta blockers, calcium blockers, and thiazide diuretics) and the likelihood of a positive or negative result on COVID-19 testing, as well as the likelihood of severe illness among patients who tested positive.
Results showed no positive association between any of the analyzed drug classes and either a positive test result or severe illness.
In an accompanying editorial, a group led by John A. Jarcho, MD, of Harvard Medical School, Boston, and deputy editor of the New England Journal of Medicine, wrote: “Taken together, these three studies do not provide evidence to support the hypothesis that ACE inhibitor or ARB use is associated with the risk of SARS-CoV-2 infection, the risk of severe COVID-19 among those infected, or the risk of in-hospital death among those with a positive test.
“Each of these studies has weaknesses inherent in observational data, but we find it reassuring that three studies in different populations and with different designs arrive at the consistent message that the continued use of ACE inhibitors and ARBs is unlikely to be harmful in patients with COVID-19. Several other smaller studies from China and the United Kingdom have come to the same conclusion,” the authors of the editorial stated.
In the study published in JAMA Cardiology, a group led by Neil Mehta, MBBS, of the Cleveland Clinic, Ohio, analyzed data on 18,472 patients who had been tested for COVID-19 between March 8 and April 12 in the Cleveland Clinic Health System in Ohio and Florida. Of these patients, 9.4% tested positive.
After overlap propensity score weighting for both ACE inhibitors and ARBs to take into account relevant comorbidities, there was no difference in risk for testing positive among patients taking an ACE inhibitor or an ARB in comparison with those not taking such medication.
Are there different effects between ACE inhibitors and ARBs?
A secondary exploratory analysis showed a higher likelihood of hospital admission among patients who tested positive and who were taking either ACE inhibitors (OR, 1.84) or ARBs (OR, 1.61), and there was a higher likelihood of ICU admission among patients who tested positive and who were taking an ACE inhibitor (OR 1.77), but no such difference was observed among those taking ARBs.
Coauthor Ankur Kalra, MD, of the Cleveland Clinic, said in an interview that results of the exploratory analysis fit with the hypothesis that the two drugs classes may have different effects in patients with COVID-19.
“Angiotensin II promotes vasoconstriction, inflammation, and fibrosis in the lungs, and ARBs block the effects of angiotensin II more effectively than ACE inhibitors. In addition, ACE inhibitors (but not ARBs) increase levels of bradykinin, which may be one factor leading to acute respiratory distress syndrome,” he noted.
“However, these results should only be considered exploratory, as there is inherent bias in observational data,” Dr. Kalra stressed.
In an accompanying editorial in JAMA Cardiology, a group led by Laine E. Thomas, PhD, of Duke Clinical Research Institute, Durham, North Carolina, said that the results of this secondary exploratory analysis are limited by a small number of patients and “are likely explained by confounding and should not be inferred as causal.”
The New England Journal of Medicine editorialists reached a similar conclusion regarding the lower mortality in COVID-19 patients who took ACE inhibitors in the study by Dr. Mehra and colleagues. They say this unexpected result “may be due to unmeasured confounding and, in the absence of a randomized trial, should not be regarded as evidence to prescribe these drugs in patients with COVID-19.”
Providing further comment, Dr. McMurray said: “Normally, I would not read too much into the different effects of ACE inhibitors and ARBs suggested in the Cleveland study because of the small numbers (about 28 ACE inhibitor–treated patients admitted to ICU) and the limited information about matching and/or adjustment for potential differences between groups.
“I could also argue that the comparison that would best answer the question about risk related to type of RAS blocker would be the direct comparison of people taking an ACE inhibitor with those taking an ARB (and that doesn’t look very different). The only thing that makes me a little cautious about completely dismissing the possibility of a difference between ACE inhibitor and ARB here is the suggestion of a similar trend in another large study from the VA [Veterans Affairs] system,” he added.
He also noted that speculation about there being mechanisms that involve different effects of the two drug classes on bradykinin and angiotensin II was “plausible but unproven.”
Dr. Messerli added: “Before turning the page, I would like to see an analysis comparing ACE inhibitors and ARBs, since experimentally, their effect on ACE2 (the receptor to which the virus binds) seems to differ. The study of Mehta et al in JAMA Cardiology may be the first clinical hint indicating that ARBs are more protective than ACEIs. However even here, the looming possibility of confounding cannot be excluded.”
Dr. Messerli also pointed to a hypothesis that suggests that direct viral infection of endothelial cells expressing ACE2 receptors may explain worse outcomes in patients with cardiovascular comorbidities, which provides a rationale for therapies to stabilize the endothelium, particularly with anti-inflammatory anticytokine drugs, ACE inhibitors, and statins.
A version of this article originally appeared on Medscape.com.
Don’t delay antibiotic treatment in elderly patients with UTI
Background: If left untreated, UTIs may lead to severe complications. Although campaigns aimed at decreasing unnecessary prescriptions have reduced the number of antibiotic prescriptions for UTI, a concurrent rise in the rates of gram-negative bloodstream infections (BSIs) has also been observed.
Study design: Retrospective, population-based cohort study with data compiled from primary care records from 2007 to 2015 linked to hospital episode statistics and death records.
Setting: General practices in England.
Synopsis: The investigators analyzed 312,896 UTI episodes among 157,264 unique patients (65 years of age or older) during the study period. Exclusion criteria included asymptomatic bacteriuria and complicated UTI. Of 271,070 patients who received antibiotics on the day of presentation with symptoms, 0.2% developed BSI within 60 days versus 2.2% of patients in whom antibiotics were delayed and 2.9% among patients not prescribed antibiotics. After adjustment for comorbidities, sex, and socioeconomic status, patients in whom antibiotics were deferred had a 7.12-fold greater odds of BSI, compared with the immediate-antibiotic group. BSIs were more common among men and older patients. All-cause mortality, a secondary outcome, was 1.16-fold higher with deferred antibiotics and 2.18 times higher with no antibiotics.
While the cohort studied was very large, a causal relationship cannot be firmly established in this observational study. Also, researchers were unable to include laboratory data, such as urinalysis and culture, in their analysis.
Bottom line: Delayed prescription of antibiotics for elderly patients presenting with UTI in primary care settings was associated with higher rates of BSI and death.
Citation: Gharbi M et al. Antibiotic management of urinary tract infection in elderly patients in primary care and its association with bloodstream infections and all-cause mortality: Population-based cohort study. BMJ. 2019 Feb;364:1525.
Dr. Torres is a hospitalist at Massachusetts General Hospital.
Background: If left untreated, UTIs may lead to severe complications. Although campaigns aimed at decreasing unnecessary prescriptions have reduced the number of antibiotic prescriptions for UTI, a concurrent rise in the rates of gram-negative bloodstream infections (BSIs) has also been observed.
Study design: Retrospective, population-based cohort study with data compiled from primary care records from 2007 to 2015 linked to hospital episode statistics and death records.
Setting: General practices in England.
Synopsis: The investigators analyzed 312,896 UTI episodes among 157,264 unique patients (65 years of age or older) during the study period. Exclusion criteria included asymptomatic bacteriuria and complicated UTI. Of 271,070 patients who received antibiotics on the day of presentation with symptoms, 0.2% developed BSI within 60 days versus 2.2% of patients in whom antibiotics were delayed and 2.9% among patients not prescribed antibiotics. After adjustment for comorbidities, sex, and socioeconomic status, patients in whom antibiotics were deferred had a 7.12-fold greater odds of BSI, compared with the immediate-antibiotic group. BSIs were more common among men and older patients. All-cause mortality, a secondary outcome, was 1.16-fold higher with deferred antibiotics and 2.18 times higher with no antibiotics.
While the cohort studied was very large, a causal relationship cannot be firmly established in this observational study. Also, researchers were unable to include laboratory data, such as urinalysis and culture, in their analysis.
Bottom line: Delayed prescription of antibiotics for elderly patients presenting with UTI in primary care settings was associated with higher rates of BSI and death.
Citation: Gharbi M et al. Antibiotic management of urinary tract infection in elderly patients in primary care and its association with bloodstream infections and all-cause mortality: Population-based cohort study. BMJ. 2019 Feb;364:1525.
Dr. Torres is a hospitalist at Massachusetts General Hospital.
Background: If left untreated, UTIs may lead to severe complications. Although campaigns aimed at decreasing unnecessary prescriptions have reduced the number of antibiotic prescriptions for UTI, a concurrent rise in the rates of gram-negative bloodstream infections (BSIs) has also been observed.
Study design: Retrospective, population-based cohort study with data compiled from primary care records from 2007 to 2015 linked to hospital episode statistics and death records.
Setting: General practices in England.
Synopsis: The investigators analyzed 312,896 UTI episodes among 157,264 unique patients (65 years of age or older) during the study period. Exclusion criteria included asymptomatic bacteriuria and complicated UTI. Of 271,070 patients who received antibiotics on the day of presentation with symptoms, 0.2% developed BSI within 60 days versus 2.2% of patients in whom antibiotics were delayed and 2.9% among patients not prescribed antibiotics. After adjustment for comorbidities, sex, and socioeconomic status, patients in whom antibiotics were deferred had a 7.12-fold greater odds of BSI, compared with the immediate-antibiotic group. BSIs were more common among men and older patients. All-cause mortality, a secondary outcome, was 1.16-fold higher with deferred antibiotics and 2.18 times higher with no antibiotics.
While the cohort studied was very large, a causal relationship cannot be firmly established in this observational study. Also, researchers were unable to include laboratory data, such as urinalysis and culture, in their analysis.
Bottom line: Delayed prescription of antibiotics for elderly patients presenting with UTI in primary care settings was associated with higher rates of BSI and death.
Citation: Gharbi M et al. Antibiotic management of urinary tract infection in elderly patients in primary care and its association with bloodstream infections and all-cause mortality: Population-based cohort study. BMJ. 2019 Feb;364:1525.
Dr. Torres is a hospitalist at Massachusetts General Hospital.
Multisociety roadmap eyes restarting elective cardiac cases
As COVID-19 case levels plateau in some regions, 16 North American cardiovascular societies have released a framework for reintroducing cardiovascular services disrupted by the pandemic.
The consensus document outlines a phased approach to restarting invasive cardiovascular (CV) procedures and diagnostic tests that aims to reduce patient and health care provider exposure to the coronavirus and still provide essential care. It also emphasizes some of the ethical considerations in patient selection and the need for a collaborative approach.
“The key message in our document is we need a new unprecedented collaboration with public health officials so that we can carefully monitor the situation and we’re aware of what’s happening with the penetrance of the pandemic in the community, but they’re aware of the morbidity and mortality that’s occurring on our ever-growing waiting list,” lead author David A. Wood, MD, told theheart.org | Medscape Cardiology.
The recommendations were jointly published May 4 in the Canadian Journal of Cardiology , the Journal of the American College of Cardiology, and The Annals of Thoracic Surgery, and are endorsed by, among others, the American Heart Association, American College of Cardiology (ACC), and Canadian Cardiovascular Society.
The guidance comes as hospitals are facing revenue shortfalls because of canceled elective procedures and resource-intensive COVID-19 cases, prompting some healthcare systems to furlough, lay off, or even fire staff.
“It’s obvious that volumes are down between 40% and 60%,” said Wood, director of the cardiac catheterization laboratory at Vancouver General Hospital and professor of medicine at the University of British Columbia, Canada. “Part of that is that some areas have restricted case volumes totally appropriately and it’s partly because patients are very afraid of coming to the hospital and, unfortunately, are having bad events at home. And some are dying.”
The new report features a detailed table outlining three different response levels: reintroduction of some services (level 2); reintroduction of most services (level 1); and regular services (level 0). It covers a range of services from transthoracic echocardiography and exercise testing with imaging to care for acute coronary syndrome and ST-segment elevation myocardial infarction.
“We’ve learned that we can very quickly turn off the tap and go to doing only 10% of our normal volumes, whether that’s surgery, cath lab, EP, diagnostic tests,” Wood said. “It’s much more difficult to thoughtfully turn the tap part way back on or restart the engine … you don’t just go from 0 to 100 [mph]. You go from 0 to 30 to 60 then maybe to 80 [mph].”
The document also includes eight guiding principles such as:
- The expectation that response levels will be different between regions, and even within a given region.
- A “transparent collaborative plan” for COVID-19 testing and personal protective equipment (PPE) must be in place before restarting cases.
- A less invasive test or alternate imaging modality should be considered, if both tests have similar efficacy.
- In general, a minimally invasive procedure with a shorter length of stay is preferable, if both strategies have similar efficacy and safety.
Although previous reports on cath lab considerations during the pandemic or restarting elective surgeries peg various actions to specific thresholds or time intervals, the language here is noticeably and intentionally broad.
Instead of stating when cardiovascular services should resume, for example, the experts say it’s appropriate to put the guidance document into place if there’s a “sustained reduction” in the rate of new COVID-19 admissions and deaths in the relevant geographic region for a “prespecified time interval.”
As for when or how frequently patients and healthcare providers should be tested for COVID-19, the document encourages “routine screening of all patients prior to any cardiovascular procedure or test.”
Overly prescriptive language in previous documents wasn’t felt to be that helpful, whereas language like “selective” cases and “some” or “most” cardiovascular procedures gives clinicians, health systems, and policy makers flexibility when moving between response levels, Wood explained.
“Different regions might be at different levels based on principles of public health as far as the penetrance of the pandemic in that community, as well as how can you actually do the physical distancing in your hospital or ambulatory clinic. Because, I tell you, that is the Achilles heel,” he said. “Our run rates are going to be determined by testing, the availability of PPE, but also how we’re going to use our existing infrastructure and maintain physical distancing.”
That may mean using telehealth for initial visits, having clinics open earlier in the morning or on weekends, or doing partial volumes for surgery or in the cath lab so patients can be staggered and recover at different times and in different areas of the hospital. “These are very granular, specific infrastructure things that we’ve never really had to consider before,” Wood observed.
The document also had to be flexible and nimble enough to respond to a potential rebound of COVID-19 cases, which in newly released models are projected to rise sharply to 200,000 cases a day and be accompanied by some 3,000 deaths each day by June 1.
“This is my own personal opinion but I think it’s foolish to think that we are going to be able to come back to 100% of the cases we were doing before, even with testing, PPE, and all of that until we have a vaccine,” he said.
Similar to decisions made in preparation for the initial COVID-19 surge, the consensus document outlines the need for ethical considerations when turning the tap back on. This means prioritizing procedures and tests that are likely to benefit more people and to a greater degree, and ensuring that patients are treated fairly and consistently, regardless of their ethnicity, perceived social worth, or ability to pay, said coauthor and ACC President Athena Poppas, MD, Brown University School of Medicine, Providence, Rhode Island.
“It’s an ethical tenet that exists in a lot of places but it’s usually not overtly called out,” Poppas told theheart.org | Medscape Cardiology. “It’s not rationing care; I think people jump to that but it’s actually the opposite of rationing care. It’s about being thoughtful about prioritizing patients.”
“There’s a variety of data that should help in the prioritization, not only how much hospital resources are utilized, that’s on one side, but there’s also the patient risk of delaying or doing a procedure, and then the societal risk,” she said.
Susheel Kodali, MD, of New York–Presbyterian Hospital/Columbia University Irving Medical Center, who recently published recommendations on restructuring structural heart disease practice during the pandemic, said the document is timely as centers, including his own, are trying to restart some outpatient visits, as early as next week.
“They made a point about talking about cohesive partnerships with regional public health officials and I think that’s great. The question is how does that happen,” he told theheart.org | Medscape Cardiology. “In New York, we’re not allowed to do elective cases but what’s considered elective is not so clearly defined. An AS [aortic stenosis] patient that had a syncopal episode 2 weeks ago, is that considered elective or is that semi-urgent? I think that’s one of the challenges and that’s where these partnerships would be useful.”
Other challenges include the need for regional partnerships to better align hospitals, which in the New York area means half a dozen large healthcare systems, and to coordinate care between hospital departments – all of which will be scheduling imaging and OR time for their own backlog of hernia, knee, or hip surgeries.
Finally, there’s the need for a lot of conversation with the patient and their family about returning to a hospital amid a deadly pandemic.
“I had a patient today and the daughter was very concerned about bringing her in,” Kodali said. “She’s in class IV heart failure but her [daughter’s] big concern was: who is she going to be exposed to when she gets the echo? What kind of protection is there for her? Is the tech wearing a mask?
“It’s not just the health care providers that have to have the comfort, but it’s the patients and their families who have to feel comfortable bringing their loved ones here for treatment,” he said. “Because everyone is concerned about the environment.”
Wood reports receiving unrestricted grant support from Edwards Lifesciences and Abbott Vascular and serving as a consultant for Edwards Lifesciences, Medtronic, Abbott Vascular, and Boston Scientific. Poppas reports no relevant conflicts of interest. Kodali reports consultant (honoraria) from Admedus, Meril Life Sciences, JenaValve, and Abbott Vascular; SAB (equity) from Dura Biotech, MicroInterventional Devices, Thubrikar Aortic Valve, Supira, and Admedus; and institutional funding from Edwards Lifesciences, Medtronic, Abbott Vascular, Boston Scientific, and JenaValve.
This article first appeared on Medscape.com.
As COVID-19 case levels plateau in some regions, 16 North American cardiovascular societies have released a framework for reintroducing cardiovascular services disrupted by the pandemic.
The consensus document outlines a phased approach to restarting invasive cardiovascular (CV) procedures and diagnostic tests that aims to reduce patient and health care provider exposure to the coronavirus and still provide essential care. It also emphasizes some of the ethical considerations in patient selection and the need for a collaborative approach.
“The key message in our document is we need a new unprecedented collaboration with public health officials so that we can carefully monitor the situation and we’re aware of what’s happening with the penetrance of the pandemic in the community, but they’re aware of the morbidity and mortality that’s occurring on our ever-growing waiting list,” lead author David A. Wood, MD, told theheart.org | Medscape Cardiology.
The recommendations were jointly published May 4 in the Canadian Journal of Cardiology , the Journal of the American College of Cardiology, and The Annals of Thoracic Surgery, and are endorsed by, among others, the American Heart Association, American College of Cardiology (ACC), and Canadian Cardiovascular Society.
The guidance comes as hospitals are facing revenue shortfalls because of canceled elective procedures and resource-intensive COVID-19 cases, prompting some healthcare systems to furlough, lay off, or even fire staff.
“It’s obvious that volumes are down between 40% and 60%,” said Wood, director of the cardiac catheterization laboratory at Vancouver General Hospital and professor of medicine at the University of British Columbia, Canada. “Part of that is that some areas have restricted case volumes totally appropriately and it’s partly because patients are very afraid of coming to the hospital and, unfortunately, are having bad events at home. And some are dying.”
The new report features a detailed table outlining three different response levels: reintroduction of some services (level 2); reintroduction of most services (level 1); and regular services (level 0). It covers a range of services from transthoracic echocardiography and exercise testing with imaging to care for acute coronary syndrome and ST-segment elevation myocardial infarction.
“We’ve learned that we can very quickly turn off the tap and go to doing only 10% of our normal volumes, whether that’s surgery, cath lab, EP, diagnostic tests,” Wood said. “It’s much more difficult to thoughtfully turn the tap part way back on or restart the engine … you don’t just go from 0 to 100 [mph]. You go from 0 to 30 to 60 then maybe to 80 [mph].”
The document also includes eight guiding principles such as:
- The expectation that response levels will be different between regions, and even within a given region.
- A “transparent collaborative plan” for COVID-19 testing and personal protective equipment (PPE) must be in place before restarting cases.
- A less invasive test or alternate imaging modality should be considered, if both tests have similar efficacy.
- In general, a minimally invasive procedure with a shorter length of stay is preferable, if both strategies have similar efficacy and safety.
Although previous reports on cath lab considerations during the pandemic or restarting elective surgeries peg various actions to specific thresholds or time intervals, the language here is noticeably and intentionally broad.
Instead of stating when cardiovascular services should resume, for example, the experts say it’s appropriate to put the guidance document into place if there’s a “sustained reduction” in the rate of new COVID-19 admissions and deaths in the relevant geographic region for a “prespecified time interval.”
As for when or how frequently patients and healthcare providers should be tested for COVID-19, the document encourages “routine screening of all patients prior to any cardiovascular procedure or test.”
Overly prescriptive language in previous documents wasn’t felt to be that helpful, whereas language like “selective” cases and “some” or “most” cardiovascular procedures gives clinicians, health systems, and policy makers flexibility when moving between response levels, Wood explained.
“Different regions might be at different levels based on principles of public health as far as the penetrance of the pandemic in that community, as well as how can you actually do the physical distancing in your hospital or ambulatory clinic. Because, I tell you, that is the Achilles heel,” he said. “Our run rates are going to be determined by testing, the availability of PPE, but also how we’re going to use our existing infrastructure and maintain physical distancing.”
That may mean using telehealth for initial visits, having clinics open earlier in the morning or on weekends, or doing partial volumes for surgery or in the cath lab so patients can be staggered and recover at different times and in different areas of the hospital. “These are very granular, specific infrastructure things that we’ve never really had to consider before,” Wood observed.
The document also had to be flexible and nimble enough to respond to a potential rebound of COVID-19 cases, which in newly released models are projected to rise sharply to 200,000 cases a day and be accompanied by some 3,000 deaths each day by June 1.
“This is my own personal opinion but I think it’s foolish to think that we are going to be able to come back to 100% of the cases we were doing before, even with testing, PPE, and all of that until we have a vaccine,” he said.
Similar to decisions made in preparation for the initial COVID-19 surge, the consensus document outlines the need for ethical considerations when turning the tap back on. This means prioritizing procedures and tests that are likely to benefit more people and to a greater degree, and ensuring that patients are treated fairly and consistently, regardless of their ethnicity, perceived social worth, or ability to pay, said coauthor and ACC President Athena Poppas, MD, Brown University School of Medicine, Providence, Rhode Island.
“It’s an ethical tenet that exists in a lot of places but it’s usually not overtly called out,” Poppas told theheart.org | Medscape Cardiology. “It’s not rationing care; I think people jump to that but it’s actually the opposite of rationing care. It’s about being thoughtful about prioritizing patients.”
“There’s a variety of data that should help in the prioritization, not only how much hospital resources are utilized, that’s on one side, but there’s also the patient risk of delaying or doing a procedure, and then the societal risk,” she said.
Susheel Kodali, MD, of New York–Presbyterian Hospital/Columbia University Irving Medical Center, who recently published recommendations on restructuring structural heart disease practice during the pandemic, said the document is timely as centers, including his own, are trying to restart some outpatient visits, as early as next week.
“They made a point about talking about cohesive partnerships with regional public health officials and I think that’s great. The question is how does that happen,” he told theheart.org | Medscape Cardiology. “In New York, we’re not allowed to do elective cases but what’s considered elective is not so clearly defined. An AS [aortic stenosis] patient that had a syncopal episode 2 weeks ago, is that considered elective or is that semi-urgent? I think that’s one of the challenges and that’s where these partnerships would be useful.”
Other challenges include the need for regional partnerships to better align hospitals, which in the New York area means half a dozen large healthcare systems, and to coordinate care between hospital departments – all of which will be scheduling imaging and OR time for their own backlog of hernia, knee, or hip surgeries.
Finally, there’s the need for a lot of conversation with the patient and their family about returning to a hospital amid a deadly pandemic.
“I had a patient today and the daughter was very concerned about bringing her in,” Kodali said. “She’s in class IV heart failure but her [daughter’s] big concern was: who is she going to be exposed to when she gets the echo? What kind of protection is there for her? Is the tech wearing a mask?
“It’s not just the health care providers that have to have the comfort, but it’s the patients and their families who have to feel comfortable bringing their loved ones here for treatment,” he said. “Because everyone is concerned about the environment.”
Wood reports receiving unrestricted grant support from Edwards Lifesciences and Abbott Vascular and serving as a consultant for Edwards Lifesciences, Medtronic, Abbott Vascular, and Boston Scientific. Poppas reports no relevant conflicts of interest. Kodali reports consultant (honoraria) from Admedus, Meril Life Sciences, JenaValve, and Abbott Vascular; SAB (equity) from Dura Biotech, MicroInterventional Devices, Thubrikar Aortic Valve, Supira, and Admedus; and institutional funding from Edwards Lifesciences, Medtronic, Abbott Vascular, Boston Scientific, and JenaValve.
This article first appeared on Medscape.com.
As COVID-19 case levels plateau in some regions, 16 North American cardiovascular societies have released a framework for reintroducing cardiovascular services disrupted by the pandemic.
The consensus document outlines a phased approach to restarting invasive cardiovascular (CV) procedures and diagnostic tests that aims to reduce patient and health care provider exposure to the coronavirus and still provide essential care. It also emphasizes some of the ethical considerations in patient selection and the need for a collaborative approach.
“The key message in our document is we need a new unprecedented collaboration with public health officials so that we can carefully monitor the situation and we’re aware of what’s happening with the penetrance of the pandemic in the community, but they’re aware of the morbidity and mortality that’s occurring on our ever-growing waiting list,” lead author David A. Wood, MD, told theheart.org | Medscape Cardiology.
The recommendations were jointly published May 4 in the Canadian Journal of Cardiology , the Journal of the American College of Cardiology, and The Annals of Thoracic Surgery, and are endorsed by, among others, the American Heart Association, American College of Cardiology (ACC), and Canadian Cardiovascular Society.
The guidance comes as hospitals are facing revenue shortfalls because of canceled elective procedures and resource-intensive COVID-19 cases, prompting some healthcare systems to furlough, lay off, or even fire staff.
“It’s obvious that volumes are down between 40% and 60%,” said Wood, director of the cardiac catheterization laboratory at Vancouver General Hospital and professor of medicine at the University of British Columbia, Canada. “Part of that is that some areas have restricted case volumes totally appropriately and it’s partly because patients are very afraid of coming to the hospital and, unfortunately, are having bad events at home. And some are dying.”
The new report features a detailed table outlining three different response levels: reintroduction of some services (level 2); reintroduction of most services (level 1); and regular services (level 0). It covers a range of services from transthoracic echocardiography and exercise testing with imaging to care for acute coronary syndrome and ST-segment elevation myocardial infarction.
“We’ve learned that we can very quickly turn off the tap and go to doing only 10% of our normal volumes, whether that’s surgery, cath lab, EP, diagnostic tests,” Wood said. “It’s much more difficult to thoughtfully turn the tap part way back on or restart the engine … you don’t just go from 0 to 100 [mph]. You go from 0 to 30 to 60 then maybe to 80 [mph].”
The document also includes eight guiding principles such as:
- The expectation that response levels will be different between regions, and even within a given region.
- A “transparent collaborative plan” for COVID-19 testing and personal protective equipment (PPE) must be in place before restarting cases.
- A less invasive test or alternate imaging modality should be considered, if both tests have similar efficacy.
- In general, a minimally invasive procedure with a shorter length of stay is preferable, if both strategies have similar efficacy and safety.
Although previous reports on cath lab considerations during the pandemic or restarting elective surgeries peg various actions to specific thresholds or time intervals, the language here is noticeably and intentionally broad.
Instead of stating when cardiovascular services should resume, for example, the experts say it’s appropriate to put the guidance document into place if there’s a “sustained reduction” in the rate of new COVID-19 admissions and deaths in the relevant geographic region for a “prespecified time interval.”
As for when or how frequently patients and healthcare providers should be tested for COVID-19, the document encourages “routine screening of all patients prior to any cardiovascular procedure or test.”
Overly prescriptive language in previous documents wasn’t felt to be that helpful, whereas language like “selective” cases and “some” or “most” cardiovascular procedures gives clinicians, health systems, and policy makers flexibility when moving between response levels, Wood explained.
“Different regions might be at different levels based on principles of public health as far as the penetrance of the pandemic in that community, as well as how can you actually do the physical distancing in your hospital or ambulatory clinic. Because, I tell you, that is the Achilles heel,” he said. “Our run rates are going to be determined by testing, the availability of PPE, but also how we’re going to use our existing infrastructure and maintain physical distancing.”
That may mean using telehealth for initial visits, having clinics open earlier in the morning or on weekends, or doing partial volumes for surgery or in the cath lab so patients can be staggered and recover at different times and in different areas of the hospital. “These are very granular, specific infrastructure things that we’ve never really had to consider before,” Wood observed.
The document also had to be flexible and nimble enough to respond to a potential rebound of COVID-19 cases, which in newly released models are projected to rise sharply to 200,000 cases a day and be accompanied by some 3,000 deaths each day by June 1.
“This is my own personal opinion but I think it’s foolish to think that we are going to be able to come back to 100% of the cases we were doing before, even with testing, PPE, and all of that until we have a vaccine,” he said.
Similar to decisions made in preparation for the initial COVID-19 surge, the consensus document outlines the need for ethical considerations when turning the tap back on. This means prioritizing procedures and tests that are likely to benefit more people and to a greater degree, and ensuring that patients are treated fairly and consistently, regardless of their ethnicity, perceived social worth, or ability to pay, said coauthor and ACC President Athena Poppas, MD, Brown University School of Medicine, Providence, Rhode Island.
“It’s an ethical tenet that exists in a lot of places but it’s usually not overtly called out,” Poppas told theheart.org | Medscape Cardiology. “It’s not rationing care; I think people jump to that but it’s actually the opposite of rationing care. It’s about being thoughtful about prioritizing patients.”
“There’s a variety of data that should help in the prioritization, not only how much hospital resources are utilized, that’s on one side, but there’s also the patient risk of delaying or doing a procedure, and then the societal risk,” she said.
Susheel Kodali, MD, of New York–Presbyterian Hospital/Columbia University Irving Medical Center, who recently published recommendations on restructuring structural heart disease practice during the pandemic, said the document is timely as centers, including his own, are trying to restart some outpatient visits, as early as next week.
“They made a point about talking about cohesive partnerships with regional public health officials and I think that’s great. The question is how does that happen,” he told theheart.org | Medscape Cardiology. “In New York, we’re not allowed to do elective cases but what’s considered elective is not so clearly defined. An AS [aortic stenosis] patient that had a syncopal episode 2 weeks ago, is that considered elective or is that semi-urgent? I think that’s one of the challenges and that’s where these partnerships would be useful.”
Other challenges include the need for regional partnerships to better align hospitals, which in the New York area means half a dozen large healthcare systems, and to coordinate care between hospital departments – all of which will be scheduling imaging and OR time for their own backlog of hernia, knee, or hip surgeries.
Finally, there’s the need for a lot of conversation with the patient and their family about returning to a hospital amid a deadly pandemic.
“I had a patient today and the daughter was very concerned about bringing her in,” Kodali said. “She’s in class IV heart failure but her [daughter’s] big concern was: who is she going to be exposed to when she gets the echo? What kind of protection is there for her? Is the tech wearing a mask?
“It’s not just the health care providers that have to have the comfort, but it’s the patients and their families who have to feel comfortable bringing their loved ones here for treatment,” he said. “Because everyone is concerned about the environment.”
Wood reports receiving unrestricted grant support from Edwards Lifesciences and Abbott Vascular and serving as a consultant for Edwards Lifesciences, Medtronic, Abbott Vascular, and Boston Scientific. Poppas reports no relevant conflicts of interest. Kodali reports consultant (honoraria) from Admedus, Meril Life Sciences, JenaValve, and Abbott Vascular; SAB (equity) from Dura Biotech, MicroInterventional Devices, Thubrikar Aortic Valve, Supira, and Admedus; and institutional funding from Edwards Lifesciences, Medtronic, Abbott Vascular, Boston Scientific, and JenaValve.
This article first appeared on Medscape.com.
Obstetrics during the COVID-19 pandemic
The identification of the SARS coronavirus (SARS-CoV-2) and emergence of the associated infectious respiratory disease, COVID-19, in late 2019 catapulted the citizens of the world, especially those in the health care professions, into an era of considerable uncertainty. At this moment in human history, calm reassurance – founded in fact and evidence – seems its greatest need. Much of the focus within the biomedical community has been on containment, prevention, and treatment of this highly contagious and, for some, extremely virulent disease.
However, for ob.gyns on the front lines of the COVID-19 fight, there is the additional challenge of caring for at least two patients simultaneously: the mother and her unborn baby. Studies in mother-baby dyads, while being published at an incredible pace, are still quite scarce. In addition, published reports are limited by the small sample size of the patient population (many are single-case reports), lack of uniformity in the timing and types of clinical samples collected, testing delays, and varying isolation protocols in cases where the mother has confirmed SARS-CoV-2.
Five months into a pandemic that has swept the world, we still know very little about COVID-19 infection in the general population, let alone the obstetric one. We do not know if having and resolving COVID-19 infection provides any long-term protection against future disease. We do not know if vertical transmission of SARS-CoV-2 occurs. We do not know if maternal infection confers any immunologic benefit to the neonate. The list goes on.
What we do know is that taking extra precautions works. Use of personal protective equipment saves health care practitioner and patient lives. Prohibiting or restricting visitors to only one person in hospitals reduces risk of transmission to vulnerable patients.
Additionally, we know that leading with compassion is vital to easing patient – and practitioner – anxiety and stress. Most importantly, we know that people are extraordinarily resilient, especially when it comes to safeguarding the health of their families.
To address some of the major concerns that many ob.gyns. have regarding their risk of coronavirus exposure when caring for patients, we have invited Ray Bahado-Singh, MD, professor and chair of obstetrics and gynecology at Oakland University, Rochester, Mich., and health system chair for obstetrics and gynecology at Beaumont Health System, who works in a suburb of Detroit, one of our nation’s COVID-19 hot spots.
Dr. Reece, who specializes in maternal-fetal medicine, is executive vice president for medical affairs at the University of Maryland School of Medicine as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. He is the medical editor of this column. He said he had no relevant financial disclosures. Contact him at [email protected].
The identification of the SARS coronavirus (SARS-CoV-2) and emergence of the associated infectious respiratory disease, COVID-19, in late 2019 catapulted the citizens of the world, especially those in the health care professions, into an era of considerable uncertainty. At this moment in human history, calm reassurance – founded in fact and evidence – seems its greatest need. Much of the focus within the biomedical community has been on containment, prevention, and treatment of this highly contagious and, for some, extremely virulent disease.
However, for ob.gyns on the front lines of the COVID-19 fight, there is the additional challenge of caring for at least two patients simultaneously: the mother and her unborn baby. Studies in mother-baby dyads, while being published at an incredible pace, are still quite scarce. In addition, published reports are limited by the small sample size of the patient population (many are single-case reports), lack of uniformity in the timing and types of clinical samples collected, testing delays, and varying isolation protocols in cases where the mother has confirmed SARS-CoV-2.
Five months into a pandemic that has swept the world, we still know very little about COVID-19 infection in the general population, let alone the obstetric one. We do not know if having and resolving COVID-19 infection provides any long-term protection against future disease. We do not know if vertical transmission of SARS-CoV-2 occurs. We do not know if maternal infection confers any immunologic benefit to the neonate. The list goes on.
What we do know is that taking extra precautions works. Use of personal protective equipment saves health care practitioner and patient lives. Prohibiting or restricting visitors to only one person in hospitals reduces risk of transmission to vulnerable patients.
Additionally, we know that leading with compassion is vital to easing patient – and practitioner – anxiety and stress. Most importantly, we know that people are extraordinarily resilient, especially when it comes to safeguarding the health of their families.
To address some of the major concerns that many ob.gyns. have regarding their risk of coronavirus exposure when caring for patients, we have invited Ray Bahado-Singh, MD, professor and chair of obstetrics and gynecology at Oakland University, Rochester, Mich., and health system chair for obstetrics and gynecology at Beaumont Health System, who works in a suburb of Detroit, one of our nation’s COVID-19 hot spots.
Dr. Reece, who specializes in maternal-fetal medicine, is executive vice president for medical affairs at the University of Maryland School of Medicine as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. He is the medical editor of this column. He said he had no relevant financial disclosures. Contact him at [email protected].
The identification of the SARS coronavirus (SARS-CoV-2) and emergence of the associated infectious respiratory disease, COVID-19, in late 2019 catapulted the citizens of the world, especially those in the health care professions, into an era of considerable uncertainty. At this moment in human history, calm reassurance – founded in fact and evidence – seems its greatest need. Much of the focus within the biomedical community has been on containment, prevention, and treatment of this highly contagious and, for some, extremely virulent disease.
However, for ob.gyns on the front lines of the COVID-19 fight, there is the additional challenge of caring for at least two patients simultaneously: the mother and her unborn baby. Studies in mother-baby dyads, while being published at an incredible pace, are still quite scarce. In addition, published reports are limited by the small sample size of the patient population (many are single-case reports), lack of uniformity in the timing and types of clinical samples collected, testing delays, and varying isolation protocols in cases where the mother has confirmed SARS-CoV-2.
Five months into a pandemic that has swept the world, we still know very little about COVID-19 infection in the general population, let alone the obstetric one. We do not know if having and resolving COVID-19 infection provides any long-term protection against future disease. We do not know if vertical transmission of SARS-CoV-2 occurs. We do not know if maternal infection confers any immunologic benefit to the neonate. The list goes on.
What we do know is that taking extra precautions works. Use of personal protective equipment saves health care practitioner and patient lives. Prohibiting or restricting visitors to only one person in hospitals reduces risk of transmission to vulnerable patients.
Additionally, we know that leading with compassion is vital to easing patient – and practitioner – anxiety and stress. Most importantly, we know that people are extraordinarily resilient, especially when it comes to safeguarding the health of their families.
To address some of the major concerns that many ob.gyns. have regarding their risk of coronavirus exposure when caring for patients, we have invited Ray Bahado-Singh, MD, professor and chair of obstetrics and gynecology at Oakland University, Rochester, Mich., and health system chair for obstetrics and gynecology at Beaumont Health System, who works in a suburb of Detroit, one of our nation’s COVID-19 hot spots.
Dr. Reece, who specializes in maternal-fetal medicine, is executive vice president for medical affairs at the University of Maryland School of Medicine as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. He is the medical editor of this column. He said he had no relevant financial disclosures. Contact him at [email protected].
FMT may improve outcomes without clearing multidrug-resistant organisms
For seriously ill patients with multidrug-resistant organisms (MDROs) in their gastrointestinal tract, performing a fecal microbiota transplant (FMT) may result in fewer and less severe infections, as well as shorter hospital stays, according to investigators.
Significant clinical improvements were observed across the group even though 59% of patients did not clear MDROs, which suggests that complete decolonization of resistant organisms may be unnecessary for patients to benefit from FMT, reported lead author Julian Marchesi, PhD, of Cardiff (Wales) University and Imperial College London (England).
“We see the quality of life for these patients is hugely improved even when we don’t get rid of the organism totally,” Dr. Marchesi said in a virtual press conference.
Although previous studies have suggested that FMT may be used to decolonize MDROs, little research has addressed other clinical outcomes, the investigators wrote in an abstract released as part of the annual Digestive Disease Week®, which was canceled because of COVID-19.
The present study involved 20 patients with MDROs, including extended-spectrum beta-lactamase Enterobacteriaceae (ESBL), carbapenemase-producing Enterobacteriaceae (CPE), or vancomycin-resistant enterococci (VRE). Approximately half of the population (n = 11) had chronic hematological disease. The other half (n = 9) had recurrent urinary tract infections with ESBL, including patients who had undergone renal transplant or had recurrent Clostridioides difficile infection.
For each transplant, 200-300 mL of fecal slurry was delivered via nasogastric tube into the small intestine. Fecal donors underwent a strict screening process that included blood, fecal, and behavioral testing.
Multiple clinical outcomes were evaluated in the 6 months leading up to FMT, then compared with outcomes in the 6 months following fecal transplant. Out of 20 patients, 17 completed the 6-month follow-up. Although only 7 of these patients (41%) were decolonized of MDROs, multiple significant clinical improvements were observed across the group, including reductions in MDRO bloodstream infections (P = .047), all bloodstream infections (P = .03), length of stay in hospital (P = .0002), and duration of carbapenem use (P = .0005). Eight out of 11 patients with hematologic disease improved enough to undergo stem cell transplantation within 6 months of FMT, and in the subgroup of patients who had undergone renal transplant, the rate of urinary tract infections was significantly improved (P = .008).
No serious adverse events were encountered during the trial, which led the investigators to conclude that FMT was safe and well tolerated, even in patients with bloodstream infections and those who were highly immunosuppressed.
Beyond clinical implications, Dr. Marchesi suggested that the study findings should influence FMT trial methodology.
“We’ve got to start thinking a little bit differently in terms of how we measure the impact of FMT,” he said. “It’s not all about ... getting rid of these opportunistic pathogens. There are other quality-of-life factors that we need to measure, because they’re also important for the patient.”
Dr. Marchesi said that more research is needed to confirm findings and gain a mechanistic understanding of why patients may improve despite a lack of decolonization.
“We think we’re on a strong foundation here to take this into a clinical trial,” he said.
The research was funded by the National Institute for Health Research and the Medical Research Council. The investigators reported no conflicts of interest.
For seriously ill patients with multidrug-resistant organisms (MDROs) in their gastrointestinal tract, performing a fecal microbiota transplant (FMT) may result in fewer and less severe infections, as well as shorter hospital stays, according to investigators.
Significant clinical improvements were observed across the group even though 59% of patients did not clear MDROs, which suggests that complete decolonization of resistant organisms may be unnecessary for patients to benefit from FMT, reported lead author Julian Marchesi, PhD, of Cardiff (Wales) University and Imperial College London (England).
“We see the quality of life for these patients is hugely improved even when we don’t get rid of the organism totally,” Dr. Marchesi said in a virtual press conference.
Although previous studies have suggested that FMT may be used to decolonize MDROs, little research has addressed other clinical outcomes, the investigators wrote in an abstract released as part of the annual Digestive Disease Week®, which was canceled because of COVID-19.
The present study involved 20 patients with MDROs, including extended-spectrum beta-lactamase Enterobacteriaceae (ESBL), carbapenemase-producing Enterobacteriaceae (CPE), or vancomycin-resistant enterococci (VRE). Approximately half of the population (n = 11) had chronic hematological disease. The other half (n = 9) had recurrent urinary tract infections with ESBL, including patients who had undergone renal transplant or had recurrent Clostridioides difficile infection.
For each transplant, 200-300 mL of fecal slurry was delivered via nasogastric tube into the small intestine. Fecal donors underwent a strict screening process that included blood, fecal, and behavioral testing.
Multiple clinical outcomes were evaluated in the 6 months leading up to FMT, then compared with outcomes in the 6 months following fecal transplant. Out of 20 patients, 17 completed the 6-month follow-up. Although only 7 of these patients (41%) were decolonized of MDROs, multiple significant clinical improvements were observed across the group, including reductions in MDRO bloodstream infections (P = .047), all bloodstream infections (P = .03), length of stay in hospital (P = .0002), and duration of carbapenem use (P = .0005). Eight out of 11 patients with hematologic disease improved enough to undergo stem cell transplantation within 6 months of FMT, and in the subgroup of patients who had undergone renal transplant, the rate of urinary tract infections was significantly improved (P = .008).
No serious adverse events were encountered during the trial, which led the investigators to conclude that FMT was safe and well tolerated, even in patients with bloodstream infections and those who were highly immunosuppressed.
Beyond clinical implications, Dr. Marchesi suggested that the study findings should influence FMT trial methodology.
“We’ve got to start thinking a little bit differently in terms of how we measure the impact of FMT,” he said. “It’s not all about ... getting rid of these opportunistic pathogens. There are other quality-of-life factors that we need to measure, because they’re also important for the patient.”
Dr. Marchesi said that more research is needed to confirm findings and gain a mechanistic understanding of why patients may improve despite a lack of decolonization.
“We think we’re on a strong foundation here to take this into a clinical trial,” he said.
The research was funded by the National Institute for Health Research and the Medical Research Council. The investigators reported no conflicts of interest.
For seriously ill patients with multidrug-resistant organisms (MDROs) in their gastrointestinal tract, performing a fecal microbiota transplant (FMT) may result in fewer and less severe infections, as well as shorter hospital stays, according to investigators.
Significant clinical improvements were observed across the group even though 59% of patients did not clear MDROs, which suggests that complete decolonization of resistant organisms may be unnecessary for patients to benefit from FMT, reported lead author Julian Marchesi, PhD, of Cardiff (Wales) University and Imperial College London (England).
“We see the quality of life for these patients is hugely improved even when we don’t get rid of the organism totally,” Dr. Marchesi said in a virtual press conference.
Although previous studies have suggested that FMT may be used to decolonize MDROs, little research has addressed other clinical outcomes, the investigators wrote in an abstract released as part of the annual Digestive Disease Week®, which was canceled because of COVID-19.
The present study involved 20 patients with MDROs, including extended-spectrum beta-lactamase Enterobacteriaceae (ESBL), carbapenemase-producing Enterobacteriaceae (CPE), or vancomycin-resistant enterococci (VRE). Approximately half of the population (n = 11) had chronic hematological disease. The other half (n = 9) had recurrent urinary tract infections with ESBL, including patients who had undergone renal transplant or had recurrent Clostridioides difficile infection.
For each transplant, 200-300 mL of fecal slurry was delivered via nasogastric tube into the small intestine. Fecal donors underwent a strict screening process that included blood, fecal, and behavioral testing.
Multiple clinical outcomes were evaluated in the 6 months leading up to FMT, then compared with outcomes in the 6 months following fecal transplant. Out of 20 patients, 17 completed the 6-month follow-up. Although only 7 of these patients (41%) were decolonized of MDROs, multiple significant clinical improvements were observed across the group, including reductions in MDRO bloodstream infections (P = .047), all bloodstream infections (P = .03), length of stay in hospital (P = .0002), and duration of carbapenem use (P = .0005). Eight out of 11 patients with hematologic disease improved enough to undergo stem cell transplantation within 6 months of FMT, and in the subgroup of patients who had undergone renal transplant, the rate of urinary tract infections was significantly improved (P = .008).
No serious adverse events were encountered during the trial, which led the investigators to conclude that FMT was safe and well tolerated, even in patients with bloodstream infections and those who were highly immunosuppressed.
Beyond clinical implications, Dr. Marchesi suggested that the study findings should influence FMT trial methodology.
“We’ve got to start thinking a little bit differently in terms of how we measure the impact of FMT,” he said. “It’s not all about ... getting rid of these opportunistic pathogens. There are other quality-of-life factors that we need to measure, because they’re also important for the patient.”
Dr. Marchesi said that more research is needed to confirm findings and gain a mechanistic understanding of why patients may improve despite a lack of decolonization.
“We think we’re on a strong foundation here to take this into a clinical trial,” he said.
The research was funded by the National Institute for Health Research and the Medical Research Council. The investigators reported no conflicts of interest.
FROM DDW 2020
Pandemic effect: All other health care visits can wait
according to survey conducted at the end of April.
When asked how likely they were to visit a variety of health care settings for treatment not related to the coronavirus, 62% of respondents said it was unlikely that they would go to a hospital, 64% wouldn’t go to a specialist, and 65% would avoid walk-in clinics, digital media company Morning Consult reported May 4.
The only setting with less than a majority on the unlikely-to-visit side was primary physicians, who managed to combine a 39% likely vote with a 13% undecided/no-opinion tally, Morning Consult said after surveying 2,201 adults on April 29-30 (margin of error, ±2 percentage points).
As to when they might feel comfortable making such an in-person visit with their primary physician, 24% of respondents said they would willing to go in the next month, 14% said 2 months, 18% said 3 months, 13% said 6 months, and 10% said more than 6 months, the Morning Consult data show.
“Hospitals, despite being overburdened in recent weeks in coronavirus hot spots such as New York City, have reported dips in revenue as a result of potential patients opting against receiving elective surgeries out of fear of contracting COVID-19,” Morning Consult wrote, and these poll results suggest that “health care companies could continue to feel the pinch as long as the coronavirus lingers.”
according to survey conducted at the end of April.
When asked how likely they were to visit a variety of health care settings for treatment not related to the coronavirus, 62% of respondents said it was unlikely that they would go to a hospital, 64% wouldn’t go to a specialist, and 65% would avoid walk-in clinics, digital media company Morning Consult reported May 4.
The only setting with less than a majority on the unlikely-to-visit side was primary physicians, who managed to combine a 39% likely vote with a 13% undecided/no-opinion tally, Morning Consult said after surveying 2,201 adults on April 29-30 (margin of error, ±2 percentage points).
As to when they might feel comfortable making such an in-person visit with their primary physician, 24% of respondents said they would willing to go in the next month, 14% said 2 months, 18% said 3 months, 13% said 6 months, and 10% said more than 6 months, the Morning Consult data show.
“Hospitals, despite being overburdened in recent weeks in coronavirus hot spots such as New York City, have reported dips in revenue as a result of potential patients opting against receiving elective surgeries out of fear of contracting COVID-19,” Morning Consult wrote, and these poll results suggest that “health care companies could continue to feel the pinch as long as the coronavirus lingers.”
according to survey conducted at the end of April.
When asked how likely they were to visit a variety of health care settings for treatment not related to the coronavirus, 62% of respondents said it was unlikely that they would go to a hospital, 64% wouldn’t go to a specialist, and 65% would avoid walk-in clinics, digital media company Morning Consult reported May 4.
The only setting with less than a majority on the unlikely-to-visit side was primary physicians, who managed to combine a 39% likely vote with a 13% undecided/no-opinion tally, Morning Consult said after surveying 2,201 adults on April 29-30 (margin of error, ±2 percentage points).
As to when they might feel comfortable making such an in-person visit with their primary physician, 24% of respondents said they would willing to go in the next month, 14% said 2 months, 18% said 3 months, 13% said 6 months, and 10% said more than 6 months, the Morning Consult data show.
“Hospitals, despite being overburdened in recent weeks in coronavirus hot spots such as New York City, have reported dips in revenue as a result of potential patients opting against receiving elective surgeries out of fear of contracting COVID-19,” Morning Consult wrote, and these poll results suggest that “health care companies could continue to feel the pinch as long as the coronavirus lingers.”
FDA grants EUA to muscle stimulator to reduce mechanical ventilator usage
The Food and Drug Administration has issued an Emergency Use Authorization (EUA) for the VentFree Respiratory Muscle Stimulator in order to potentially reduce the number of days adult patients, including those with COVID-19, require mechanical ventilation, according to a press release from Liberate Medical.
In comparison with mechanical ventilation, which is invasive and commonly weakens the breathing muscles, the VentFree system uses noninvasive neuromuscular electrical stimulation to contract the abdominal wall muscles in synchrony with exhalation during mechanical ventilation, according to the press release. This allows patients to begin treatment during the early stages of ventilation while they are sedated and to continue until they are weaned off of ventilation.
A pair of pilot randomized, controlled studies, completed in Europe and Australia, showed that VentFree helped to reduce ventilation duration and ICU length of stay, compared with placebo stimulation. The FDA granted VentFree Breakthrough Device status in 2019.
“We are grateful to the FDA for recognizing the potential of VentFree and feel privileged to have the opportunity to help patients on mechanical ventilation during the COVID-19 pandemic,” Angus McLachlan PhD, cofounder and CEO of Liberate Medical, said in the press release.
VentFree has been authorized for use only for the duration of the current COVID-19 emergency, as it has not yet been approved or cleared for usage by primary care providers.
The Food and Drug Administration has issued an Emergency Use Authorization (EUA) for the VentFree Respiratory Muscle Stimulator in order to potentially reduce the number of days adult patients, including those with COVID-19, require mechanical ventilation, according to a press release from Liberate Medical.
In comparison with mechanical ventilation, which is invasive and commonly weakens the breathing muscles, the VentFree system uses noninvasive neuromuscular electrical stimulation to contract the abdominal wall muscles in synchrony with exhalation during mechanical ventilation, according to the press release. This allows patients to begin treatment during the early stages of ventilation while they are sedated and to continue until they are weaned off of ventilation.
A pair of pilot randomized, controlled studies, completed in Europe and Australia, showed that VentFree helped to reduce ventilation duration and ICU length of stay, compared with placebo stimulation. The FDA granted VentFree Breakthrough Device status in 2019.
“We are grateful to the FDA for recognizing the potential of VentFree and feel privileged to have the opportunity to help patients on mechanical ventilation during the COVID-19 pandemic,” Angus McLachlan PhD, cofounder and CEO of Liberate Medical, said in the press release.
VentFree has been authorized for use only for the duration of the current COVID-19 emergency, as it has not yet been approved or cleared for usage by primary care providers.
The Food and Drug Administration has issued an Emergency Use Authorization (EUA) for the VentFree Respiratory Muscle Stimulator in order to potentially reduce the number of days adult patients, including those with COVID-19, require mechanical ventilation, according to a press release from Liberate Medical.
In comparison with mechanical ventilation, which is invasive and commonly weakens the breathing muscles, the VentFree system uses noninvasive neuromuscular electrical stimulation to contract the abdominal wall muscles in synchrony with exhalation during mechanical ventilation, according to the press release. This allows patients to begin treatment during the early stages of ventilation while they are sedated and to continue until they are weaned off of ventilation.
A pair of pilot randomized, controlled studies, completed in Europe and Australia, showed that VentFree helped to reduce ventilation duration and ICU length of stay, compared with placebo stimulation. The FDA granted VentFree Breakthrough Device status in 2019.
“We are grateful to the FDA for recognizing the potential of VentFree and feel privileged to have the opportunity to help patients on mechanical ventilation during the COVID-19 pandemic,” Angus McLachlan PhD, cofounder and CEO of Liberate Medical, said in the press release.
VentFree has been authorized for use only for the duration of the current COVID-19 emergency, as it has not yet been approved or cleared for usage by primary care providers.