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The Pathophysiology of Paroxysmal
Nocturnal Haemoglobinuria

Richard John Kelly

Submitted in accordance with the requirements for the degree of Doctor of Philosophy

The University of Leeds
School of Medicine
January 2014

1

Jointly-Authored Publications

The candidate confirms that the work submitted is his own, except where work which has formed part of jointly authored publications has been included. The contribution of the candidate and the other authors to this work has been explicitly indicated below. The candidate confirms that appropriate credit has been given within the thesis where reference has been made to the work of others.

The work in Chapter 3 of the thesis has appeared in publication as follows: Kelly RJ, Hill A, Arnold LM, Brooksbank GL, Richards SJ, Cullen M, Mitchell LD, Cohen DR, Gregory WM, Hillmen P. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood 2011;117:6786-6792.

I was responsible for designing the study, collecting and analysing the data and writing the paper. Dena Cohen and Walter Gregory performed the statistical analysis. All the other authors reviewed the paper.

The work in Chapter 4 of the thesis has appeared in publication as follows: Kelly R, Arnold L, Richards S, Hill A, Bomken C, Hanley J, Loughney A, Beauchamp J, Khursigara G, Rother RP, Chalmers E, Fyfe A, Fitzsimons E, Nakamura R, Gaya A, Risitano AM, Schubert J, Norfolk D, Simpson N, Hillmen P. The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab. Br J

Haematol 2010;149:446-450.

I was responsible for designing the study, collecting and analysing the data and writing the paper. All the other authors reviewed the paper.

This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement.

2

Abstract

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, life-threatening condition caused by an expansion of a clone of haemopoietic stem cells (HSC) harboring a somatic mutation of the PIG-A gene. PNH blood cells are deficient in glycophosphatidylinositollinked (GPI) proteins rendering PNH erythrocytes susceptible to complement attack which leads to intravascular haemolysis and an increased tendency to develop thromboses. The survival of 79 consecutive patients treated with eculizumab was compared to both age and sex matched normal controls and to 30 similar patients managed in the era immediately prior to anti-complement therapy. The survival of those treated with eculizumab was no different that of the control group and was significantly better than the group with PNH that did not receive eculizumab (p=0.3). Transfusion requirements and documented thromboses were reduced with eculizumab. Sixty-six percent of transfusion dependent patients became transfusion independent and thrombotic events reduced from 5.6 to 0.8 events per 100 years. Eleven women were monitored through 15 pregnancies whilst on eculizumab. There was 1 first trimester miscarriage and 15 healthy babies born. There were no maternal deaths observed and no thrombotic events occurred in the pregnancy or the postpartum period. Eculizumab did not appear to cross the placenta or be expressed in breast milk. Thirty-five patients were evaluated for PIG-M mutations to see if this mutation was prevalent in PNH. No PIG-M promoter mutations were identified. Two genes were evaluated to see if secondary mutations affecting them could account for clonal expansion in PNH. Thirty-six patients underwent JAK2 V617F mutation analysis with 1 patient shown to have a JAK2 mutation. Forty-two patients were evaluated for increased HMGA2 levels by 2 different PCR methods. There was an overall reduction in HMGA2 expression in PNH patients as compared to normal controls. An in vitro model of the bone marrow in PNH was developed and 18 PNH bone marrow samples were evaluated using this model. Colony forming assays (CFA) showed an increase in colony formation when T-cells were removed from the PNH bone marrow samples. This improvement was reversed when the T-cells were added back to the experiments. This work supports an immune mechanism for the expansion of the PNH clone.

3

Contents

Jointly Authored Publications Abstract
23

  • Contents
  • 4

List of Figures List of Tables
914 15 17 18
Publications Resulting from this Work Acknowledgements Abbreviations

  • 1.
  • Introduction
  • 20

22 22 25 28 28 29 31 31 32 33 33 35

  • 1.1.
  • Identifying the Genetic Defect

1.1.1 Disruption of the Glycophosphatidylinositol Anchor 1.1.2 Haemolysis in PNH

  • 1.2
  • Diagnosis

1.2.1 Historical Background 1.2.2 Current Techniques for Diagnosis

  • A Classification of PNH
  • 1.3

1.4 1.5
The Relative Incidence of Molecular and Symptomatic PNH Clinical Features of PNH 1.5.1 The Consequences of Haemolysis 1.5.2 Thrombosis 1.5.3 Renal Dysfunction

4
1.5.4 Pulmonary Hypertension 1.5.5 Quality of Life
35 36 36 37 37 37 38 39 40 42 42 43 45 48 48
1.5.6 Pregnancy
1.6

1.7
Mortality and Treatment Prior to Anti-complement Therapy 1.6.1 General Measures 1.6.2 Anticoagulation 1.6.3 Allogeneic Bone Marrow Transplantation The Complement System 1.7.1 Targeting Complement 1.7.2 Anti-Complement Strategies in PNH 1.7.3 CD59 Replacement 1.7.4 Eculizumab 1.7.5 Eculizumab Clinical Studies in PNH

  • Pathogenesis
  • 1.8

1.9
1.8.1 Bone Marrow Failure 1.8.2 Mutations in Normal Individuals, Other Conditions and in the Context of

  • Antibody Therapy
  • 49

51 51 51 52 53
Clonal Expansion 1.9.1 Multiple Clones and Clonal Dominance 1.9.2 Hypotheses of Clonal Expansion 1.9.3 Animal Models of PNH 1.9.4 Potential Mechanisms Mediating HSC Destruction 1.9.5 Humoral Antibody Dependent Cell Mediated Cytotoxicity (ADCC) and

  • Complement
  • 54

54 56 57 58
1.9.6 Cell Mediated Immunity and Natural Killer (NK) cells 1.9.7 The Wilms Tumour Gene 1.9.8 Secondary Genetic Mutations – HMGA2 1.9.9 Apoptosis
1.10 Haematopoietic Stem Cell Immunophenotype and Long Term Bone Marrow

  • Culture (LTBMC) Studies
  • 59

59 59
1.10.1 Early Progenitor Cells 1.10.2 Long Term Bone Marrow Cultures in PNH and AA

5

  • 2
  • Materials and Methods
  • 61

63 63 63 64 64 64 65 65 66 66 69 69 69 70 70 70 71 72 73 73 75 75 76 76 77 78 78

  • 2.1
  • Patients

2.1.1 Patients Treated with Eculizumab 2.1.2 Patients Treated during Pregnancy Evaluation of HMGA2 in PNH Patients and Normal Subjects 2.2.1 Patient and Control Groups
2.2
2.2.2 Red Cell Lysis 2.2.3 RNA Extraction 2.2.4 DNase Treatment 2.2.5 cDNA Synthesis 2.2.6 Quantitative PCR 2.2.7 Conventional PCR Reactions 2.2.8 Agarose Gel Electrophoresis 2.2.9 CD15 Positive Selection
2.3

2.4
Evaluation of Prevalence of PIG-M Promoter Site and JAK2 Mutations 2.3.1 Patient Cohort 2.3.2 Genomic DNA Extraction 2.3.3 Val617Phe JAK2 Point Mutation Analysis 2.3.4 PIG-M Promoter Mutation Analysis Long Term Bone Marrow Cultures 2.4.1 Flow Cytometry Analysis of Bone Marrow 2.4.2 Isolation of Bone Marrow Mononuclear Cells 2.4.3 Isolation of Bone Marrow CD34+ Cells 2.4.4 T-cell Depletion of CD15+ Bone Marrow Mononuclear Cells 2.4.5 Isolation of T-cells from Bone Marrow Mononuclear Cells 2.4.6 Maintaining Long Term Cultures 2.4.7 Colony Forming Assays 2.4.8 Colony Analysis

  • 3
  • Long-Term Follow Up of Patients with PNH

Introduction

79

81 81
3.1

  • 3.2
  • Additional Patient Information

6
3.3 3.4 3.5 3.6

  • Eculizumab Therapy
  • 82

  • Statistical Analysis
  • 83

  • Individual Patient Data
  • 84

Patient Data at Diagnosis and Prior to Starting Eculizumab 3.6.1 Sex
109 109 110 111 111 112 112 113 113 117 117 117 117 117 122 123 124 124 124 124 127
3.6.2 Age 3.6.3 Symptoms at Diagnosis 3.6.4 Cytopenias in PNH 3.6.5 Haemolysis as a Complication of PNH 3.6.6 Thrombosis as a Complication of PNH Patient Data at the Start of Eculizumab Treatment 3.7.1 Laboratory Findings 3.7.2 Clone Evaluation
3.7 3.8
3.7.3 Other Laboratory Tests Patient Data on Eculizumab Treatment 3.8.1 Complications of PNH
3.8.1.1 Intravascular Haemolysis 3.8.1.2 Thrombosis 3.8.1.3 Clone Evolution
3.8.2 Effects of Eculizumab
3.8.2.1 Platelets 3.8.2.2 Meningococcal Infection 3.8.2.3 Survival

  • 3.9
  • Discussion

  • 4
  • Management of Patients During Pregnancy

Introduction

132

133 133 133 138 141 142
4.1 4.2 4.3 4.4 4.5 4.6
Additional Patient Information Individual Patient Data Complications during Pregnancy Delivery and the Postpartum Period Discussion

7

  • 5
  • PIG-M Mutations and Secondary Genetic Events

Rationale

143

144 145 145 146 150 152 156 157
5.1

  • 5.2
  • PIG-M Promoter Mutations

5.2.1 PCR Amplification of the SP1 Binding Site 5.2.2 SAPEX Purification and Sequencing

  • JAK2 Mutation Analysis
  • 5.3

5.4 5.5 5.6

HMGA2 Expression

Further Assessment of HMGA2 Expression using TaqMan Assay Discussion

  • 6
  • In Vitro Culture Experiments Involving PNH Stem Cells

Rationale

160

161 161 169 174 175 179 179 187 188 193
6.1 6.2 6.3 6.4 6.5 6.6
Normal Control Samples Initial LTBMC Findings with PNH Samples Difficulties with Stromal Layer Minimisation Experiments Extraction of T-cells from Bone Marrow MNCs 6.61 T-Cell Removal before MNCs Are Added to the Culture Model 6.62 T-Cell Removal Immediately Prior to the CFAs

  • Add-Back Experiments
  • 6.7

  • 6.8
  • Discussion

  • 7
  • General Discussion
  • 197

198 199 201 203
7.1 7.2 7.3 7.4
Clinical Overview of PNH Complement and Future Therapies Disease Pathogenesis - Secondary Genetic Events Disease Pathogenesis – Escape of the Immune Attack

  • References
  • 205

8

List of Figures

Figure 1.1 GPI biosynthesis in the endoplasmic reticulum Figure 1.2 Terminal complement activation causing cell lysis
25 27
Figure 1.3 FACS plot of erythrocytes in a PNH patient. Type I express CD59 normally, Type II have a reduced expression and Type III have no CD59 expression 28 Figure 1.4 FACS plot depicting a large granulocyte PNH clone of 98.2% (Q3) identified using FLAER and CD16 (GPI linked protein) and using these markers the population of PNH and normal granulocytes can easily be identified Figure 1.5 The complement cascade adapted from Kelly et al, 2007 Figure 1.6 Structure of the monoclonal antibody eculizumab Figure 1.7 Action of eculizumab
30 39 44 45
Figure 1.8 A representation of the two hit hypothesis leading to expansion of PNH stem

  • cells
  • 53

  • Figure 3.1 The age at diagnosis of 79 patients
  • 110

Figure 3.2 Symptoms experienced by 79 PNH patients at the time the disease was

  • diagnosed
  • 111

  • 113
  • Figure 3.3 Sites of thrombosis experienced

Figure 3.4 LDH levels taken both at the start of eculizumab treatment and at the most recent clinical review 121 Figure 3.5 Blood transfusion requirements in the 12 months before eculizumab therapy and the most recent 12 months on eculizumab treatment in 61 patients 122 Figure 3.6 Overall survival of the 79 patients from initiation of eculizumab treatment compared to age- and sex-matched controls 125 Figure 3.7 Overall survival of the 79 patients from initiation of eculizumab treatment

  • according to age
  • 126

  • 127
  • Figure 3.8 Overall survival of patients before and after eculizumab

Figure 5.1 Diagrammatic representation showing the positions of the forward and reverse

  • primers used to sequence the SP1 site in the PIG-M promoter
  • 145

9

Figure 5.2 Agarose gel electrophoresis showing an example of PCR products obtained prior to sequencing. Lane 1 is a negative control, 2-6 are patient samples (U.P.N. 6,7,10,11,16) and lane 7 is a 100 base pair ladder (New England Biolabs) Figure 5.3 Sequencing read out showing an example of the nucleotides of the PIG-M promoter region 148 Figure 5.4 Closer view of the sequencing read out of each nucleotide around -270 in the PIG-M promoter region 148 Figure 5.5 Sequence readout of the PIG-M promoter region with the forward and reverse
146

  • sequences from a patient alongside
  • 149

  • 151
  • Figure 5.6 V617F JAK2 mutation analysis of PNH patients

Figure 5.7 HMGA2 expression in PNH patients compared to the median of the normal control group 154 Figure 5.8 Level of HMGA2 expression in those with and without CD15 positive selection 155 Figure 6.1 Variations in M210B4 stromal cell concentrations and their effect on the quantity of progenitor cells 163 Figure 6.2 Flow cytometry of MNCs from a normal bone marrow sample. (A) Cells evaluated using forward and side scatter. (B) CD34+ cells selected in gate P2 and shown in green. (C) Further gating (P3, blue) of CD34+ selected cells using CD45 and side

  • scatter. (D) Expression of FLAER on CD34+ cells
  • 164

Figure 6.3 Flow cytometry of CD34+ selected cells from a normal bone marrow sample. (A) Cells evaluated using forward and side scatter. (B) CD34+ cells selected in gate P2 and shown in green. (C) Further gating (P3, blue) of CD34+ selected cells using CD45

  • and side scatter. (D) Expression of FLAER on CD34+ cells
  • 165

Figure 6.4 Light microscopy (magnification x 40) of stromal layer showing haemopoietic

  • cells clustered under the stromal layer
  • 166

  • 167
  • Figure 6.5 Light microscopy (magnification x 40) view of a CFU-GM colony

Figure 6.6 Mean number of cells from the supernant of the control group using MNCs and CD34+ selected cells 167 Figure 6.7 Mean number of colonies formed in the CFAs from the cells in the supernant

  • of the LTBMCs of the control group using MNCs and CD34+ selected cells
  • 168

10

Figure 6.8 Flow cytometry of MNCs from a PNH bone marrow sample (U.P.N. 24). (A) Cells evaluated using forward and side scatter. (B) CD34+ cells selected in gate P2 (green). (C and D) Further gating (P3, blue and P4, red) of CD34+ selected cells using CD45 (red), forward and side scatter (blue). (E) Expression of FLAER on CD34+ cells

  • (97.8% GPI deficient)
  • 170

Figure 6.9 Flow cytometry of CD34+ selected cells from a PNH bone marrow sample (U.P.N. 24). (A) Cells evaluated using forward and side scatter. (B) CD34+ cells selected in gate P2 (green). (C) Further gating (P3, blue and P4, red) of CD34+ selected cells using CD45 (red, not shown), forward and side scatter (blue). (E) Expression of FLAER on CD34+ cells (97.8% GPI deficient) Figure 6.10 Mean number of cells from the supernant of both the control and PNH samples using MNCs and CD34+ selected cells 172
171
Figure 6.11 Number of colonies formed in the CFAs from the cells in the supernant of the LTBMCs of the initial PNH samples using MNCs compared to the mean number of colonies from the PNH CD34+ selected samples and the MNCs from the control group
173

  • Figure 6.12 Light microscopy (magnification x 5) images of the stromal layer
  • 174

Figure 6.13 Flow cytometry from a control bone marrow sample used in the minimisation experiments. (A) Unmanipulated bone marrow (CD34+ proportion 0.9% in red). (B)

  • MNCs (CD34+ proportion 2.2% in red)
  • 175

Figure 6.14 Mean number of cells from the supernant of the control group using MNCs
176
Figure 6.15 Mean number of colonies formed in the CFAs from the cells in the supernant

  • of the LTBMCs of the control group using MNCs
  • 176

Figure 6.16 The number of cells from the supernant of a control group sample using different amounts of input MNCs and different volumes of MyelocultTM H5100 media
177
Figure 6.17 The number of colonies formed in the CFAs from the cells in the supernant of a control group sample using different amounts of input MNCs and different volumes

  • of MyelocultTM H5100 media
  • 178

Figure 6.18 Flow cytometry of MNCs from a PNH bone marrow sample (U.P.N. 74). (A) P1 gating (red) of the CD34+ cells (1.5% of MNCs). (B) Further gating (P2, blue) of cells

11

using forward and side scatter. (C) Gating of CD3+ cells (P3, green, 60.3% of MNCs). (D) Expression of FLAER on CD34+ CD38+ cells (80.6% GPI deficient) 179 Figure 6.19 Flow cytometry of MNCs from a PNH bone marrow sample (U.P.N. 74) with T-cells removed using anti-CD3 MicroBeads. (A) P1 gating (red) of the CD34+ cells (2.9% of MNCs). (B) Further gating (P2, blue) of cells using forward and side scatter. (C) Gating of CD3+ cells (P3, green, 5.4% of MNCs). (D) Expression of FLAER on CD34+

  • CD38+ cells (97.3% GPI deficient)
  • 180

Figure 6.20 Flow cytometry of MNCs from a PNH bone marrow sample prior to T-cell removal (U.P.N. 19). (A) P1 gating (red) of the CD34+ cells (1.4% of MNCs). (B) Further gating (P2, blue) of cells using forward and side scatter. (C) Gating of CD3+ cells (P3, green, 35% of MNCs). (D) Expression of FLAER on CD34+ CD38+ cells (77.1%

  • GPI deficient)
  • 181

Figure 6.21 Flow cytometry of MNCs from a PNH bone marrow sample (U.P.N. 19) with T-cells removed using CD15 selection followed by CD3 depletion. (A) P1 gating (red) of the CD34+ cells (1.6% of MNCs). (B) Further gating (P2, blue) of cells using forward and side scatter. (C) Gating of CD3+ cells (P3, green, 0.1% of MNCs). (D) Expression of

  • FLAER on CD34+ CD38+ cells (73.4% GPI deficient)
  • 182

Figure 6.22 Mean number of cells from the supernant of MNCs from the control group, MNCs, T-cell depleted MNCs and T-cell depleted MNCs with the T-cells added back to

  • them from PNH samples
  • 183

Figure 6.23 Number of colonies formed in the CFAs from the control group, MNCs, T- cell depleted MNCs and T-cell depleted MNCs with the T-cells added back to them from

  • PNH samples
  • 184

Figure 6.24 Flow cytometry of colonies formed from a PNH sample (U.P.N. 32). (A and B) PNH MNCs at week 1 and 2, respectively. (C, D, E and F) T-cell depleted PNH

  • MNCs at weeks 1-4, respectively
  • 185

Figure 6.25 Flow cytometry of colonies formed from a PNH sample (U.P.N. 55). (A and B) PNH MNCs at week 1 and 2, respectively. (C, D and E) T-cell depleted PNH MNCs

  • at weeks 1-3, respectively
  • 186

Figure 6.26 T-cell removal in a normal bone marrow MNC sample prior to the CFA, showing the proportion of CD45+ and CD3+ input cells after 1 week (A and B) and 2

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    Iga Nephropathy in Hereditary Angioedema Jayashri Srinivasan and Peter Beck Department Ofmedicine, Llandough Hospital, Penarth, South Glanorgan CF6 IXX, UK

    Postgrad Med J: first published as 10.1136/pgmj.69.808.95 on 1 February 1993. Downloaded from Postgrad Med J (1993) 69, 95 - 99 ©) The Fellowship of Postgraduate Medicine, 1993 IgA nephropathy in hereditary angioedema Jayashri Srinivasan and Peter Beck Department ofMedicine, Llandough Hospital, Penarth, South Glanorgan CF6 IXX, UK Summary: Hereditary angioedema is an autosomal dominant disorder of the complement system in which there is a deficiency of the inhibitor of the activated first component of complement. We have previously reported on three generations of a family with classic hereditary angioedema. Three members of this family have now developed IgA nephropathy. The association of hereditary angioedema with various immunoregulatory disorders has been previously reported but this is the first report of IgA nephropathy in association with this condition. Introduction Hereditary angioedema is an inherited disorder in report, case 1 appears at IV.2, case 2 at III.2, and which there is a quantitative or functional cases 3 and 4 at IV.3 and IV.4, respectively. deficiency of the inhibitor of the activated first Following the presentation of case 1 with component of complement, Cl inhibitor (Cl- painless haematuria in 1989, and the discovery that INH). It is characterized by recurrent attacks of this was due to IgA nephropathy, we decided to non-pitting oedema of the extremities, face, larynx review the other members of the family for and abdomen including the bowel mucosa. An haematuria and to check their renal function. copyright. association of hereditary angioedema with various immunoregulatory disorders including systemic lupus erythematosus, lupus-like disease, Sj6gren's Case reports syndrome, autoimmune thyroid disease, inflam- matory bowel disorder,' IgA deficiency,2 mesan- Case I giocapillary glomerulonephritis3 and coronary arteritis4 has been described.
  • C1 Esterase Inhibitor Deficiency, Airway Compromise, And

    C1 Esterase Inhibitor Deficiency, Airway Compromise, And

    C1 Inhibitor Deficiency and Anesthesia Niels F. Jensen, M.D. 1 John M. Weiler, M.D. 2 1. Assistant Professor, Department of Anesthesia, University of Iowa, and Iowa City VA Medical Center, Iowa City, Iowa 2. Professor, Department of Internal Medicine, University of Iowa, and Iowa City VA Medical Center, Iowa City, Iowa Address correspondence to Dr. Jensen, Department of Anesthesia, University of Iowa College of Medicine, Iowa City, Iowa 52242. (319) 356-2633 FAX 319-356-2940 1 Outline I. Introduction II. Pathophysiology III. Types and diagnosis IV. Natural history, manifestations, clinical presentation V. Airway involvement VI. Management of C1 INH deficiency A. Drug therapy: Anabolic steroids, EACA, FFP, C1 INH concentrate B. Chronic prophylaxis C. Prophylaxis before elective surgical procedures D. Prophylaxis before emergency procedures E. Treatment of acute attacks F. New and experimental therapies G. Special anesthetic considerations VII. Summary 2 Key Words: Angioedema Complement C1 INH C1 inhibitor C1 esterase Hereditary angioedema (HAE) Hereditary angioneurotic edema (HANE) SERPIN 3 I. Introduction Hereditary angioedema (HAE) is a condition that is characterized by episodic and sometimes lifethreatening airway edema. HAE represents one of the most serious genetic 1 abnormalities involving the complement system. In 1882, Heinrich I. Quincke published the first detailed description and three years later Strubing used the term “angioedema” to describe this disorder for the first time. By 1888 Osler demonstrated the hereditary nature of the clinical presentation. 2 The pathophysiologic basis of HAE, deficiency of C1 esterase inhibitor which is also called C1 inhibitor (C1 INH), was postulated in the early 1960s. 3, 4 In 1972, an aquired form of C1 INH deficiency was first reported.
  • Diagnostic Cost Group Hierarchical Condition Category Models for Medicare Risk Adjustment Final Report

    Diagnostic Cost Group Hierarchical Condition Category Models for Medicare Risk Adjustment Final Report

    Diagnostic Cost Group Hierarchical Condition Category Models for Medicare Risk Adjustment Final Report Submitted by: Gregory C. Pope, M.S.1 Randall P. Ellis, Ph.D.2 Arlene S. Ash, Ph.D.3 John Z. Ayanian, M.D., M.P.P.4 David W. Bates, M.D., M.Sc.5 Helen Burstin, M.D., M.P.H.6 Lisa I. Iezzoni, M.D., M.Sc.7 Edward Marcantonio, M.D., S.M.8 Bei Wu, Ph.D.1 Affiliations: 1Health Economics Research, Inc. Waltham, MA 2Department of Economics, Boston University, Boston, MA 3Health Care Research Unit, Boston University School of Medicine, Boston, MA 4Associate Professor of Medicine and Health Care Policy, Harvard Medical School and Brigham and Women's Hospital 5Chief, Division of General Medicine, Brigham and Women's Hospital, Medical Director of Clinical and Quality Analysis, Partners Healthcare, Associate Professor of Medicine, Harvard Medical School 6Assistant Professor, Harvard Medical School (on leave) 7Professor of Medicine at Harvard Medical School and Co-Director of Research, Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center 8Assistant Professor of Medicine, Harvard Medical School, Director of Quality and Outcomes Research, Hebrew Rehabilitation Center for Aged Prepared for: Health Care Financing Administration December 21, 2000 This report is submitted under Contract No. 500-95-048, with the Health Care Financing Administration. The views and opinions expressed in this report are the authors�; no endorsement by HCFA is intended or should be inferred. The contractor assumes responsibility for the accuracy and completeness of information in this report. The authors thank Melvin J.
  • Angioedema, ACE Inhibitor and COVID-19 Ekjot Grewal ‍ ‍ ,1 Bayu Sutarjono,1,2 Ibbad Mohammed1

    Angioedema, ACE Inhibitor and COVID-19 Ekjot Grewal ‍ ‍ ,1 Bayu Sutarjono,1,2 Ibbad Mohammed1

    Findings that shed new light on the possible pathogenesis of a disease or an adverse effect BMJ Case Rep: first published as 10.1136/bcr-2020-237888 on 9 September 2020. Downloaded from Case report Angioedema, ACE inhibitor and COVID-19 Ekjot Grewal ,1 Bayu Sutarjono,1,2 Ibbad Mohammed1 1Department of Emergency SUMMARY benazepril, approximately 4 months ago. He had Medicine, Brookdale University SARS-CoV -2, the virus responsible for COVID-19, binds to no personal or family history of facial or tongue Hospital Medical Center, the ACE2 receptors. ACE2 is thought to counterbalance swelling. Brooklyn, New York, USA ACE in the renin- angiotensin system. While presently 2Saba University School it is advised that patients should continue to use ACE of Medicine, Devens, INVESTIGATIONS Massachusetts, USA inhibitors or angiotensin receptor blockers, questions still remain as to whether adverse effects are potentiated by On examination, the patient was afebrile and normotensive, with an oxygen saturation of 96% on Correspondence to the virus. Here, we report a case of a 57-year -old man, Bayu Sutarjono; unknowingly with COVID-19, who presented to the room air. There was pronounced oedema involving b. sutarjono@ saba. edu emergency department with tongue swelling, shortness the lingual mucosa and subcutaneous tissues of the of breath and difficulty in speaking following 4 months perioral area without pain or pruritus. Cardiac Accepted 25 August 2020 taking benazepril, an ACE inhibitor. Finally, we also auscultation revealed tachycardia without any describe possible pathways that exist for SARS-CoV -2 to pathological murmurs. Auscultation of the lungs interact with the mechanism behind angioedema.
  • Angioedema in the Emergency Department and Reviews the New Higher Level of Care

    Angioedema in the Emergency Department and Reviews the New Higher Level of Care

    November 2012 Angioedema In The Volume 14, Number 11 Emergency Department: Author R. Gentry Wilkerson, MD, FACEP, FAAEM Assistant Professor, Coordinator for Research, Department of An Evidence-Based Review Emergency Medicine, University of Maryland School of Medicine, Baltimore, MD Abstract Peer Reviewers Alex Manini, MD, MS Assistant Professor of Emergency Medicine, Mount Sinai School of Angioedema is the end result of a variety of pathophysiological Medicine, New York, NY processes resulting in transient, localized, nonpitting swelling James Scott, MD Professor of Emergency Medicine and Health Policy, The George of the subcutaneous layer of the skin or submucosal layer of the Washington University of Medicine and Health Sciences, Washington, DC respiratory or gastrointestinal tracts. It is now generally accepted that the swelling is mediated by either histamine or bradykinin. CME Objectives Angioedema may result in severe upper airway compromise Upon completion of this article, you should be able to: 1. Discuss the various types of angioedema and the mechanism by or—less commonly recognized—compromise in the gastrointes- which the swelling occurs. tinal tract often associated with severe abdominal pain. A variety 2. Describe an appropriate workup of a patient with undifferentiated of new therapeutic options are becoming available for use in the angioedema. United States that have the potential to greatly impact the manage- 3. Determine appropriate therapy for treatment of angioedema and understand the rationale behind each therapeutic option. ment and outcomes for those with severe clinical manifestations. 4. Discuss appropriate disposition for these patients with an This review assesses the evidence on the causes and treatments of understanding of which patients are at higher risk of needing a angioedema in the emergency department and reviews the new higher level of care.
  • Diagnosis and Management of Immunodeficiencies in Adults By

    Diagnosis and Management of Immunodeficiencies in Adults By

    GUIDELINES Diagnosis and Management of Immunodefi ciencies in Adults by Allergologists JM García,1 P Gamboa,2 A de la Calle,3 MD Hernández,4 MT Caballero,5 on behalf of the Committee of Immunology of the Spanish Society of Allergology and Clinical Immunology (SEAIC) (BE García, M Labrador, C Lahoz, N Longo Areso, M López Hoyos, J Martínez Quesada, L Mayorga, FJ Monteseirin, ML Sanz) 1Department of Pediatric Allergology and Clinical Immunology, Hospital de Cruces, Baracaldo-Vizcaya, Spain 2Department of Allergology, Hospital de Basurto, Bilbao, Spain 3Department of Allergology, Hospital Virgen Macarena, Sevilla, Spain 4Department of Allergology, Hospital La Fe, Valencia, Spain 5Department of Allergology, University Hospital La Paz, Madrid, Spain ■ Abstract Primary immunodefi ciencies (PIDs) are genetic diseases that cause alterations in the immune response and occur with an increased rate of infection, allergy, autoimmune disorders, and cancer. They affect adults and children, and the diagnostic delay, morbidity, effect on quality of life, and socioeconomic impact are important. Therapy (γ-globulin substitution in most cases) is highly effective. We examine adult PIDs and their clinical presentation and provide a sequential and directed framework for their diagnosis. Finally, we present a brief review of the most important adult PIDs, common variable immunodefi ciency, including diagnosis, pathogenesis, clinical signs, and disease management. Key words: Immunologic defi ciency syndromes. Common variable immunodefi ciency. Adult. Allergologist. ■ Resumen Las inmunodefi ciencias primarias (IDP) son enfermedades genéticas que ocasionan alteraciones en la respuesta inmunológica y que cursan con aumento de infecciones, alergia, autoinmunidad y cáncer. Afectan tanto a adultos como a niños, y el retraso diagnóstico, la morbilidad, la afectación de calidad de vida de los pacientes y el impacto socioeconómico que implican son considerables.