Allergic and immunologic diseases : a

practical guide to the evaluation,

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Allergic and Immunologic Diseases
A Practical Guide to the Evaluation, Diagnosis and Management
of Allergic and Immunologic Diseases
Allergic and
Immunologic Diseases
A Practical Guide to the Evaluation,
Diagnosis and Management of Allergic and
Immunologic Diseases

Edited by

Christopher Chang
Division of Pediatric Immunology, Allergy and Rheumatology,
Joe DiMaggio Children‘s Hospital, Memorial Healthcare System,
Hollywood, FL, United States; Division of Rheumatology, Allergy and
Clinical Immunology, University of California Davis School of Medicine,
Davis, CA, United States
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SET ISBN: 978-0-323-95061-9
Volume 1 ISBN: 978-0-12-820603-4
Volume 2 ISBN: 978-0-323-95322-1

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 Dedication

Dedicated to Laura, Francesca, Santiago, Michael,

Jennifer and the memory of my father, who passed away
during the COVID-19 pandemic
Contents

List of contributors xliii

Preface li

Volume 1
Section A
Background
1. Introduction 3
Christopher Chang
The origin of allergy and immunology as a specialty 4
The role of allergy and immunology in the world of medicine 5
The allergy and immunology workforce in the United States 6
Training of allergy and immunology specialists 8
Professional organizations 9
Allergy and immunology journals 9
Summary 16
References 16

2. A brief history of allergy and immunology 17

Kranthi Nomula, Kyndra Liburd, Xiang Ge, JinLyu Sun and
Christopher Chang
Introduction 18
An early history of immunology 18
The age of vaccines 18
Discovery of cellular and humoral components of immunity 19
Complement 21
Allergic diseases and early descriptions and treatment of
“hay fever” and food allergy 22
Blood typing, transfusions, and plasma proteins 23
Early studies on transplantation 25
A modern history of allergy and immunology 25
Molecular immunology and the biotechnology revolution 26

vii
viii Contents

Immortal cells and the ability to produce monoclonal antibodies 28

The 21st century—a brave new world 28
Checkpoint inhibitors and the modern treatment of cancer 39
COVID-19 39
Conclusion 40
References 41

3. Basic immunology 43
Christopher Chang
Introduction 44
Primary and secondary lymphoid organs 45
Innate and adaptive immunity 45
Characteristics and attributes of the human immune system 46
Rapidity of response 46
Diversity of response 46
Specificity of the response 49
Strength (amplification) of the response 49
Regulation of the response 50
Immunological concepts 51
Autoimmunity and immune tolerance 51
Protein phosphorylation 52
The ability to recall—immunological memory 53
Apoptosis and autophagy 53
Immunosenescence 54
Epigenetics 55
Immune paradigms 55
T helper cell paradigms 55
Th17 Treg paradigm 56
Stromal immunology 56
Cellular immunity—cells of the immune system 57
Granulocytes 57
Mononuclear cells 59
Lymphocytes 59
Natural killer cells 65
Monocytes and macrophages 65
Ontogeny of immune cells and antibodies 66
T cell dependent and T cell independent antigens 66
Humoral immunity—immunoglobulins and other molecules 67
Antigen recognition 67
Cytokines 72
Chemokines 72
Growth factors 78
Complement 78
Computational immunology 86
Summary and conclusions 86
References 86
 Contents ix

4. The allergy and immunology history and physical 89

Hanadys Ale, Marlen Rodriguez and Wilfredo Cosme-Blanco
Introduction 90
The allergy and immunology chief complaint and its relevance 91
The main elements of history taking 91
The history of the present illness 92
The past medical history 92
Family history 92
Environmental history 92
Social history 93
Review of systems 93
Essentials of the clinical history and physical exam approach
in a patient with ocular complaints 94
Clinical history 94
Physical exam 96
Essentials of the clinical history and physical exam approach
in a patient with upper respiratory complaints 98
Clinical history 98
Physical examination 99
Essentials of the clinical history and physical exam approach
in a patient with lower respiratory complaints 101
Clinical history 101
Physical exam 101
Essentials of the clinical history and physical exam approach
in a patient with skin complaints 102
Clinical history 102
Physical exam 104
Essentials of the clinical history and physical exam approach
in a patient with gastrointestinal complaints 105
Clinical history 105
Physical exam 106
Essentials of the clinical history and physical exam approach
in a patient with recurrent infections 109
Clinical history 109
Physical exam 110
Conclusions 111
Acknowledgments 111
References 117

5. Basic genetics and epigenetics for the immunologist

and allergist 119
Meng Chen, Stéphanie Lejeune, Xiaoying Zhou and Kari Nadeau
Introduction 120
The human genome and the genetic code 120
Epigenetic modifications 121
x Contents

Types of genetic studies 121

Gene environment interactions 125
Ongoing research and future areas of research 127
Diagnostic tools 127
Genetic and epigenetic basis of allergic disease 127
Atopic dermatitis 127
Asthma 131
Allergic rhinitis 132
Food allergy 132
Drug allergy 133
Genetic and epigenetic basis of immunologic diseases 134
Primary immunodeficiency 134
Hereditary angioedema 135
Applications of genetics and epigenetics 135
Understanding endotypes 135
Predicting who will be affected 136
Predicting response to treatment 136
Challenges and limitations of genetic testing 138
Interpretation 138
Cost 138
Accessibility 138
Ethical considerations 138
Conclusions 139
References 139

6. Laboratory skills for immunologists: utility and

limitations with emphasis on allergy research 145
Rasika Patkar, Christine Y.Y. Wai, Nicki Y.H. Leung, Iris Nkamba,
Shang An Shu and Patrick S.C. Leung
Abbreviations 146
Introduction 148
Section 1: Western blotting 150
Overview 150
Preparation and procedure 150
Data analysis 152
Applications 152
Section 2: Enzyme-linked immunosorbent assay 154
Overview 154
Preparation and procedure 154
Data analysis 157
Applications 157
Section 3: Flow cytometry 158
Overview 158
Preparation and procedure 158
Data analysis 161
Applications 163
 Contents xi

Section 4: Basophil activation test 165

Overview 165
Preparation and procedure 165
Data analysis 167
Applications 168
Section 5: Microarray 169
Overview 169
Preparation and procedure 169
Data analysis 170
Applications 171
Section 6: Animal models 172
Overview 172
Preparation and procedure 172
Data analysis 175
Applications 175
Conclusion 176
Future directions and challenges 176
Western blotting 176
ELISA 177
Flow cytometry 177
BAT 177
Microarray 177
Animal models 179
References 179

7. Developments and emerging technologies in allergic

and immunologic disease management 187
Nicki Y.H. Leung, Christine Y.Y. Wai, Tihong Shao,
Ka Hou Chu and Patrick S.C. Leung
Abbreviations 187
Introduction 189
Section 1: Diagnosis of allergic diseases 190
Component-resolved diagnosis 190
Molecular microarray for the diagnosis of allergic diseases 192
Basophil activation test 193
Section 2: Latest development of allergen-specific immunotherapy 193
Novel routes of AIT 194
Novel adjuvants of AIT 197
Virus-like particles for AIT 198
DNA vaccines for AIT 198
Section 3: Omics in the management of allergic diseases 199
Multiomics approach on severe food-associated respiratory allergy 203
Multiomics approach on reaction severity in peanut allergy 203
Section 4: Artificial intelligence in the management of allergic diseases 204
AI in asthma research 204
AI in food allergy research 205
xii Contents

AI in atopic dermatitis research 206

Section 5: Omics and AI in the management of immunodeficiency
diseases and autoimmune diseases 206
Concluding remarks—implications of novel technologies in
allergy and immunology research and care 210
References 211

8. Genomics technologies and bioinformatics in allergy

and immunology 221
Satishkumar Ranganathan Ganakammal, Ke Huang, Magdalena
Walkiewicz and Sandhya Xirasagar
Introduction 222
Types of genetic diseases and variants 223
High throughput methods 224
Chromosomal microarray 224
Sanger sequencing 225
Next-generation sequencing 225
Application of high-throughput sequencing 232
Research variants 240
Downstream exploratory analysis 240
Data science and big data analytics 245
Importance of scalable infrastructure and data standardization 248
Conclusion 251
Acknowledgment 251
References 251

Section B
Diagnosis of allergic diseases
9. Epicutaneous and intradermal skin testing 263
Divya Seth and Pavadee Poowuttikul
Introduction 264
Mechanism of skin response 265
Indications of skin testing 266
Allergic rhinitis/conjunctivitis 266
Food allergy 266
Drug allergy 266
Insect sting allergy 266
Latex allergy 267
Allergic broncho-pulmonary aspergillosis 267
Factors affecting skin testing 267
Medications 267
Allergen extracts 272
Skin test sites 273
 Contents xiii

Physiological characteristics 273

Number of skin test 275
Selection of allergens 275
Cross-reactivity 277
Methods of skin testing 279
Prick-puncture tests 280
Intradermal tests 287
False-positive and false-negative skin test results 291
The use of skin tests for nondiagnostic purposes 292
Standardization of allergens 292
Immunotherapy studies 293
Pharmacologic studies 293
Epidemiological studies 293
Correlation with other diagnostic tests for diagnosing allergic diseases 293
In vitro tests/serology 293
In vivo tests/allergen challenges 294
Conclusion 295
References 295

10. Skin prick testing for foods 303

Roxanne C. Oriel and Scott H. Sicherer
Introduction 304
Approach to food allergy diagnosis 304
Pathophysiology of immunoglobulin E-mediated food allergy and
rationale for skin prick testing to foods 308
Skin prick testing procedure 311
Skin prick test measurement 314
Skin prick test interpretation 314
Skin prick testing variability 316
Device type variability 316
Quantity of antigen 317
Limitations of skin prick testing 317
Safety 318
Conclusions 318
References 318

11. In vitro methods to assess allergy 323

Nicole Akar-Ghibril and Christopher Chang
Introduction 324
Total IgE levels 325
Allergen-specific IgE 326
In vitro testing for environmental allergens 334
In vitro testing for food allergens 334
In vitro testing for venom allergy 335
In vitro testing for latex 336
xiv Contents

In vitro testing for drugs 337

In vitro testing for occupational protein allergens 337
Tryptase 338
In vitro tests primarily used in research—basophil tests and
eosinophil cationic protein 338
Unvalidated in vitro tests 339
Conclusion 340
References 340

12. Oral food challenges 345

Christopher Chang, Nicole Akar-Ghibril and Kathleen Hathaway
Introduction 346
Epidemiology of food allergies 346
The heterogeneity of adverse food reactions 346
Oral food challenges 349
Selection of the patient for an oral food challenge 349
Setting up the site for conducting oral food challenges 351
Preparing the patient for an oral food challenge 355
Shared decision making 355
Informed consent 356
Oral food challenge procedure 358
Before the challenge 358
The day of the challenge 361
Terminating the challenge 361
Documentation of the challenge results 373
Postchallenge management 373
A “positive” challenge 373
A “negative” challenge 373
Discharge instructions 374
Special populations 374
Oral food challenges in the infant 374
Oral food challenges in the adult patient 375
Specific foods 375
Baked food challenges 375
Variations on oral food challenges 378
Food-dependent exercise-induced anaphylaxis 378
Oral food challenges for food protein induced enterocolitis syndrome 381
Frequently asked questions 383
Conclusions 384
References 384

13. Physical urticarias: diagnosis and testing 389

Karen M. Anstey and Iris M. Otani
Introduction 390
General recommendations for provocation testing 390
 Contents xv

Symptomatic dermographism 391

Characteristics 391
Provocation testing 391
Delayed pressure induced urticaria 392
Characteristics 392
Provocation Testing 393
Cold-contact urticaria 393
Characteristics 393
Provocation testing 394
Heat-contact urticaria 395
Characteristics 395
Provocation testing 395
Solar urticaria 396
Characteristics 396
Testing 396
Vibratory urticaria 396
Characteristics 396
Provocation testing 397
Conclusion 397
Conflict of interest 397
References 397

14. Techniques to evaluate asthma 401

Gerald B. Lee and Katherine L. Tison
Introduction 402
Subjective evaluations 403
Physiologic evaluations 404
Pulmonary function testing 404
Peak flow monitoring 409
Impulse oscillometry 409
Bronchoprovocation with direct and indirect challenge testing 409
Mechanistic evaluations 412
Total and allergen-specific immunoglobulin E 413
Peripheral blood eosinophils 413
Sputum eosinophils 413
Fractional exhaled nitric oxide 413
Periostin 414
T2-low biomarkers 414
Conclusion 416
References 416

15. Drug allergy testing 419

Min J. Lee and Jeffrey M. Chambliss
Introduction 420
Types of adverse drug reactions 420
xvi Contents

Evaluation of immediate drug reactions 421

Skin testing other drug classes 423
Laboratory studies and in vitro testing 431
Direct oral challenge 432
Evaluation of delayed hypersensitivity reactions 433
Discussion/Conclusion 436
References 436

16. Diagnosis and management of rhinitis and

rhinosinusitis 441
Auddie M. Sweis and David W. Kennedy
Introduction 442
Definition 442
Epidemiology 443
Etiology and pathogenesis 443
Clinical presentation 444
Patient demographics/signs and symptoms 444
Diagnostics 445
Typical computed tomography radiographic features 450
Medical management and outcomes 452
Topical therapy 454
Systemic therapy 457
Surgical management and outcomes 459
Conclusion 461
References 462

17. Approach to the rash from an allergy and

immunology perspective 471
Sonam Sani and Luz Fonacier
Introduction 472
Eczematous rashes 473
Atopic dermatitis 473
Introduction 473
Pathophysiology 473
Clinical features 474
Diagnosis 474
Contact dermatitis 474
Introduction 474
Pathophysiology 475
Clinical features 475
Diagnosis 476
Seborrheic dermatitis 476
Introduction 476
Pathophysiology 477
Clinical features 477
 Contents xvii

Diagnosis 478
Nummular eczema 478
Introduction 478
Pathophysiology 478
Clinical features 478
Diagnosis 478
Lichen simplex chronicus/prurigo nodularis 479
Introduction 479
Pathophysiology 479
Clinical features 479
Diagnosis 480
Mycosis fungoides 480
Introduction 480
Pathophysiology 480
Clinical features 480
Diagnosis 481
Urticarial rashes 481
Acute urticaria 481
Chronic urticaria 484
Introduction 484
Pathophysiology 484
Clinical features 485
Diagnosis 485
Physical urticaria 486
Dermatographism 486
Cholinergic 486
Cold induced 487
Aquagenic 487
Solar 487
Vibratory angioedema/urticaria 488
Delayed pressure 488
Urticarial vasculitis 488
Introduction 488
Pathophysiology 489
Clinical features 489
Diagnosis 490
Cutaneous mastocytosis 491
Introduction 491
Pathophysiology 491
Clinical features 491
Diagnosis 492
Papulosquamous disorders 492
Psoriasis 492
Pityriasis rosea 495
Lichen planus 496
Drug eruptions 497
Exanthematous/maculopapular drug eruption 497
xviii Contents

Stevens Johnson syndrome/toxic epidermal necrolysis 498

Introduction 498
Pathophysiology 498
Clinical features 498
Diagnosis 499
Drug reaction with eosinophilia and systemic symptoms 500
Introduction 500
Pathophysiology 500
Clinical features 500
Diagnosis 501
Acute generalized exanthematous pustulosis 501
Introduction 501
Pathophysiology 502
Clinical features 502
Diagnosis 502
Fixed drug eruption 502
Introduction 502
Pathophysiology 503
Clinical features 503
Diagnosis 503
Bullous disorders 503
Bullous pemphigoid 503
Pemphigus vulgaris 505
Introduction 505
Pathophysiology 505
Clinical features 505
Diagnosis 505
Conclusion 505
References 506

18. Patch testing and the evaluation of contact allergy 511

Stephanie L. Mawhirt and Luz Fonacier
Abbreviations 512
Introduction 513
Pathophysiology 514
Clinical history 515
Physical examination 518
Histologic findings 520
Site-specific considerations 520
Face and neck 520
Eyelid 520
Lip 521
Hand 521
Foot 521
Axillary 521
Ano-genital region 522
 Contents xix

Other important considerations 522

Allergic contact dermatitis in children 522
Atopic dermatitis 522
Systemic contact dermatitis 524
Allergens causing allergic contact dermatitis 524
Nickel sulfate 527
Fragrances 528
Balsam of Peru 528
Preservatives 528
Methylchloroisothiazolinone/methylisothiazolinone and
methylisothiazolinone 529
Paraben 529
p-Phenylenediamine 529
Lanolin 530
Cocamidopropyl betaine 530
Rubber 530
Medications 530
Corticosteroids 531
Patch testing and patch test allergens 531
Patch testing technique 532
Patch test reading and interpretation 532
False-positive and false-negative patch testing results 534
Determining clinical relevance 534
Repeat open application test and use test 534
Management: allergen avoidance and treatment 535
Conclusion 536
References 536

19. Skin biopsies: their utility to allergists and

immunologists 543
Maxwell A. Fung, Smita Awasthi, Samuel T. Hwang and Joyce S. Lee
Introduction 550
Biopsy types 551
Direct immunofluorescence testing 552
Eczematous reactions 552
Atopic dermatitis (eczema) 552
Contact dermatitis 553
Dyshidrotic dermatitis (dyshidrosis, pompholyx) 554
Id reaction (autoeczematization) 554
Nummular dermatitis 554
Seborrheic dermatitis 554
Stasis dermatitis 554
Xerotic (asteatotic) dermatitis 555
Urticarial eruptions 555
Urticaria 555
Urticarial vasculitis 556
Neutrophilic urticarial dermatosis 556
xx Contents

Urticarial dermatitis 556

Papular urticaria 557
Other urticarial reactions 557
Autoinflammatory syndromes 557
ADAM17 deficiency 558
Aicardi-Goutières syndrome 558
AP1S3 and autoinflammatory psoriasis 558
Autoimmunity and PLCγ2-associated antibody deficiency and
immune dysregulation 558
Autoinflammatory periodic fever, immunodeficiency, and
thrombocytopenia 558
Behçet syndrome 559
Blau syndrome 559
CANDLE syndrome 559
CARD14-mediated psoriasis 559
Cryopyrin-associated periodic syndromes 560
Deficiency of adenosine deaminase 2 560
Deficiency of interleukin-1 receptor antagonist 560
Familial chilblain lupus 560
Familial Mediterranean fever 561
H syndrome 561
Majeed syndrome 561
NLRP1-associated disease 561
NLRP12-associated autoinflammatory disease 561
Pyogenic sterile arthritis, pyoderma gangrenosum, acne 561
PLCγ2-associated antibody deficiency and immune
dysregulation 562
Singleton Merton syndrome 562
Schnitzler syndrome 562
Spondyloenchondrodysplasia with immune dysregulation 562
STING-associated vasculopathy with onset in infancy 562
Synovitis, arthritis, pustulosis, hyperostosis, osteitis 563
Tumor necrosis factor receptor associated periodic syndrome 563
Immunodeficiency syndromes 563
Ataxia-telangiectasia 563
Chédiak Higashi syndrome 563
Chronic granulomatous disease (Bridges Good syndrome,
Quie syndrome) 564
Combined immunodeficiency 564
Common variable immunodeficiency 564
DiGeorge syndrome (22q11.2 deletion) 564
Griscelli syndrome 565
Good syndrome 565
Hemophagocytic lymphohistiocytosis 565
Hereditary angioedema 565
Hyper-IgE syndrome 565
Immunodysregulation polyendocrinopathy enteropathy X-linked
syndrome 566
 Contents xxi

Leukocyte adhesion deficiency 566

Netherton syndrome 566
Nijmegen breakage syndrome 566
Severe combined immunodeficiency 566
Wiskott Aldrich syndrome 567
X-linked agammaglobulinemia (Bruton disease) 567
Other inflammatory disorders of the skin 567
Autoimmune diseases 567
Granulomatous dermatitis 568
Immunobullous disorders 568
Morbilliform eruptions 569
Acknowledgment 569
References 569

20. Evaluation and diagnosis of mast cell associated

disorders 579
Young Hwan Park and Jonathan J. Lyons
Introduction 580
Physiologic roles of mast cells 581
Evolution of mast cells 582
Host defense 583
Wound healing 583
Toxin clearance 584
Mast cell activation and mediator release 584
IgE FcεRI signaling 584
Mas-related G protein coupled receptor-X2 585
SCF KIT (CD117) signaling 585
IL-33 ST2 signaling 586
IL-6 IL-6R/GP130 signaling 586
Mast cell mediators 587
Defining mast cell associated disorders 589
Clonal disorders of mast cells 589
Nonclonal disorders associated with mast cell activation 593
Genetic disorders involving mast cells 596
Hereditary alpha-tryptasemia 596
PLCG2-associated antibody deficiency and immune dysregulation 598
Adhesion G protein coupled receptor E2 gain-of-function 599
Clinical testing modalities 600
Testing of mast cell mediators in blood and urine 600
Tryptase genotyping 605
KIT p.D816V variant detection by allele-specific and ddPCR 607
Next-generation sequencing panels 607
Bone marrow and tissue biopsy 608
Clinical evaluation for mast cell associated disorders 608
Evaluation of patients with suspected mast cell associated disorders 608
Conclusion 612
xxii Contents

Acknowledgments 614
Funding 614
References 614

21. The evaluation of a patient with urticaria

and angioedema 627
Omar Elsayed-Ali and Jennifer Shih
Urticaria 628
Clinical definition of urticaria and angioedema 628
Classification of urticaria 628
Differential diagnosis of urticaria 629
History and physical examination of urticaria 629
Workup of urticaria 630
Recurrent angioedema in the absence of wheals 632
Classification and differential diagnosis of recurrent angioedema
in the absence of wheals 632
History and physical examination of recurrent angioedema
in the absence of wheals 632
Workup of recurrent angioedema in the absence of wheals 634
Assessing disease activity/control 635
Discussion 636
References 636

22. Evaluation of a patient with anaphylaxis 639

Sehrish Viqar and Panida Sriaroon
Introduction 640
History taking 641
Differential diagnosis 644
Mechanisms of anaphylaxis 645
Causes of anaphylaxis 647
Foods 647
Drugs 649
Perioperative medications 650
Latex 651
Radiocontrast media 651
Hymenoptera sting 652
Exercise-induced anaphylaxis 653
Idiopathic anaphylaxis 654
Mast cell activation syndromes and mastocytosis 655
Workup 657
Laboratory assay 657
Skin testing 659
Graded challenge 660
Conclusions 660
References 661
 Contents xxiii

23. Evaluating patients with eosinophilia and eosinophilic

disorders 665
Heather Stern, D.O. and Gisoo Ghaffari, M.D.
Introduction 666
Eosinophil biology 667
What is eosinophilia? 668
Severity classification of eosinophilia 668
Mechanisms of eosinophilia 669
Target organs 669
Causes of eosinophilia 669
“Secondary” eosinophilia 670
Allergic and atopic diseases 670
Drug-induced 670
Infection-related 672
Neoplastic/hematologic 673
Immune 674
Miscellaneous 675
Primary eosinophilia 675
Hypereosinophilic syndrome 675
Organ-specific eosinophilic disorders 678
Eosinophilic skin disease 679
Eosinophilic lung disease 680
Eosinophilic gastrointestinal disease 680
Eosinophilic cystitis 681
Approach to the patient with eosinophilia 681
Summary 684
References 684

24. Unproven and controversial tests and treatments

in allergy and immunology 687
Suqing Zhou, Haijing Wu, Christopher Chang and Qianjin Lu
Introduction 688
Unconventional diagnostic methods 689
Leukocytotoxic test 689
Provocation neutralization tests 690
Electrodermal testing 691
Applied kinesiology testing 692
Serum IgG or IgG4 testing 693
Unproven treatment methods 694
Rotary diversified diet 695
Nambudripad’s allergy elimination technique 695
Spiritual healing 696
Concluding remarks 700
References 700
xxiv Contents

Section C
Evaluation of immune function
25. Newborn screening for severe combined
immunodeficiency and related issues 705
Amandeep Sandhu and Jennifer Heimall
Introduction 706
Newborn screening for severe combined immunodeficiency and
other immunodeficiencies 707
Severe combined immunodeficiency diagnosis 712
Nonsevere combined immunodeficiency lymphopenia 715
Clinical evaluation 716
Laboratory evaluation 718
Genetic testing 718
Management 719
Treatment 721
Discussion/conclusion 722
Acknowledgment 722
References 723

26. Testing the innate immune system 725

Jacqueline D. Squire and Jennifer W. Leiding
Background 726
Testing techniques 726
Immunoassays 726
Flow cytometry 727
Testing components of the innate immune system 728
Polymorphonuclear leukocytes (neutrophils) 728
Natural killer cells 729
Complement system 729
Interferon-gamma and interleukin-12/23 pathway 730
Toll-like receptor and NF-κB pathway 732
Immune dysregulatory disorders 733
Conclusions 734
References 734

27. Testing the adaptive immune system 737

Jacqueline D. Squire and Jennifer W. Leiding
Background 738
Testing components of the adaptive immune system 738
Immunoglobulin levels 739
Vaccine titers and isohemagglutinins 740
Lymphocyte subsets 741
Lymphocyte function 742
 Contents xxv

T-cell receptor excision circle 743

Discussion and conclusion 744
References 744

28. Infections in primary immunodeficiency 747

Ahnika Kline and Christa Zerbe
Immunodeficiencies affecting cellular and humoral immunity 748
Introduction 748
Infections in severe combined immune deficiency 748
Combined immune deficiencies less profound than severe combined
immune deficiency 752
Combined immunodeficiencies with syndromic features 756
Wiskott-Aldrich syndrome and related deficiencies 756
DNA repair defects with syndromic features 757
Thymic defects with additional congenital anomalies 758
Immune-osseous dysplasias 758
Hyper-IGE syndromes 759
Dyskeratosis congenita 759
Defects of vitamin B12 and folate metabolism 760
Anhidrotic ectodermodysplasia with immunodeficiency 760
Calcium channel defects 760
Other defects 761
Predominantly antibody deficiencies 761
Introduction 761
Diseases of immune dysregulation 764
Introduction 764
Congenital defects of phagocyte number or function 767
Introduction 767
Defects in intrinsic and innate immunity 768
Introduction 768
Autoinflammatory disorders 773
Complement deficiencies 773
Introduction 773
Phenocopies and therapies 775
Conclusion 776
Acknowledgments 776
References 777

29. Periodic fever syndromes and autoinflammatory

diseases 791
Angel A. Herrera Guerra and Victoria R. Dimitriades
Introduction 792
xxvi Contents

Familial Mediterranean fever 793

Background 793
Epidemiology 793
Pathophysiology 793
Clinical manifestations 794
Laboratory features 795
Diagnosis 795
Treatment 796
Prognosis 796
Mevalonate kinase deficiency 797
Background 797
Epidemiology 797
Pathophysiology 797
Clinical manifestations 797
Laboratory features 798
Diagnosis 798
Treatment 798
Prognosis 799
Tumor necrosis factor receptor-associated periodic syndrome 799
Background 799
Epidemiology 799
Pathophysiology 800
Clinical manifestations 800
Laboratory features 800
Diagnosis 800
Treatment 801
Prognosis 801
Cryopyrin associated autoinflammatory syndrome 802
Background 802
Epidemiology 802
Pathophysiology 802
Clinical manifestations 802
Laboratory features 803
Diagnosis 804
Treatment 804
Prognosis 805
Periodic fever with adenitis, pharyngitis, and aphthous stomatitis 805
Background 805
Epidemiology 805
Pathophysiology 806
Clinical manifestations 806
Laboratory features 806
Diagnosis 807
Treatment 807
Prognosis 808
Other autoinflammatory conditions 808
Conclusion 816
References 816
 Contents xxvii

30. Primary immune regulatory disorders 829

Maria Chitty-Lopez and Jolan E. Walter
Background 830
ALPS/ALPS-like disorders 833
IPEX and IPEX-related disorders 835
CVID, CVID-like, and profound/late-onset combined immune
deficiency disorders 836
Immune phenotype and genetic testing in PIRD 837
Hyperinflammatory disorders and immune dysregulation 838
Discussion and conclusion 840
References 840

31. The history, diagnosis, and pathophysiology of

human immunodeficiency virus and acquired
immunodeficiency syndrome 845
Kelly Valentini, Eric McGrath, Divya Seth and Elizabeth Secord
Introduction 846
Human immunodeficiency virus and acquired immunodeficiency
syndrome 846
Background and history 846
Pathophysiology and immune dysfunction 849
Atopy and human immunodeficiency virus 851
Diagnosis 852
Retroviral conversion syndrome 853
Diagnosis in asymptomatic persons and treatment as prevention 853
Human immunodeficiency virus testing 854
Human immunodeficiency virus testing in infants and children 854
Human immunodeficiency virus testing in breastfed infants 856
Missed opportunities and postexposure prophylaxis 856
Diagnosis of acquired immunodeficiency syndrome 856
Conclusion 857
References 857

32. The evaluation and treatment of autoimmune diseases 863

Kristina Wiers-Shamir, Jessica Simpson and Christopher Chang
Introduction 864
The history of present illness and physical examination in the
evaluation of the rheumatologic patient 864
Laboratory testing for autoimmune diseases 865
What to consider when using a test 865
Specific antibodies 866
Antinuclear antibodies 866
Antidouble-stranded DNA antibodies 868
Extractable nuclear antigens 868
xxviii Contents

Inflammatory markers 871

Human leukocyte antigen associations in autoimmune diseases 875
Imaging in autoimmune diseases 875
Treatment of autoimmune diseases 876
Disease-modifying antirheumatic drugs 876
Corticosteroids 878
Cytotoxic agents 878
T cell targets 879
Antiinflammatory agents 879
Monoclonal antibodies 880
Conclusions 881
References 881

33. Neurologic autoimmune diseases 887

Yhojan Rodrı́guez, Lucas Restrepo, Christopher Chang and
Juan-Manuel Anaya
Introduction 888
Multiple sclerosis 889
Epidemiology 889
Environmental factors 889
Genetic factors 890
Immunopathology 890
Clinical features 890
Diagnosis 895
Treatment 896
Neuromyelitis optica 898
Epidemiology 898
Genetic factors 898
Environmental factors 898
Immunopathology 899
Clinical features 899
Diagnosis 900
Treatment 903
Guillain Barré syndrome 905
Epidemiology 905
Genetic factors 905
Environmental factors 906
Immunopathology 907
Clinical features and diagnosis 912
Treatment 912
Chronic inflammatory demyelinating polyneuropathy 913
Epidemiology 913
Genetic factors 913
Environmental factors 913
Immunopathology 913
Clinical features and diagnosis 924
 Contents xxix

Treatment 925
Myasthenia gravis 925
Epidemiology 925
Genetic and environmental factors 926
Immunopathology 926
Clinical features and diagnosis 929
Treatment 930
Autoimmune encephalitis 934
Epidemiology 934
Genetic factors 934
Environmental factors 935
Immunopathology 935
Clinical features 936
Diagnosis 938
Treatment 940
Paraneoplastic neurological disorder 941
Epidemiology 941
Immunopathology 942
Clinical features 943
Treatment 945
Summary 945
References 945

Volume 2
Section D
Treatment of allergic diseases
34. Immunotherapy to environmental allergens 979
Kristine Vanijcharoenkarn and Merin Kuruvilla
Background 980
Patient selection 980
Formulation of allergen immunotherapy extract 982
Injection schedules 985
Duration of immunotherapy 985
Monitoring of treatment 988
Reactions to allergen immunotherapy 989
Local reactions 989
Systemic reactions 989
Pretreatment 990
Subcutaneous immunotherapy versus sublingual immunotherapy 990
Clinical efficacy 990
Asthma 990
xxx Contents

Rhinoconjunctivitis 991
Atopic dermatitis 992
Efficacy of fungal extracts 992
Efficacy of multiallergen immunotherapy 993
Other administration routes 998
New technologies 999
Conclusion 999
References 1000

35. Drug desensitization 1005

Lourdes Ramirez, Faina Shenderov and Christopher Chang
Introduction 1006
Mechanisms of drug hypersensitivity 1006
Type I hypersensitivity reactions: IgE mediated and non-IgE mediated 1007
Type II hypersensitivity reactions 1008
Type III hypersensitivity reactions 1008
Type IV hypersensitivity reactions 1009
Drug desensitization 1009
Mechanisms of drug desensitization 1009
Indications 1010
Choosing desensitization protocols 1010
Premedication 1011
Route and dosing 1012
Desensitization protocols 1012
Desensitization to vaccines 1012
Desensitization to antibiotics 1013
Desensitization to nonsteroidal anti-inflammatory drugs 1018
Desensitization to monoclonal and chemotherapeutic agents 1022
Optimization of the desensitization procedure—pharmacy
considerations 1028
Conclusion 1034
References 1035

36. Oral, sublingual, and dermatologic immunotherapy

for food allergy 1039
Mary Grace Baker and Julie Wang
Introduction 1040
Oral immunotherapy 1040
Background/mechanism 1040
Studies 1041
In combination with other therapies: allergen oral
immunotherapy 1 omalizumab or probiotics 1058
Pros/cons 1060
How to incorporate oral immunotherapy into clinical practice 1061
Future directions 1061
Epicutaneous immunotherapy 1061
 Contents xxxi

Background 1061
Mechanism 1062
Studies 1062
Pros/cons 1064
Future directions 1065
Sublingual immunotherapy 1065
Background 1065
Mechanism 1065
Studies 1066
Pros/cons 1069
Future directions 1069
Summary 1069
References 1070

37. Conventional medications for the treatment of

allergic rhinitis and conjunctivitis 1077
Elizabeth J. Feuille, Wanda Phipatanakul and Perdita Permaul
Introduction 1078
Medications used for allergic rhinitis and allergic conjunctivitis 1079
Overview 1079
Nasal saline 1090
Antihistamines 1090
Glucocorticoids 1095
Mast cell-stabilizing agents 1097
Anticholinergics 1099
Leukotriene receptor antagonists 1099
Decongestants 1100
Future directions/conclusion 1101
Disclosure statement 1103
References 1103

38. New biologics in allergy 1111

Heather K. Lehman and Colleen M. Sabella
Introduction 1112
Currently available biologics for allergic diseases 1112
Anti-IgE monoclonal antibodies 1112
Anti-IL-5 monoclonal antibodies 1119
Biologics currently in development 1127
Anti-IL-13 monoclonal antibody 1127
Anti-thymic stromal lymphopoietin monoclonal antibody 1129
CRTH2 antagonists 1130
Anti-IL-31 monoclonal antibody 1131
Anti-IL-33 monoclonal antibody 1131
Non-Th2 biologics in atopic disease 1132
Anti-IL-17 monoclonal antibodies 1132
Another random document with
no related content on Scribd:
and learn to know you, and feed tamely out of your hand, would you
not desire to have some food to give it?”
“O yes: I would give it part of my dinner.”
“But if you had very little dinner, scarcely enough to satisfy your
own hunger, you would buy more bread for your rat if you could. If
your jailer asked you much more than the bread would be worth out
of prison, you would give it him rather than your rat should not come
and play with you. You would pay him first all your copper, and then
all your silver, and then all your gold.”
“Yes, because I could not play with money so pleasantly as with a
live animal, and there would be nothing else that I could buy in such
a place. I had rather have the company of my rat than a pocket full of
gold.”
“So White thought,” observed Marguerite, “and he gave the
turnkey every thing he had left for bread, till his buttons, and his
pencil case, and even his watch were all gone. It was a long time
before he could bring himself to part with his watch; for the moving of
the wheels was something to look at, and the ticking kept his ears
awake, and made him feel less desolate: but when it came to giving
up his watch or his rat, he thought he could least spare his live
companion: so he carefully observed for some time the shifting of the
glimmering light upon the wall, as the morning passed into noon, and
noon into afternoon and evening, and then he thought this sort of dial
might serve him instead of a watch, and he gave it to the turnkey on
condition of having an ounce more bread every day for a year.”
“He must have been pleased to have made his bargain for a whole
year.”
“His pleasure lasted a very short while. The turnkey came earlier
than usual one day when the rat was there, and twisted its neck
before White could stop him.”
Julien stamped with grief and anger when he heard this; but
presently supposed the turnkey was honest enough to restore the
watch. Charles shook his head in answer, and told his little son that
poor White had been quite crazy since that day, and had talked
about nothing but a rat, and shown no desire for any thing but bread
and water since, though it was six years ago that his misfortune had
happened.
 “Did you ever hear of paying for water, Julien; or for air?”
No: Julien thought that God had given both so freely that it would
be a sin to sell them. His father thought this not a good reason; for it
seemed to him fair that men should buy and sell whenever one
wanted something that another person had too much of; as much air
and water as corn and flax, which were also given by God.
“Ah, but, papa, it costs men a great deal of trouble to prepare corn
and flax.”
“True; and now you have hit upon the right reason. If corn and flax
grew of themselves on land which belonged to nobody, would you
pay for them, or just gather them without paying?”
“I should be very silly to pay when I might have them without.”
“So I think: but would corn and flax be less valuable then than
now, when we have to pay very dear for them?”
“The corn would be just as good to eat, and the flax to make linen
of: but they would not to change away.”
“No more than the air, which is very useful in breathing, or water
which we could not do without, and which yet would be a very poor
thing to carry to market. Now, would you call water a valuable thing
or not, Julien?”
“No, not at all, because it will buy nothing——O yes, but it is
though; because we could not do without it.—Mamma, is water
valuable or not?”
“Very valuable in use, but not usually in exchange. When things
are valuable in exchange, it is either because they cost labour before
they could be used, or because they are very scarce.”
“So,” observed Charles, “if a mine should ever be dug so deep that
the air is not fresh at the bottom where the miners work, the owner of
the mine would be very glad to buy air of any one who could convey
it down by a machine. Such an one would be wise to charge so
much a gallon for the fresh air he supplied, to pay for the labour and
expense of his machine, and for the trouble of working it.”
Marguerite then mentioned that she once staid in a small country
town during a drought. There was no reservoir of water, and all the
pumps and cisterns were dry. The poor people went out by night into
the neighbouring country, and watched the springs; and any one who
was fortunate enough to obtain a gallon of fresh water was well paid
for it. The price rose every day, till at last one woman gave a calf for
a pailfull of water, hoping to save her cow, it being certain that both
must die without this supply.
“And did she save her cow?”
“Yes. While the woman was anxiously sitting up in bed, planning
what she should change away next, she fancied there was a
different feel in the air; and on looking out of the window, she found
the sky covered with black clouds; and before morning, the trade in
water was over. There was nobody to give a doit for a cistern-full.”
“It was just so with me,” observed Charles, “when I was besieged
in the cellar. I was parched with thirst, and would have given a pipe
of my best wine to any one who would have let me down a quart of
water through the trap-door. Three hours after, I myself threw
hundreds of gallons on the fire at the guard houses, when the order
was given to take them down in an orderly way; and I did not
consider such use of the water any waste. So much for the value
which is given by scarcity.”
“But, papa, though things are more valuable to people when there
is a scarcity of them, the people are less rich than they were before.
That seems to me very odd.”
“Because you have been accustomed to consider value and
wealth as the same things, which they are not. Our wealth consists
in whatever is valuable in use as well as in exchange. Owing to the
storm of last year, I have less wealth in my possession now than I
had then, though what I have may, perhaps, exchange for more
wealth still. I have as much furniture, and as many clothes and
luxuries, and as much money; but I have fewer growing vines, and
much less wine. If I were to use up my own grapes and wine instead
of selling them, they would last a much shorter time than my stock of
the former year would have lasted. So I have less wealth in
possession. But the value of wine has risen so high, in consequence
of scarcity, that I can get as much now of other things in exchange
for a pint, as I could, fourteen months ago, in exchange for a gallon.”
“But that is partly because the wine is older. Mr. Steele is very
particular about the wine being old, and he pays you much more, he
told me, the longer it has been kept.”
 “And it is very fair he should, for reasons which you can hardly
understand yet.”
“Try him,” said Marguerite.
“It is impossible, my dear. I refer to the charges I am at for the rent
of my cellar, the wear of my casks, and the loss of interest upon the
capital locked up in the wine. All this must be paid out of the
improvement in the quality of the article; and all this, Julien must wait
a few years to understand.
“Now tell me, my boy, whether you think it a good thing or not that
there should be a scarcity of wine?”
“Why, papa, as we do not want to drink all you have ourselves,
and as people will give you as much for it as they would for twice as
much, I do not think it signifies to you; but it must be a bad thing for
the people of Paris that there is so little wine to be had. At least you
said so about the bread.”
“But if my wine should be as dear next year, and I should have no
more losses from storms, and no more expense than in common
years, in growing my wine, would the high price be a good thing for
me or not?”
“It would be good for you, and bad for your customers; only I think
they would not give you so much for your wine. They would
remember that there had been no more storms, and they would find
people that had cheaper wine to sell, and then they would leave off
buying of you.”
“And they would be very right, if there was anybody to sell
cheaper; as there would be, if labourers had less wages, and so
made it less expensive to grow and prepare wine. But if some way
was found of making more wine than ever, in a cheaper way than
ever, who would be the better for that?”
“The people that buy of you, because I suppose you would let
them have it cheaper.”
“And papa too,” said Marguerite, “for many people would buy wine
who cannot afford it now.”
“Therefore,” concluded Charles, “a high exchangeable value is not
at all a good thing for everybody, though it may be for a time to some
few. And a low exchangeable value is a very good thing to
everybody, if it arises from the only cause which can render it
permanent,—a diminution of the cost of production.”
“But if this happened with every article,” pursued Marguerite,
“there would be an end of the cheapness, though not of the plenty.
As many of one thing would exchange for a certain number of other
things as before.”
“True; but less labour would purchase them all; and this is the
grand consideration. As less labour will now purchase a deal table
than was once necessary to procure a rough hewn log in its place,
less labour still may hereafter buy a mahogany one; and this is a
desirable thing for the purchasers of tables, and no less for the
makers, who will then sell a hundred times the number they can
dispose of now.”
 Chapter VI.

NEW DEVICES.

The Parisians soon after showed that they knew little of the
resources on which the supply of the wants of the state should
depend, by having recourse to a measure which, however popular,
was one of great folly;—folly to be exceeded only by an act of the
populace which took place nearly at the same time.
The coffers of the government had long been empty. Loans of
almost every kind, and under every species of pretence, had been
raised upon the suffering nation, some of which proved failures in
their primary object, while others, however great the proceeds in
amount, seemed to be exhausted with somewhat the same speed as
water that is poured into a sieve. Never money went away so fast
before; and whilst the government was dismayed at its magic
property of disappearance, the people grew more and more angry at
what they thought the extravagance of their rulers. Neither of them
took into the account the scarcity of most of the necessaries of life,
and both regarded money as having the same value as ever,—as
being, in itself, the thing required to supply the necessities of the
state. To both it was equally inconceivable why, if so much had
defrayed such and such expenses in former years, double the sum
would go no way at all at present. The ministers and the court could
only tremble at the necessity of owning the truth, while the people
raged, and could be appeased only by court largesses for the relief
of the starving: which largesses went as little way when they had
changed hands as before. Neither party suspected that money,
although scarce, had become very cheap through the still greater
scarcity of other things; and in the absence of this necessary
knowledge, everybody was eager about gold and silver.
The National Assembly had tried all means, first by themselves,
and then with the assistance of Necker, to raise a supply, without
which the affairs of the state could not, they believed, proceed; and
all in vain. Then Necker had leave given him to pursue his own
methods; and, popular as he was, no one had a doubt that he would
succeed. But he failed, though he issued the most tempting
proposals; offered the highest interest that ever was heard of, even
in such an emergency; and exerted his utmost personal influence in
favour of the loan. The subscription was not half filled: the reason of
which was that many had no money, having spent it all in buying
necessaries; and as many in France as had taken their money
(much of it had gone into other countries) expected to want it
themselves for the same purposes, or had not confidence enough in
the stability of the government to take it for a creditor. So the king’s
horses went on to eat borrowed hay or to want it; and the king’s
servants to clamour for their wages; and the king’s tradesmen to
decline orders on one pretence or another; and the police threatened
to leave the home minister to keep order by himself; and state
couriers went unwillingly forth on their journies; and business lagged
in every department of the administration.
At this moment, it entered some wise head that, if people would
not lend money, they might lend or give something else; not corn or
hay, or any of the necessaries of life; for every one knew there was
still less of these things than of money; but gold and silver in any
form. It would have been hard to say what lasting good this could do
amidst the impossibility of procuring the necessaries of which gold
and silver are only the representatives: but no matter for that.
Nobody was asked to explain the affair, and apparently none
troubled themselves to think about it; so delighted were all with the
new notion of giving away trinkets to save the state. The idea of a
patriotic contribution was charming,—a contribution in which almost
everybody could join; women and children, and persons of many
degrees below the class of capitalists. The court joined: the
gentlemen sacrificing nearly half their watches and seals, and the
ladies adopting simplicity as a fashion, and sending away the
jewellery they could not wear as Arcadian shepherdesses and
Sicilian nymphs. The Assembly followed, every member thereof
stooping down at the same moment to strip his shoes of their
buckles, so that their act of patriotic devotion made really a very fine
show. This gave the signal to the whole country, and all France was
forthwith unbuckled in respect of the feet. She became also
quakerlike as to the hands, for not a maiden but took out her lover’s
hair from his parting gift, and flung the ring into the lap of the nation;
not a wife that did not part with the token of her wifehood in the
cause. Pecks of gold rings, bushels of silver buckles, with huge store
of other baubles, were at once in the possession of the state; and
the people no longer doubted that all would henceforth be well.
And what was really the event?—The gold answered the same
purpose as it does when a basin full of it coined stands on the
banker’s counter during a run. It satisfied the ignorant that all must
be safe where there is so much wealth actually before one’s eyes. It
hushed the clamours of the people for a little while; and made the
servants of the government willing to go on somewhat longer upon
credit; so that more industry and briskness prevailed for a time, at
the risk of ultimate disappointment, and an aggravation of popular
fury,—now diverted but not dispersed. A mob went about to levy
these voluntary offerings, an act ludicrously inconsistent with their
next proceeding; if, indeed, any of the events of this extraordinary
time could be regarded as ludicrous.
They called at Charles’s house among others, whence, as it
happened, no such offerings had yet gone forth. Charles had
resisted Pauline’s wish to lend the queen her thimble, and Julien’s
offer to pay his first tax with the silver-tipped riding-whip grandpapa
had given him. Neither would he allow Marguerite’s few ornaments,
all keepsakes, to be thrown away in any such manner. He would give
the coat off his back to the state, he said, when it could do any
service; but the proposed gifts could only help to make jewellery a
drug, without supplying one more person with bread, or lessening by
so much as one scruple the burdens of the state. He was disposed
to be vexed when he came home one day, and found a short
allowance of spoons at the dinner-table, the clock on the mantel-
piece gone, and his wife as destitute of external ornament as any
Arcadian shepherdess at Versailles. He laughed, however, at his
wife’s apologies for having made a voluntary offering against her
own will as well as his, and hoped that she would be as little the
worse as the state would be the better for the sacrifice. Goldsmiths
and jewellers of enterprise and capital would profit by the fancy, he
observed, if nobody else did; and the many losers might find some
comfort in sympathy with the very few winners.
The people, meanwhile, were bitterly complaining of famine, and
the more gold was carried to the treasury, the more bread was
bought up before the eyes of those who were deprived of it from its
increased price. It mattered not that some was given away in charity
by the king, and more, to suit his own purposes, by the duke of
Orleans; the people were rendered unable to purchase it, and
furnished with the plea of want, wherewith to make the streets of
Paris echo. It would have been better to have let the exchange of
wedding rings for bread be made without the interposition of the king
or his ministers, even without taking into consideration the events
which followed. A report was soon industriously spread that the
bread furnished by court charity was of a bad quality. It was believed,
like everything that was then said against the court; and the
consequence was that an anomalous and melancholy sight was
seen by as many as walked in the city. Clamorous, starving crowds
besieged the bakers’ shops, and carried off all the bread from their
ovens, all the flour from their bins; while the discontented among the
mob politicians of the Orleans faction were on the way to snatch the
food from the mouths of the hungry and throw it into the river, and to
cut the sacks, and mix the flour with the puddles of the streets. Want
and waste, faction and delusion were here seen in their direct
extremes.
At this time, Charles and Marguerite did not allow their children to
go out under any guardianship but that of their father, as it was
impossible to foresee what might happen in the streets before they
could get home again. They were as safe as any could be at such a
time;—safer than the few who ventured abroad in carriages at the
risk of insult wherever they turned; safer than the sordidly fed and
clad, who were seized upon by the agents of faction to augment their
mobs, and be made the instruments of violence under the penalty of
suffering it themselves. The parents and children were also safer
together than separate; as a domestic party, abroad to take the air,
presented as unsuspicious a group, and one as likely to pass
unnoticed, as could well be imagined. Yet they had their occasional
alarms; and when there was no cause to fear for themselves, were
too often grieved and shocked at what they beheld inflicted on
others.
“O papa!” cried Julien, one day, as they were walking; “what are
they doing at Maigrot’s shop? I do believe the crowd is coming there
next.”
Maigrot was a baker, well known to Charles’s family, and much
beloved by the children, on account of the little hot cakes which
seemed to be always ready to pop out of the oven and into their
mouths, when they went with the servant to deliver orders or pay
bills.
Instead of his usual smiling face, Maigrot was now seen in a state
of desperate anxiety, as well as could be judged from the glimpse of
him at his door, trying first to slip out, and then to force his way
between the two men who were evidently placed at the entrance as
guards till the mob should come up. Foiled in his attempt, Maigrot
disappeared, and Charles thought that it might depend on whether
there was a way of exit at the back of the house, whether his head
would presently be carried on a pike, between two loaves of his own
bread, or whether he would be kneading and baking in peace ten
years hence. There seemed to be just time to run and give a word of
advice to whomsoever might be waiting in the shop, and Charles ran
forward to do so. He was prevented entering; but seeing Maigrot’s
wife sinking and trembling behind the counter, and looking absolutely
incapable of any resolution whatever, he called out to her to assist in
emptying the flour bins and distributing the bread, and to fear
nothing, and all would be well. The woman tossed off a glass of
water which stood beside her, and rallied for the effort. In such effort
lay the only resource of sufferers under violence in those days; for
the magistracy were unable to afford assistance; or, if able, were not
to be depended on. The shop was presently emptied and gutted, and
its stock carried away, without, however, being in this instance
preceded by the horrible display of a human head. Maigrot had
escaped and actually joined in with the mob in time to see his own
flour cast into the Seine. Nobody thought more of the baker, and he
took advantage of this disregard to learn a great deal of his own
doings which he did not know before. He now overheard that his
flour was mixed with hurtful ingredients by order of his customer, the
king; that an inferior kind was sold at high prices as the best; and
that there were stores of meal concealed somewhere about his
premises, to victual the soldiers who were to be brought to rule the
city, and give the king his own way. All this was news to Maigrot, who
was compelled to listen to these falsehoods in silence: more
fortunate than many who had lost their lives as well as their good
name under similar charges. A defender sprang up, however, when
he least expected it.
Charles and his little son could not help following to look on, when
the mob proceeded with the flour down to the river. They stood on
the outskirts of the crowd, watching sack after sack as, with hoarse
shouts, it was heaved into the water so as to make the heaviest
splash possible. A new amusement presently occurred to some of
the leaders; that of testing the political opinions of the passers by by
the judgment they should pronounce on the quality of the flour.
Those who declared it good must, of course, be parasites of the
court; those who made mouths at it were the friends of the people;
and the moment this point was settled, every gazer from a distance
was hauled to the water’s edge to undergo the test; every
approaching carriage was waylaid and stopped, and its inmates
brought on the shoulders of the mob. Of course, all gave judgment
on the same side;—a thing likely to happen without much
dishonesty, when the raw flour was crammed into the mouth by foul
and sometimes bloody hands. It would have been difficult to
pronounce it very good under such circumstances of administration.
Among the most piteous looking of those under test was the
marquis de Thou, who was taken from a non-descript sort of
carriage, on his way, as he vowed, to the duke of Orleans, but
certainly attended by more than one servant of the royal household.
While prosecuting his explanations with gesture and grimace,
uplifted as he was above the crowd, he looked so like a monkey
riding a bear that a universal shout of mockery arose. He was
lowered for a moment, out of sight; and the laugh rose louder than
ever when he reappeared, held at arms’ length by a hundred hands,
powdered all over like a miller. His position made the judgment he
had to give all the more difficult, for it enabled him to perceive the
royal servants watching him on one side, the duke of Orleans and
some of his fiercest followers on another, and the pitiless mob
around.
“Ah! it is very, very good food for the poor, without doubt,” he
declared, while in full view of the court party, and with his mouth
stuffed with a compound which had just been taken from a puddle
underfoot. “Very fine nourishment for a good king to buy dear, and
give away to a hungry people.—Ah! no more,—no more, I pray you! I
shall presently dine, and it is enough. I cannot praise it more than I
have done.—Ah! but” (seeing the duke frowning) “I do not say but it
may be a little sour,—and somewhat bitter,—yes, O yes, and gritty,—
and, O do not murder me, and I will also say hurtful.—And
poisonous? Yes, no doubt it is poisonous,—clearly poisonous.—But,
how bountiful of the king to think of how the poor should be fed!”
The marquis might think himself fortunate in getting off with a
ducking in the yeasty flood, into which he was let down astride on a
flour sack. While sneaking away through the crowd, after shaking his
dripping queue, and drawing a long breath, he encountered Charles,
whom he immediately recognised, and with inconsiderate
selfishness, exposed to the notice of the crowd by his appeal.
“Ah, my friend, here is a condition I am in! For our old friendship’s
sake,—for the sake of our vicinity in Guienne, aid me!”
“Do not answer him. Take no notice,” whispered Maigrot from
behind; “’tis as much as your life is worth.”
But Charles could not be inhuman. He gave the old man his arm to
conduct him to the carriage which he intended to order to his own
house. Before he had well turned his back, however, a piercing
shriek from Julien made him look round. The mob were about to
carry the boy towards the sacks.
“Do not be alarmed, my dear,” said he. “Taste the flour, and say
whether you think it good; and I will come to you in a moment to do
the same.”
Julien shrieked no more, but he looked ruefully in his father’s face,
when Charles returned. As soon as he had gulped down his share
and could speak, he said he had never tasted raw flour before, but it
was not so good as the hot cakes that were made of it sometimes.—
The boy escaped with being only laughed at.—His father’s turn
came next.
 Charles stipulated, when laid hold of, to be allowed to feed
himself, and refused laughingly to taste what came out of the puddle
till his neighbours should have separated the mud from the flour.
With a very oracular look, he then proceeded from sack to sack,
tasting and pronouncing, apparently unmoved by the speculations he
heard going on all round him as to whether he was a royalist from
about the court, or a spy from Versailles, or only an ignorant stranger
from the provinces. When he had apparently made up his mind, he
began a sort of conversation with those nearest to him, which he
exalted by degrees into a speech.
“When I,” he observed, “I, the very first, opened a prisoner’s cell in
the Bastille——”
He was interrupted by loud cheers from all who heard; and this
drew the attention of more.
“——I found,” continued Charles, “a mess of wholesome food in
that horrible place. Every other kind of poison was there,—the
poison of damps and a close atmosphere; the poison of inactivity
which brings on disease and death; the poison of cruelty by which all
the kindly feelings are turned into bitterness in the soul of the
oppressed; and the poison of hopelessness, by which the currents of
life are chilled, and the heart of the captive is sunk within him till he
dies. All these poisons we found in every cell; but to all their inmates
was denied that quicker poison which would have been welcome to
end their woes. Some, we know, have lived thirty-five years under
this slow death, while a very small mixture of drugs with their bread
would have released them in fewer hours. That this quicker method
was ever used, we have no proof; that it was not used in the case of
those whom we released, we know, not by their state of health alone;
for that, alas! was not to be boasted of;—but by the experience of
some of us. When we were heated with toil and choked with dust, we
drank the draughts which the prisoners left untasted in their cells.
When a way was made among the ruins, women came to see what a
work their husbands had achieved; and when their children craved
food, rather than return home before all was finished, they gave their
little ones the bread which the captives had loathed. Many thus ate
and drank; and I appeal to you whether any evil came of that day;
whether the sleep of the next night was not sound as became the
rest which succeeds to an heroic effort. No one was poisoned with
the food then provided by the government; and yet that horrible
dungeon was the place, if there be any, for poison to do its work.
And if not attempted there, will it be here? Here, where there are a
million of eyes on the watch to detect treasons against the people?
Here, where there are hundreds of thousands of defenders of the
public safety? No, fellow citizens: this is not the kind of treason which
is meditated against us. There are none that dare practise so directly
on your lives. But there is a treason no less fatal, though more
disguised, which is even at this moment in operation against you.
You ask me two questions;—whether this food is of a bad quality;
and whether you are not half-starved; and both these evils you
ascribe to your rulers.—To the first I answer, that this food is, to the
best of my judgment, good; and, whether good or bad, that the
government has nothing to do with it, since it forms no part of the
stores that the king has bought up for distribution. It is flour of the
same harvest, the same field, the same mill, the same bin, that I and
mine have been supplied from; and it has nourished me well for the
work I have had to do; for letting in the light of day upon the foulest
dungeon that ever deformed the earth,—for watching over those who
have been released from it,—for attending to the proceedings of the
Assembly,—for meditating by night and consulting by day how the
rights of the people may best be attained and secured. Keep the
same food to strengthen you for the same purposes. Do not forget
your other complaint;—that you are starving: and remember that
however much this may be owing to the misrule and courtly
extravagance you denounce, the grievance will not be removed by
your feeding the fishes with that which your children are craving. I
spoke of another kind of treason than that which you suspect, and I
see about me too many tokens of its existence;—the treason which
would not poison but starve you.
“Of the motives of this treason I have nothing to say, for I am
wholly ignorant of them. I only insist that there can be no truly
patriotic aim under the project of depriving you of the food which is at
best but scantily supplied. Do you find in the most plentiful seasons
that we have corn enough to make sport with in the river? Are your
houses even then so filled with grain that, after feeding your children
and domestic animals, you have enough left for the eels of the
Seine? Is it to give you this over-supply that the peasantry of the
provinces live under roofs of rushes, and couch upon beds of straw?
Tell me,—is there in the happiest of times such a superfluity that no
Frenchman has a want or wish for more?”
Furious cries of denial rose from all sides, joined with curses upon
the government which year by year, by its extravagance, snatched
the hard-earned bread from the labourer’s hands.
“This is all true,” replied Charles, “and is in course of being
reformed: but when did even a tyrannical government inflict upon
you such evils as you are this day inflicting upon yourselves? When
has it robbed the shops of one of the most useful class of men
among you, and carried away boat-loads of the food for which
thousands are pining, and destroyed your means of life before your
eyes? A worse enemy than even a weak king and a licentious court
is making sport of your miseries, and overwhelming you with such as
cannot be repaired. Yes! let it not hurt your pride to hear of woes that
cannot be repaired; for even the power of the sovereign people is not
unlimited, great as you have proved it to be. You have abolished
servile parliaments, and obtained a virtuous assembly of
representatives. You have swept away the stronghold of oppression,
and can tread with free steps the turf from which its very foundations
have been extracted. You have rejected a constitution which was an
insufficient warrant for your liberties, and are in the way to obtain
universal assent to that noble Declaration of Rights which shall
become the social contract of every civilized nation.—All these
things, and others which would have been called impossibilities ten
years ago, you have achieved. But there are impossibilities
remaining which more truly deserve the name. You cannot prevent
multitudes dying when famine is in the land; you cannot call up a
new harvest before the seed has sprouted; you cannot insist upon
supplies from other lands which are already drained. You can waste
your resources, but you cannot recall them. With however much
pride or levity you may at this hour fling away the staff of your life,
you cannot retard the day when you will sink for want of it,—when
you will kneel in the mud by the brink of this very current, and crave
the waters to give up what you have buried in them, or to drown your
miseries with your life.—Will you suffer yourselves thus to be made
sport of? Will you permit yourselves to be goaded into madness, in
order that you may be ready for madmen’s deeds? Will you throw
away what is in your own hands, that others may reduce you to
crave the small pittance which will remain in theirs? Those who have
incited you to the deeds of this day take very good care that all our
granaries shall not be emptied. They reserve a few, that you may at
length,—when all their schemes are ripe,—be their tools through
your literal dependence on them for bread.—Disappoint this plot as
far as you can. It is now too late to keep plenty in your own hands;
but baffle the approaches of famine to the last moment; for with
hunger comes slavery; or, if you will not have slavery, death; and in
either case, your country must surrender your services at the very
moment when she wants them most.—Where is the patriotism of
bringing things to this pass?—Where also is the justice of
condemning unheard so useful a class of men as those from whom
you have taken their property without accusation, and, in many
cases, their lives, on nothing better than suspicion of their having
communicated with the court?—We must respect rights, as well as
frame a Declaration of them. We must cherish the innocent and
useful of society, if we wish to restrain those who are neither the one
nor the other. Let there be a contrast between the oppressors and
the friends of the people. Let tyrants tremble, while industrious
citizens dwell in peace.”
It was now easy to wind up the discourse to the point
contemplated. Charles proposed that Maigrot should be permitted,
under proper guardianship, to bake a provision of loaves out of this
very flour; and if they proved good, that all that remained of his
property should be restored to him. The crowd rather relished the
idea of waiting the operation, in full prospect of a batch of hot rolls
gratis as the result, and the proposal was received with
acclamations.—Charles immediately singled out Maigrot, as he
stood on the outskirts of the mob, requested him to lead the way
homewards, put a loaf into each arm of his little son, swung a sack of
flour on his own shoulders, and headed the most singular of all the
extraordinary processions which attracted the gaze of Paris in those
times.
 The duke of Orleans made no opposition. He saw that the game
was up for this day, and departed in an opposite direction, having no
particular wish to hear the verdict which he knew would be passed
upon the bread, or to witness the exultation of the baker.—Before
night, Maigrot not only felt his head safe upon his shoulders, but was
the most eminent baker in Paris; and, if he had but had any flour
remaining, might have boasted such a business as he had till now
never thought of aspiring to.
 Chapter VII.

MOB SOVEREIGNTY.

The endeavours of individuals like Charles to make the people wise

were of little avail, however successful at the moment, in opposition
to influences of a different character which were perpetually at work
upon the mob of Paris. The obstinacy of the king in refusing to sign
the declaration of rights, the imbecility of the ministry, the arts and
clamours of the leaders of different parties, and, above all, the
destitution of which they took advantage, overcame all principles of
subordination, all sentiments of loyalty, and filled the people with a
rage which rendered them as blind to their own interests as unjust
towards those of the ranks above them. Riot and waste spread and
grew from day to day, and the wise saw no more prospect of relief
than the foolish of danger.
The king had been told, on the day the Bastille was taken, that his
capital was in a state of revolution; but, nearly three months
afterwards, he was still wondering what the event might mean;
talking over with the queen the kindnesses he had always intended
showing to his people, and assuring the people’s parliament that the
best thing he could do for them was to preserve his dignity and
prerogative. He could still at Versailles ride abroad unmolested in the
mornings, feast his body-guard in the middle of the day, and look on
while the ladies of the court were dancing in the evening, and sleep
the whole night without hearing the drums and larums which kept all
Paris awake; and could not therefore believe that all would not come
right, when the people should have been persuaded of the atrocious
unreasonableness of the Declaration they wanted him to sign. When
he heard that they drowned their flour in hatred of him, he did all he
could think of in ordering that more should be given them; and when
the queen discovered that which every one would have kept from
her,—that she was hated,—she curled her proud lip, and reared her
graceful head, and thought that the citizens must be ignorant indeed
if they fancied they could understand her springs of action, or
believed that they could intimidate her. With the dauphin at her knee,
she expatiated to the ladies of her court on the misfortune of kings
and queens having any connexion at all with the people beneath
them, whom it was at all times difficult to manage, and who might, as
now, cause serious trouble, and interfere materially with the peace of
royalty. She had at that moment little idea how the peace of royalty
was to be invaded this very day.
A murmur of horror and looks of dismay penetrated even into the
presence of her majesty, when tidings arrived of the approach of an
army of women from Paris.
“Of women!” cried the gouvernante of the dauphin. “Is it because
they can crave bread with a shriller wail?”
“Of women!” exclaimed the lady Alice de Thou. “They come to
plead for the rights of their children. I remember when they brought
the little ones in their arms after the storm, and we gave them all we
had.”
“Of women!” said the queen, thoughtfully. Then, with fire in her
eyes, she continued, looking steadfastly on the trembling
chamberlain who brought the news, “Since they are women, it is my
head they want. Is it not so? Speak. Are they not come for me?”
As soon as the chamberlain could speak, he muttered that he
feared they were indeed not women, but ruffians in disguise.
“Aye, just so,” observed the queen. “Their womanhood is
emblematical; and the hint of their purpose is not lost upon me. I
hope they are indeed men, and can handle arms. I would take my
death more willingly, being shot at as a mark, than being torn to
pieces by the foul hands of the rabble. A death-blow from afar rather
than a touch from any one of them!”
All present, except the chamberlain, were loud in their
protestations against the possibility of any such danger. It was
inconceivable; it was barbarous; it was horrific; it was a thing
unheard of; in short, it was absolutely inconceivable. The
chamberlain mournfully admitted that the whole was indeed
inconceivable to all who had not witnessed the procession, like a
troop of furies from the regions below, taking their way through every
savage district on the earth, and swelling their ranks with all that
could be gathered up of hideous and corrupt. That her majesty’s
sacred person should fall into such hands——
All now began to urge flight, and the queen was for a moment
disposed to listen; but finding that the king was out shooting, had
been sent for, and was expected every instant, she resolved to wait
his arrival, and then it was too late. The poissardes, real and
pretended, had by that time rushed into the place, filled the streets,
stopped up the avenue, and taken up a position of control in the
Chamber of Assembly. The king reached the palace through a back
entrance, in safety, but it was in vain to think of leaving it again.
A hasty council was summoned, consisting of the royal family, and
a few confidential servants, whose attachment to the persons of
majesty might set against the enervating terror which had seized
upon the ministers, and prevented their exerting any influence over
these new and appalling circumstances. Within the circle, rapid
consultation went on in low voices, while some kept watch at the
doors. When discussing the necessity of signing the declaration of
rights,—which was one of the demands of the mob without,—the
queen’s manner and tone were perceived suddenly to change, and
she appeared to make light of the danger under which even her spirit
had quailed but just before.
“Be careful;” she whispered to the person next her. “There is a
creature of the duke of Orleans in the room. I wonder how he got in.”
The lady Alice, who was watching her, followed the glance of her
eye, and saw that it rested on one whom she little expected to see.
“Madam!” she exclaimed, “it is my father!”
“Yes, my child; come to share your loyalty, now that the women
below have made him afraid. If the palace is stormed, he must find a
refuge once more under the Orleans provision-carts, which are, I
suppose, in waiting, as usual. We must give him no news to carry;
and Alice, as soon as he is gone, I must have your head-dress to
wear, as the best protection while your father points the way to us. I
would not, however, be so cruel, my child, as to deck you with mine.
You would lose your pretty head in a trice, and then the marquis