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Thromboembolic events in patients with severe pandemic influenza A/H1N1

Published:September 10, 2015DOI:https://doi.org/10.1016/j.ejim.2015.08.017

      Abstract

      Background

      The 2009 pandemic influenza A/H1N1 developed as a novel swine influenza which caused more diseases among younger age groups than in the elderly. Severe hypoxemic respiratory failure from A/H1N1 pneumonia resulted in an increased need for ICU beds. Several risk groups were identified that were at a higher risk for adverse outcomes. Pregnant women were a particularly vulnerable group of patients The CDC reported on the first ten patients with severe illness and acute hypoxemic respiratory failure associated with A/H1N1 infection, none of whom were pregnant, but they noticed that half of the patients had a pulmonary embolism.

      Methods

      During a four-month period from September to December 2009, 252 patients were admitted to our hospital with confirmed pandemic influenza H1N1 by real-time reverse transcriptase-polymerase chain reaction test (rRT-PCR). We cared for twenty patients (7.9%) admitted to MICU with severe A/H1N1. Results on Thrombotic events were identified in five (25%) of our critically ill patients.

      Conclusions

      We recommend that patients with severe influenza A/H1N1 pneumonitis and respiratory failure be administered DVT prophylaxis in particular if there are additional risk factors for TVE. Further prospective studies on the relationship of influenza A/H1N1 and VTE are needed.

      Keywords

      1. Introduction

      The 2009 pandemic influenza A/H1N1 developed as a novel swine influenza which caused more diseases among younger age groups than in the elderly [
      • Bautista E.
      • Chotpitayasunondh T.
      • Gao ZHarper S.A.
      • Shaw M.
      • Uyeki T.M.
      • Zaki S.R.
      • et al.
      Writing committee of the WHO consultation on clinical aspects of pandemic (H1N1) 2009 influenza. Clinical aspects of pandemic 2009 influenza virus.
      ]. Although not as devastating as the 1918 Spanish Flue, it did cause more than 17,700 deaths worldwide. Severe hypoxemic respiratory failure from A/H1N1 pneumonia resulted in an increased need for ICU beds [
      • Venkata C.
      • Sampathkumar P.
      • Afessa B.
      Hospitalized patients with 2009 H1N1 influenza infection: the Mayo clinic experience.
      ]. Several risk groups were identified that were at a higher risk for adverse outcomes [
      • Venkata C.
      • Sampathkumar P.
      • Afessa B.
      Hospitalized patients with 2009 H1N1 influenza infection: the Mayo clinic experience.
      ]. Pregnant women were a particularly vulnerable group of patients; in the Californian cohort of 94 pregnant women with A/H1N1, 18 required ICU admissions and among them 6 died [
      • Louie J.K.
      • Acosta M.
      • Jamison D.J.
      • Honein MA for the Californian pandemic (H1N1) working group
      Severe 2009 H1N1 influenza in pregnant and postpartum women in California.
      ]. The CDC reported on the first ten patients with severe illness and acute hypoxemic respiratory failure associated with A/H1N1 infection, none of whom were pregnant, but they noticed that half of the patients had a pulmonary embolism [
      • Center for Disease Control and Prevention
      Intensive-care patients with severe novel influenza A (H1N1) virus infection. Michigan June 2009.
      ]. This is in contrast to the findings from a Dutch group that patients with proven pulmonary embolism were less likely to have evidence of recent influenza illness than a control group in whom pulmonary embolism had been ruled out [
      • van Wissen M.
      • Keller T.T.
      • Ronkes B.
      • Gerdes V.E.A.
      • Zaaijer H.L.
      • van Gorp E.C.M.
      • et al.
      Influenza infection and risk of pulmonary embolism.
      ].
      We report our experience with five patients that suffered clinically striking thrombotic events among 20 patients admitted to the medical intensive care unit (MICU) with severe A/H1N1.

      2. Methods and results

      During a four-month period from September to December 2009, 252 patients were admitted to our hospital with confirmed pandemic influenza H1N1 by real-time reverse transcriptase-polymerase chain reaction test (rRT-PCR). We cared for twenty patients (7.9%) admitted to MICU with severe A/H1N1 (Table 1); seven men and 13 women. Their mean age (SD) was 36 (14) years (range: 19–67). None had received vaccination. All patients received oseltamivir as soon as the suspicion of A/H1N1 was raised in addition to broad spectrum AB. Fourteen patients (67%) developed ARDS with intractable hypoxemia and needed prolonged mechanical ventilation with nitric oxide and prone position. Five of our 13 women were pregnant (38.5%); they underwent three 2nd semester pregnancy losses; two 3rd trimester emergency cesarean sections (CS) with the delivery of healthy babies that survived.
      Table 1Our patients.
      Patients without VTEPatients suffering VTE
      Number15/205/20 (25%)
      Male/female6/92/3
      Mean aged (SD) years39.5 (15.7)26.4 (8.3)
      Bedouins94
      Mortality in MICU

      Mortality 30 days

      60 days
      1

      3

      4
      2

      2

      2
      Comorbidities
      Pregnancy23
      Malignancy2

      Lung cancer

      s/p AML 7 years
      2

      s/p induction for B cell lymphoma

      s/p initial cycle for AML
      Obesity20
      s/p transplantation2

      s/p heart transplant 8 weeks

      s/p bone marrow AML 7 years
      0
      Asthma20
      Liver cirrhosis10
      DM10
      Kidney disease10
      None10
      Thrombotic events were identified in five patients (25%) of our critically ill patients (Table 2). Two of these patients did not receive DVT prophylaxis as they had thrombocytopenia after chemotherapy for their hematological malignancy; one of whom also received an inferior vena cava filter for that same reason. There were two surprising arterial thrombotic events in two young pregnant women: extensive ischemic cerebrovascular event (CVA) and an acute myocardial infarction. The patient with CVA had an elevated anti-cardiolipin (IgG: 25/5 U/ml) when the CVA was diagnosed but it returned to normal four months later. Among these five patients two of the pregnant women died (Table 2). The patient with acute myocardial infarction and the woman after emergency cesarean section suffered a subclavian and external jugular vein DVT without a prior central line. The patient with CVA underwent rehabilitation and her aphasia improved but she has hemiparesis and needs a wheel chair when she leaves her home.
      Table 2Thrombotic complications in our patients with influenza A/H1N1.
      Gender age/ethnicAdmitted from/LOS MICU/all LOS days; outcome:Co-morbidityICU management

      In addition to oseltamivir
      ICU complicationsThrombotic complications
      Patient 1.

      F 19/Bedouin
      From ED

      66/227

      Survived
      Pregnancy 21 weeks, spontaneous abortion day 1MV day 1, Muscle relaxants; Vasopressors; Prone position

      Nitric oxide

      Sc heparin 5000 U x3

      Iv Rocefin

      Iv perimivir X2
      Intractable hypoxemia, Concomitant pneumococcal bacteremia,

      Polyneuropathy

      Bilateral barotraumas

      Prolonged fever

      Prolonged H1N1 secretion (4 weeks)
      CVA bilateral diagnosed day 34

      Aphasia and left hemiparesis



      ECHO: sinus tachycardia. Normal left and right ventricular size and function. NO valvulopathy
      Patient 2.

      F 28/Bedouin
      From ED

      13/13

      Deceased
      Pregnancy 24 weeks;MV day 2;

      Muscle relaxants

      Vasopressors

      Prone position

      Sc heparin 5000 U x3
      Intractable hypoxemiaAcute anterior ST elevation MI day 2

      ECHO: sinus tachycardia. Severe left ventricular dysfunction. Global hypokinesis. Preserved right ventricular function.
      Patient 3

      F 40/Bedouin
      From OR after CS

      36/37

      Deceased
      Pregnant 36 weeks; emergency CS before admission to MICUMV in OR (37 days)

      Vasopressors

      Nitric oxide

      Prone position

      Sc heparin 5000 U x3

      Iv rocefin, azenil
      Intractable hypoxemia

      Leukopenia on admission 2600

      Barotraumas
      DVT of subclavian and jugularis vein in bedside douplex day 16 (no central line on that side)
      Patient 4

      M 23/Jewish
      From ED

      36/66

      Survived
      Cerebral palsy; after induction chemo-therapy for B cell Lymphoma (CHOP).MV on day 4 (for 36 days) Tracheostomy

      Muscle relaxants;

      Iv tazocin
      Neutropenic fever after chemotherapy; Concomitant Staph aureus furunculosis of skin

      MV day 3

      Bilateral barotraumas

      Guillain Barre
      DVT left subclavian day 15 (no central line on that side) did not receive sc heparin for DVT prophylaxis d/t post-chemotherapy thrombocytopenia;
      Patient 5

      M 22/Bedouin

      he was admitted twice on both admissions A/H1N1 was positive 18 days apart
      11/41

      Survived
      On second admission with neutropenic fever after induction therapy for new diagnosed AMLMV on admission (14 days)

      Vasopressors

      Iv rocefin ciproxsin
      DVT of rt leg day 5 (no central line); due to chemotherapy induced thrombocytopenic did not receive prophylactic sc heparin. Had inferior vena cava filter inserted
      LOS: length of stay.

      3. Discussion

      We reported on five patients (25%) among 20 severely ill ICU patients with proven A/H1N1 pandemic infection, who experienced a clinically significant thrombotic event among them two arterial thrombotic events in two young pregnant women: CVA and acute myocardial infarction. Three patients had DVT without an underlying central line. All three women were pregnant and two of them succumbed to their severe illness.
      One report has described thromboembolic events (TVE) as a complication in proven A/H1N1 infection [
      • Brunch P.E.
      • High S.M.
      • Nadjafi M.
      • Stanley K.
      • Liles W.C.
      • Christian M.D.
      Pandemic H1N1 Influenza infection and vascular thrombosis.
      ]. Among 112 patients with severe as well as mild H1N1 disease they identified seven patients with VTE (6.3%), including acute myocardial infarction in two, deep vein thrombosis (DVT) in three and one patient with an arterial thrombosis. The presence of vascular thrombosis was associated with increased mortality (30% versus 8%) [
      • Brunch P.E.
      • High S.M.
      • Nadjafi M.
      • Stanley K.
      • Liles W.C.
      • Christian M.D.
      Pandemic H1N1 Influenza infection and vascular thrombosis.
      ]. Interestingly, none of their seven patients were pregnant [
      • Brunch P.E.
      • High S.M.
      • Nadjafi M.
      • Stanley K.
      • Liles W.C.
      • Christian M.D.
      Pandemic H1N1 Influenza infection and vascular thrombosis.
      ]. In the first report from the CDC on ten patients with severe ARDS from A/H1N1 it was noted that 5 had pulmonary embolism (50%) and it was recommended to use DVT prophylaxis [
      • Center for Disease Control and Prevention
      Intensive-care patients with severe novel influenza A (H1N1) virus infection. Michigan June 2009.
      ]. None of these ten patients were reported to have been pregnant [
      • Center for Disease Control and Prevention
      Intensive-care patients with severe novel influenza A (H1N1) virus infection. Michigan June 2009.
      ]. Our three pregnant patients did receive DVT prophylaxis with subcutaneous unfractionated heparin.
      The first autopsy report on 21 patients with confirmed A/H1N1 infection identified four (19%) with pulmonary embolism [
      • Maud T.
      • Hajjar L.A.
      • Callegari G.D.
      • da Silva L.F.F.
      • Schout D.
      • Galas F.R.B.G.
      • et al.
      Lung pathology in fatal novel human influenza A (H1N1) infection.
      ]; another USA autopsy study on eight patients, revealed pulmonary embolism in two, and DVT and portal vein thrombosis in one each, i.e. half their patients had suffered VTE [
      • Harms P.W.
      • Schmidt L.A.
      • Smith L.B.
      • Newton D.W.
      • Pletneva M.A.
      • Walters L.L.
      • et al.
      Autopsy findings in eight patients with fatal H1N1 Influenza.
      ]. This in contrast to a Spanish report on 382 patients with ARDS not related to A/H1N1 viral pneumonitis, they found three patients with pulmonary embolism among the patients in whom diffuse alveolar damage was not revealed at the post-mortem examination although clinically and physiologically they were diagnosed as ARDS [
      • Estaban A.
      • Fernandez-Segoviano P.
      • Frutos-Vivar F.
      • Aramburu J.A.
      • Najera L.
      • Ferguson N.D.
      • et al.
      Comparison of clinical criteria for the acute respiratory distress syndrome with autopsy findings.
      ]. This highlights the fact that patients with severe A/H1N1 infection suffered a high frequency of VTEs more so than patients with usual causes of ARDS and sepsis, and that arterial thrombosis is of particular concern as seen in two of our patients with CVA and acute myocardial infarction. Among our fourteen patients with severe ARDS and hypoxemic respiratory failure it could be questioned whether undetected pulmonary embolism contributed to the intractable hypoxemia they experienced; we did not systematically investigate our patients for this but they were administered DVT prophylaxis with unfractionated heparin.
      Pregnancy and the post-partum period are known to be hypercoagulability states and in the developed world pulmonary embolism is an important cause of maternal mortality [
      • Bourjeily G.
      • Paidas M.
      • Khalil H.
      • Rosene-Montella K.
      • Rodger M.
      Pulmonary embolism in pregnancy.
      ]. But in a review of pregnant Californian women with A/H1N1 infection VTE was not reported as a complication [
      • Louie J.K.
      • Acosta M.
      • Jamison D.J.
      • Honein MA for the Californian pandemic (H1N1) working group
      Severe 2009 H1N1 influenza in pregnant and postpartum women in California.
      ]. Furthermore in the Australian cohort of pregnancy associated critical ill patients with A/H1N1, VTE was not reported as a complication [
      • Seppelt I
      ANZIC influenza investigators and Australasian Outcomes Surveillance System. Critical illness due to 2009A/H1N1 influenza in pregnant women: population based cohort study.
      ].
      In the Brazilian autopsy study three distinct pathological patterns were described in the lungs of patients succumbing to A/H1N1 infection: extensive diffuse alveolar damage (DAD) present in nine of their patients; this is the pattern associated with ARDS. Six patients had necrotizing bronchiolitis and five patients had DAD with intense alveolar hemorrhage [
      • Maud T.
      • Hajjar L.A.
      • Callegari G.D.
      • da Silva L.F.F.
      • Schout D.
      • Galas F.R.B.G.
      • et al.
      Lung pathology in fatal novel human influenza A (H1N1) infection.
      ]. In our practice hemoptysis was not a clinical complication among our patients on mechanical ventilation for A/H1N1 pneumonitis.
      Two of our pregnant patients suffered an arterial thrombosis, extensive CVA and an acute myocardial infarction. Acute myocardial infarction is rare among pregnant women; a recent review for the period 2006–2011 identified 150 reported patients with pregnancy-associated-acute-myocardial-infarction (PAMI) with a fatal outcome in nine patients (7%) [
      • Elkayam U.
      • Jalnapurkar S.
      • Barakkat M.N.
      • Khatri N.
      • Kealey A.J.
      • Mehra A.
      • et al.
      Pregnancy-associated acute myocardial infarction a review of contemporary experience in 150 cases between 2006–2011.
      ]. Only 37 women with PAMI (24.7%) were younger than 30 years of age, like our patient. PAMI is more frequent in the third trimester and post-partum and only 25 (16.7%) occurred during the second trimester. PAMI was associated with coronary dissection (43%), atherosclerosis (27%), clot formation (17%), spasm (2%) and Takotsubo cardiomyopathy (2%); while 11 (9%) had normal coronary arteries [
      • Elkayam U.
      • Jalnapurkar S.
      • Barakkat M.N.
      • Khatri N.
      • Kealey A.J.
      • Mehra A.
      • et al.
      Pregnancy-associated acute myocardial infarction a review of contemporary experience in 150 cases between 2006–2011.
      ]. In our patient it was impossible to perform coronary angiography due to her severe ARDS thus it could be argued that she may have had Takotsubo cardiomyopathy. Interestingly acute infections were not mentioned as a cause of PAMI [
      • Elkayam U.
      • Jalnapurkar S.
      • Barakkat M.N.
      • Khatri N.
      • Kealey A.J.
      • Mehra A.
      • et al.
      Pregnancy-associated acute myocardial infarction a review of contemporary experience in 150 cases between 2006–2011.
      ].
      Arterial thrombosis has been associated with increased levels of von Willebrand factor which is also increased during advanced pregnancy [
      • Reininger A.J.
      Function of von Willebrand factor in hemostasis and thrombosis.
      ]. It may be speculated that bleeding in the lungs as identified in autopsy studies may have contributed to the activation of the von Willebrand factor thus predisposing for developing arterial thrombosis.
      Our two male patients with DVT were in their initial treatment cycles for hematological malignancy. Patients with lymphoma are at a higher risk for developing VTE during the initial cycles of treatment than during later cycles [
      • Zhou X.
      • Teegala S.
      • Huen A.
      • Ji Y.
      • Fayad L.
      • Hagemeister F.B.
      • et al.
      Incidence and risk factors of venous thrombo-embolic events in lymphoma.
      ].
      It is common practice to administer DVT prophylaxis to ICU patients with severe illness although the risk of administering DVT prophylaxis should be weighed against the risk of bleeding [
      • Kahn S.R.
      • Lim W.
      • Dunn A.S.
      • Cushman M.
      • Debtali F.
      • Akl E.A.
      • et al.
      Prevention of VTE in non-surgical patients. Antithrombotic therapy and prevention of thrombosis, 9th edition: American College of Chest Physicians Evidence-based clinical practice guideline.
      ].
      A peculiar propensity for thrombotic events has been reported for cytomegalo virus (CMV) infection; nine Israeli immune-competent patients with CMV associated thrombotic events, two of whom were arterial thrombosis (spleen and liver) [
      • Friedlander Z.G.
      • Khamaisi M.
      • Leitersdorf E.
      Association between cytomegalovirus infection and venous thrombosis.
      ]. The pathogenic mechanisms are unknown but among a number of mechanisms suggested that an increased level of von Willebrand factor was seen with higher levels of CMV titers in plasma [
      • Kahn S.R.
      • Lim W.
      • Dunn A.S.
      • Cushman M.
      • Debtali F.
      • Akl E.A.
      • et al.
      Prevention of VTE in non-surgical patients. Antithrombotic therapy and prevention of thrombosis, 9th edition: American College of Chest Physicians Evidence-based clinical practice guideline.
      ]. It was noted that simultaneously with CMV infection IgM anticardiolipin antibodies appeared leading to acquired anti-phospholipid syndrome [
      • Friedlander Z.G.
      • Khamaisi M.
      • Leitersdorf E.
      Association between cytomegalovirus infection and venous thrombosis.
      ]. Our patient with CVA did have increased levels of IgG anticardiolipin that disappeared four months later.
      Since the 2009/2010 pandemic there have been sporadic patients with H1N1 illness as well as other viral illnesses, but during the last few years patients with influenza like illness admitted have not presented with very severe hypoxemic respiratory failure that we saw during the pandemic. Public health predictions foresee that it is only a matter of time before the next pandemic arrives.
      In conclusion: we report on five patients (25%) with severe influenza H1N1 that developed clinically significant VTE events among 20 patients admitted to MICU during four months of the influenza A/H1N1 pandemic 2009, this included three of the five pregnant women (60%). Forty percent of the VTE were surprising arterial thrombosis with an extensive CVA and an acute myocardial infarction, the latter pregnant woman is deceased. All patients had additional hypercoagulability states: pregnancy and under initial chemotherapy for hematological malignancies that definitely rendered our patients prone for thrombotic events. The arterial thrombotic events were surprising and unusual in such young patients. We recommend that patients with severe influenza A/H1N1 pneumonitis and respiratory failure be administered DVT prophylaxis in particular if there are additional risk factors for TVE. Further prospective studies on the relationship of influenza A/H1N1 and VTE are needed.

      Conflict of interests

      The authors have no conflicts of interest to report and they have not been paid for the work submitted.

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