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EDITORIAL
Pneumonia and venous thromboembolism: Is the evidence catching up with the guidelines? Key words: deep venous thrombosis, pneumonia, pulmonary embolism, streptococcus pneumonia, venous thromboembolism. Abbreviations: ACCP, American College of Chest Physicians; DVT, deep vein thrombosis; PAF, platelet-activating factor; PE, pulmonary embolism; VTE, venous thromboembolism
Venous thromboembolism (VTE) prophylaxis in medical patients is a challenging subject. Surgeons are arguably ahead of physicians, having published thromboprophylaxis guidelines using large cohorts of patients which show VTE prophylaxis reduces the incidence of perioperative deep venous thrombosis, pulmonary embolism (PE) and death.1 VTE prophylaxis in medical patients has a weaker evidence base. The American College of Chest Physicians (ACCP) guidelines give a strong recommendation that all patients admitted with medical illness should receive VTE prophylaxis. This approach, however, has recently been challenged.2 We know that 80% of all VTE in the community occur within 1 month of a hospital admission.3 Efforts to increase VTE prophylaxis targets to 85% of all medical inpatients, however, have not resulted in a discernable decrease in VTE development, taking into account the associated cost and potential risks of anticoagulation to the patient.4 In the current issue of Respirology, a large Taiwanese retrospective case–control study provides evidence for an informed discussion.5 Based on a cohort of almost 20 000 patients admitted with pneumococcal pneumonia, in comparison with 75 000 age-matched controls (reasons for medical admission not published), the authors report increased short and long term risks for both deep vein thrombosis (DVT) and PE.5 Patients were tracked for up to 14 years to calculate cumulative incidences of DVT and PE. The incidences of both were highest in the first 4 weeks following diagnosis. This is a very important observation as the likely influence of new confounding factors would be low at this time. These findings are similar to those reported in epidemiological studies investigating VTE development in surgical patients.1 Over longer periods of time, however, many confounding factors may impact upon VTE risk, reducing the robustness of subsequent observations. As Chen et al. described, patients who have undergone recent surgery, have pre-existing cancer and/or have cardiovascular disease were at higher risk for subsequent development of DVT/PE than patients without these comorbidities. Comparisons between cases and controls were limited in this regard, as patients in the © 2015 Asian Pacific Society of Respirology
control cohort had a significantly lower prevalence of medical comorbidities and rates of thrombophilia were not recorded in either cohort. Infection, immobility, recent surgery, cardiac disease and cancer are recognized risk factors for VTE development.6 Pneumococcal infection specifically has been associated with host coagulation/ anticoagulation, stimulated by components of the bacterial cell wall.7 The cell wall also stimulates recruitment of leukocytes and promotes inflammatory cytokine production such as TNFα, IL-1 and IL-6.8,9 During the inflammatory process, endothelial cells activate and separate, reducing barrier function and exposing the extracellular matrix. This induces coagulation by exposing subendothelial tissue factor which, in combination with circulating factor VII, is the major initiator of the coagulation cascade. This leads to intravascular deposits of fibrin which may act as a host defence mechanism inhibiting dissemination of the bacteria. As has been described by the author, platelet-activating factor (PAF) has also been implicated in pneumococcus-associated venous thrombosis as it promotes vascular endothelial cell activation and platelet aggregation.10 The activity of PAF appears to be mediated by phosphorylcholine, a component of the pneumococcal cell wall.10 The results indicate that DVT and PE risk are higher after hospitalization with pneumococcal pneumonia. Although inherent bias does impact on the outcome of this retrospective analysis, the findings add to the weight of evidence associating comorbidity with VTE development. It also lends support to current international guidelines recommending thromboprophylaxis to medical inpatients. Case ascertainment bias has been minimized as 99% of Taiwan’s population are covered by a single national health insurance programme. It appears that an approach by a quality assurance unit using management strategies to increase the adherence of doctors to prescribe VTE prophylaxis may lead to increased prescribing but not to reduced harm. It may well be that this is related to increased prescribing in a low risk population. The median length of stay in the American cohort study was only 4 days, implying that a large number of low risk inpatients received VTE prophylaxis. However in this cohort, underlying malignancy was associated with an increased risk of VTE. In summary, VTE is the third most common vascular risk of death following ischaemic heart disease and stroke. Based on epidemiological data, VTE should be preventable and this approach has been successful in Respirology (2015) doi: 10.1111/resp.12544
2 surgical patients. This study adds to our evidence base that patients admitted with a pneumococcal pneumonia may be at increased risk of VTE and should be considered for VTE prophylaxis as per ACCP guidelines. Prospective studies will be required to clarify the relative influences of comorbidities such as immobility, other cardiovascular diseases and cancer on VTE risk in inpatients with pneumococcal pneumonia. Lutz Beckert1 MD, FRACP and Anthony Rahman2 FRACP 1 Department of Medicine, University of Otago and 2 Department of Oncology, Canterbury District Health Board, Christchurch, New Zealand
REFERENCES 1 Sweetland S, Green J, Liu B, Berrington de González A, Canonico M, Reeves G, Beral V, on behalf of the Million Women Study Collaborates. Duration and magnitude of the postoperative risk of venous thromboembolism in middle aged women: prospective cohort study. BMJ 2009; 339: b4583. 2 Spencer A, Cawood T, Frampton C, Jardine D. Heparin-based treatment to prevent symptomatic deep venous thrombosis, pulmonary embolism or death in general medical inpatients is not supported by best evidence. Intern. Med. J. 2014; 44: 1054–65. 3 National Institute of Clinical Studies. The incidence and risk factors for venous thromboembolism in hospitals in Western
Respirology (2015)
Editorial
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Australia 1999–2001. Prepared by The School of Population Health, University of Western Australia. NICS, Melbourne; 2005. Flanders SA, Greene MT, Grant P, Kaatz S, Paje D, Lee B, Barron J, Chopra V, Share D, Bernstein SJ. Hospital performance for pharmacologic venous thromboembolism prophylaxis and rate of venous thromboembolism—a cohort study. JAMA Intern. Med. 2014; 174: 1577–84. Chen Y-G, Lin T-Y, Huang W-Y, Lin C-L, Dai M-S, Kao C-H. Association between pneumococcal pneumonia and venous thromboembolism in hospitalized patients: a nationwide population based study. Respirology 2015; 20: doi: 10.1111/resp.12501. [Epub ahead of print]. Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ 3rd. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch. Intern. Med. 2000; 160: 761–8. Geelen S, Bhattacharyya C, Tuomanen E. Induction of procoagulant activity on human endothelial cells by Streptococcus pneumoniae. Infect. Immun. 1992; 60: 4179–83. Heumann D, Barras C, Severin A, Glauser MP, Tomasz A. Grampositive cell walls stimulate synthesis of tumor necrosis factor alpha and interleukin-6 by human monocytes. Infect. Immun. 1994; 62: 2715–21. Riesenfeld-Orn I, Wolpe S, Garcia-Bustos JF, Hoffmann MK, Tuomanen E. Production of interleukin-1 but not tumor necrosis factor by human monocytes stimulated with pneumococcal cell surface components. Infect. Immun. 1989; 57: 1890–3. Cabellos C, MacIntyre DE, Forrest M, Burroughs M, Prasad S, Tuomanen E. Differing roles for platelet-activating factor during inflammation of the lung and subarachnoid space. The special case of Streptococcus pneumoniae. J. Clin. Invest. 1992; 90: 612– 18.
© 2015 Asian Pacific Society of Respirology
EDITORIAL
Pneumonia and venous thromboembolism: Is the evidence catching up with the guidelines? Key words: deep venous thrombosis, pneumonia, pulmonary embolism, streptococcus pneumonia, venous thromboembolism. Abbreviations: ACCP, American College of Chest Physicians; DVT, deep vein thrombosis; PAF, platelet-activating factor; PE, pulmonary embolism; VTE, venous thromboembolism
Venous thromboembolism (VTE) prophylaxis in medical patients is a challenging subject. Surgeons are arguably ahead of physicians, having published thromboprophylaxis guidelines using large cohorts of patients which show VTE prophylaxis reduces the incidence of perioperative deep venous thrombosis, pulmonary embolism (PE) and death.1 VTE prophylaxis in medical patients has a weaker evidence base. The American College of Chest Physicians (ACCP) guidelines give a strong recommendation that all patients admitted with medical illness should receive VTE prophylaxis. This approach, however, has recently been challenged.2 We know that 80% of all VTE in the community occur within 1 month of a hospital admission.3 Efforts to increase VTE prophylaxis targets to 85% of all medical inpatients, however, have not resulted in a discernable decrease in VTE development, taking into account the associated cost and potential risks of anticoagulation to the patient.4 In the current issue of Respirology, a large Taiwanese retrospective case–control study provides evidence for an informed discussion.5 Based on a cohort of almost 20 000 patients admitted with pneumococcal pneumonia, in comparison with 75 000 age-matched controls (reasons for medical admission not published), the authors report increased short and long term risks for both deep vein thrombosis (DVT) and PE.5 Patients were tracked for up to 14 years to calculate cumulative incidences of DVT and PE. The incidences of both were highest in the first 4 weeks following diagnosis. This is a very important observation as the likely influence of new confounding factors would be low at this time. These findings are similar to those reported in epidemiological studies investigating VTE development in surgical patients.1 Over longer periods of time, however, many confounding factors may impact upon VTE risk, reducing the robustness of subsequent observations. As Chen et al. described, patients who have undergone recent surgery, have pre-existing cancer and/or have cardiovascular disease were at higher risk for subsequent development of DVT/PE than patients without these comorbidities. Comparisons between cases and controls were limited in this regard, as patients in the © 2015 Asian Pacific Society of Respirology
control cohort had a significantly lower prevalence of medical comorbidities and rates of thrombophilia were not recorded in either cohort. Infection, immobility, recent surgery, cardiac disease and cancer are recognized risk factors for VTE development.6 Pneumococcal infection specifically has been associated with host coagulation/ anticoagulation, stimulated by components of the bacterial cell wall.7 The cell wall also stimulates recruitment of leukocytes and promotes inflammatory cytokine production such as TNFα, IL-1 and IL-6.8,9 During the inflammatory process, endothelial cells activate and separate, reducing barrier function and exposing the extracellular matrix. This induces coagulation by exposing subendothelial tissue factor which, in combination with circulating factor VII, is the major initiator of the coagulation cascade. This leads to intravascular deposits of fibrin which may act as a host defence mechanism inhibiting dissemination of the bacteria. As has been described by the author, platelet-activating factor (PAF) has also been implicated in pneumococcus-associated venous thrombosis as it promotes vascular endothelial cell activation and platelet aggregation.10 The activity of PAF appears to be mediated by phosphorylcholine, a component of the pneumococcal cell wall.10 The results indicate that DVT and PE risk are higher after hospitalization with pneumococcal pneumonia. Although inherent bias does impact on the outcome of this retrospective analysis, the findings add to the weight of evidence associating comorbidity with VTE development. It also lends support to current international guidelines recommending thromboprophylaxis to medical inpatients. Case ascertainment bias has been minimized as 99% of Taiwan’s population are covered by a single national health insurance programme. It appears that an approach by a quality assurance unit using management strategies to increase the adherence of doctors to prescribe VTE prophylaxis may lead to increased prescribing but not to reduced harm. It may well be that this is related to increased prescribing in a low risk population. The median length of stay in the American cohort study was only 4 days, implying that a large number of low risk inpatients received VTE prophylaxis. However in this cohort, underlying malignancy was associated with an increased risk of VTE. In summary, VTE is the third most common vascular risk of death following ischaemic heart disease and stroke. Based on epidemiological data, VTE should be preventable and this approach has been successful in Respirology (2015) doi: 10.1111/resp.12544
2 surgical patients. This study adds to our evidence base that patients admitted with a pneumococcal pneumonia may be at increased risk of VTE and should be considered for VTE prophylaxis as per ACCP guidelines. Prospective studies will be required to clarify the relative influences of comorbidities such as immobility, other cardiovascular diseases and cancer on VTE risk in inpatients with pneumococcal pneumonia. Lutz Beckert1 MD, FRACP and Anthony Rahman2 FRACP 1 Department of Medicine, University of Otago and 2 Department of Oncology, Canterbury District Health Board, Christchurch, New Zealand
REFERENCES 1 Sweetland S, Green J, Liu B, Berrington de González A, Canonico M, Reeves G, Beral V, on behalf of the Million Women Study Collaborates. Duration and magnitude of the postoperative risk of venous thromboembolism in middle aged women: prospective cohort study. BMJ 2009; 339: b4583. 2 Spencer A, Cawood T, Frampton C, Jardine D. Heparin-based treatment to prevent symptomatic deep venous thrombosis, pulmonary embolism or death in general medical inpatients is not supported by best evidence. Intern. Med. J. 2014; 44: 1054–65. 3 National Institute of Clinical Studies. The incidence and risk factors for venous thromboembolism in hospitals in Western
Respirology (2015)
Editorial
4
5
6
7
8
9
10
Australia 1999–2001. Prepared by The School of Population Health, University of Western Australia. NICS, Melbourne; 2005. Flanders SA, Greene MT, Grant P, Kaatz S, Paje D, Lee B, Barron J, Chopra V, Share D, Bernstein SJ. Hospital performance for pharmacologic venous thromboembolism prophylaxis and rate of venous thromboembolism—a cohort study. JAMA Intern. Med. 2014; 174: 1577–84. Chen Y-G, Lin T-Y, Huang W-Y, Lin C-L, Dai M-S, Kao C-H. Association between pneumococcal pneumonia and venous thromboembolism in hospitalized patients: a nationwide population based study. Respirology 2015; 20: doi: 10.1111/resp.12501. [Epub ahead of print]. Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ 3rd. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch. Intern. Med. 2000; 160: 761–8. Geelen S, Bhattacharyya C, Tuomanen E. Induction of procoagulant activity on human endothelial cells by Streptococcus pneumoniae. Infect. Immun. 1992; 60: 4179–83. Heumann D, Barras C, Severin A, Glauser MP, Tomasz A. Grampositive cell walls stimulate synthesis of tumor necrosis factor alpha and interleukin-6 by human monocytes. Infect. Immun. 1994; 62: 2715–21. Riesenfeld-Orn I, Wolpe S, Garcia-Bustos JF, Hoffmann MK, Tuomanen E. Production of interleukin-1 but not tumor necrosis factor by human monocytes stimulated with pneumococcal cell surface components. Infect. Immun. 1989; 57: 1890–3. Cabellos C, MacIntyre DE, Forrest M, Burroughs M, Prasad S, Tuomanen E. Differing roles for platelet-activating factor during inflammation of the lung and subarachnoid space. The special case of Streptococcus pneumoniae. J. Clin. Invest. 1992; 90: 612– 18.
© 2015 Asian Pacific Society of Respirology
