1 Immunology
Historical Milestones . . . . . . . . . . . . . . . . 1
The Immune System . . . . . . . . . . . . . . . . . 1
Systems of Immunity . . . . . . . . . . . . . . . 2
Organs and Cells of the Immune System . . . . . . 4
Cells of the Immune System . . . . . . . . . . . . . 9
Two Families of Lymphocytes . . . . . . . . . . 9
Structure and Molecular Framework . . . . . . 25
T and B Cell Receptors . . . . . . . . . . . . . . . . 56
T-Cell Antigen Receptors . . . . . . . . . . . . 57
B-Cell Antigen Receptors . . . . . . . . . . . . 59
Immunogens, Antigens and Allergens . . . . . . . 60
Epitopes and Paratopes . . . . . . . . . . . . . 61
Antibodies . . . . . . . . . . . . . . . . . . . . 64
Idiotypes and Anti-idiotypes . . . . . . . . . . 67
The HLA System . . . . . . . . . . . . . . . . . . . 74
Initial Phase of the Immune Response . . . . . . . 79
Functions of HLA Molecules
and Antigen Processing . . . . . . . . . . . . . 79
Cells of the Immune System Participating
in Immune Responses . . . . . . . . . . . . . . . . 82
Additional Cells . . . . . . . . . . . . . . . . . . 97
Afferent Phase of Immune Response . . . . . . . . 99
Antigen Processing and Presentation . . . . . . 99
Lymphocyte Activation . . . . . . . . . . . . . . . 103
Role of T Lymphocytes . . . . . . . . . . . . . . 104
Role of B Lymphocytes . . . . . . . . . . . . . . 106
Expression of Genes
and Transcriptional Activity . . . . . . . . . . . 107
Signal Transduction . . . . . . . . . . . . . . . 109
Mean Values of Lymphocyte Populations
and Subpopulations
and of Other Immune Cells . . . . . . . . . . . 111
Central Phase of the Immune Response:
Synthesis of IgE Antibodies . . . . . . . . . . . . . 116
A Two-Signal Model for Induction
of IgE Synthesis . . . . . . . . . . . . . . . . . . 116
Immune Responses . . . . . . . . . . . . . . . . . . 123
Immediate and Delayed Reactions . . . . . . . 123
Hypersensitivity Reactions . . . . . . . . . . . 124
Mediators . . . . . . . . . . . . . . . . . . . . . . . 129
Primary Mediators . . . . . . . . . . . . . . . . 130
Secondary Mediators . . . . . . . . . . . . . . . 133
Mechanisms of Cell Adhesion:
Interleukins and Adhesion Molecules . . . . . . . 133
Mechanisms of Cellular Adhesion . . . . . . . 135
Integrins . . . . . . . . . . . . . . . . . . . . . . 136
Selectins . . . . . . . . . . . . . . . . . . . . . . 138
Relationships Between ILs
and Adhesion Molecules . . . . . . . . . . . . . 140
Chemokines . . . . . . . . . . . . . . . . . . . . 140
Leukocyte Trafficking and Migration . . . . . . 148
Interrelations with Other Organs . . . . . . . . . . 151
Innate Immunity . . . . . . . . . . . . . . . . . . . 152
Therapeutic Perspectives . . . . . . . . . . . . . . 171
Allergens . . . . . . . . . . . . . . . . . . . . . . . 174
Allergen Standardization . . . . . . . . . . . . 175
Standardization Techniques . . . . . . . . . . . 175
Transgenic Foods . . . . . . . . . . . . . . . . . 182
Allergen Characteristics . . . . . . . . . . . . . 183
References . . . . . . . . . . . . . . . . . . . . . 202
2 Fetal and Neonatal Immunology
and the Mucosal Immune System
Immunodeficiency and Immaturity . . . . . . . . 221
Fetal–Neonatal Immune System:
Immunocompetence or Immune Depression? . . . 222
Ontogeny of the Immune System . . . . . . . . . . 225
T Cells . . . . . . . . . . . . . . . . . . . . . . . 229
B Cells . . . . . . . . . . . . . . . . . . . . . . . 231
Phagocyte Cells . . . . . . . . . . . . . . . . . . 233
Complement Factors . . . . . . . . . . . . . . . 233
Neonatal Immunodeficiency . . . . . . . . . . . . 234
Cellular Immunity . . . . . . . . . . . . . . . . 234
Humoral Immunity . . . . . . . . . . . . . . . 236
Innate Immunity . . . . . . . . . . . . . . . . . 237
Mucosal Immune System . . . . . . . . . . . . . . 238
Immune Components
of the Intestinal Mucosa . . . . . . . . . . . . . 239
Nutrition and Absorption
of Antigenic Macromolecules . . . . . . . . . . . . 247
Immunology of Breast Milk . . . . . . . . . . . 248
Immunology of Colostrum . . . . . . . . . . . 254
Experimental Studies on Neonatal Tolerance
and/or Immunocompetence . . . . . . . . . . . 258
Local Immunity in the Respiratory Mucosa . . . . 259
Local Immunity in the Skin . . . . . . . . . . . . . 261
Pediatricians and Neonates . . . . . . . . . . . 262
References . . . . . . . . . . . . . . . . . . . . . 262
Contents
XIII
3 Neonatal Immunology:
The Neonate at Risk of Atopy
The Neonate at Risk: Predisposing Factors . . . . 269
Supplementary Feeding in Maternity Wards . . 270
Prenatal Sensitization . . . . . . . . . . . . . . . . 270
Methods of Predicting the Development
of Allergic Disease . . . . . . . . . . . . . . . . . . 272
Alternative Tests to CBIgE Determination . . . 272
Pediatricians and Neonates at Risk . . . . . . . 280
References . . . . . . . . . . . . . . . . . . . . . 281
4 Genetic and Environmental Predisposing
Factors
Genes and Atopy . . . . . . . . . . . . . . . . . . . 285
Genetics of Atopy . . . . . . . . . . . . . . . . . . . 285
Genome-Wide Screens . . . . . . . . . . . . . . 288
Candidate Genes for Asthma and Atopy . . . . 288
Other Regions of Interest . . . . . . . . . . . . 294
Genetics of Pediatric Atopic Disease . . . . . . 297
Prenatal Genetic Factors
and the Fetal Immune System . . . . . . . . . . . 306
Postnatal Genetic Factors and Related Influence . 307
Environmental Factors . . . . . . . . . . . . . . . . 309
Residential Influences . . . . . . . . . . . . . . 311
Aeroallergens . . . . . . . . . . . . . . . . . . . 313
Environmental Pollutants . . . . . . . . . . . . 321
Immunotoxicology . . . . . . . . . . . . . . . . . . 327
Environmental Tobacco Smoke . . . . . . . . . 335
Hygiene Hypothesis . . . . . . . . . . . . . . . 346
Interactions Between Genetic
and Environmental Factors . . . . . . . . . . . 347
Pediatricians, Genotype, Phenotype
and Early Predisposing Factors . . . . . . . . . 347
References . . . . . . . . . . . . . . . . . . . . . 349
5 Epidemiology and Natural History
of Atopic Disease
Epidemiology . . . . . . . . . . . . . . . . . . . . . 363
Lack of Uniformity of Diagnostic Parameters . . . 363
Age at Onset . . . . . . . . . . . . . . . . . . . . . . 365
Atopic March . . . . . . . . . . . . . . . . . . . 366
Atopic Dermatitis . . . . . . . . . . . . . . . . . . 373
Oral Allergic Syndrome . . . . . . . . . . . . . . . 380
Urticaria and Angioedema . . . . . . . . . . . . . 380
Allergic Contact Dermatitis . . . . . . . . . . . . . 380
Food Allergy . . . . . . . . . . . . . . . . . . . . . 381
Asthma . . . . . . . . . . . . . . . . . . . . . . . . 384
Allergy to Inhalants . . . . . . . . . . . . . . . . . 399
Allergic Rhinitis . . . . . . . . . . . . . . . . . . . 402
Allergic Conjunctivitis . . . . . . . . . . . . . . . . 408
Insect Allergy . . . . . . . . . . . . . . . . . . . . . 408
Prevalence of Atopic Disease at Various Ages . . . 408
Prevalence of Immunodeficiencies . . . . . . . . . 409
Pediatricians and Epidemiology . . . . . . . . 409
References . . . . . . . . . . . . . . . . . . . . . 410
6 Diagnosis of Pediatric Allergy
From History to Clinical–Functional Examination 421
Allergy History . . . . . . . . . . . . . . . . . . . . 422
Family Allergy History . . . . . . . . . . . . . . 422
Personal Allergy History . . . . . . . . . . . . . 422
Past and Present Allergy History . . . . . . . . 423
Present Allergy History for Atopic Dermatitis
and Food Allergy . . . . . . . . . . . . . . . . . 423
Present Allergy History for Urticaria
and Angioedema and Additional Skin Allergies 424
Present Allergy History
for Asthma Rhinoconjunctivitis . . . . . . . . . 424
Environmental History . . . . . . . . . . . . . . 424
Medical Examination . . . . . . . . . . . . . . . . 425
Diagnosis Type . . . . . . . . . . . . . . . . . . 430
Immunoallergic Diagnosis . . . . . . . . . . . . . 431
In vivo Immunoallergic Tests . . . . . . . . . . 431
Skin Prick Tests . . . . . . . . . . . . . . . . . . 431
Prick + Prick Testing . . . . . . . . . . . . . . . 436
Patch Test or Epicutaneous Test . . . . . . . . . 438
Photopatch Testing . . . . . . . . . . . . . . . . 439
In vitro Immunoallergic Tests . . . . . . . . . . . . 439
Total Serum IgE . . . . . . . . . . . . . . . . . . 439
Specific IgE Antibody Determination . . . . . . 441
Prerequisites, Advantages and Disadvantages
of Diagnostic Tests . . . . . . . . . . . . . . . . . . 445
Advantages and Disadvantages of In vivo Tests 446
Advantages and Disadvantages of In vitro Tests 447
Future Diagnostic Avenues . . . . . . . . . . . . . 451
Recombinant Allergens . . . . . . . . . . . . . 451
CD203c . . . . . . . . . . . . . . . . . . . . . . 451
Provocation Tests . . . . . . . . . . . . . . . . . . . 452
Conjunctival Testing . . . . . . . . . . . . . . . 452
Nasal Testing . . . . . . . . . . . . . . . . . . . 452
Bronchial Provocation Testing . . . . . . . . . . 453
Overall Evaluation of Provocation Tests . . . . 455
Conjunctival Provocation Test . . . . . . . . . . 455
Nasal Provocation Test . . . . . . . . . . . . . . 455
Bronchial Provocation Test . . . . . . . . . . . 456
Additional Tests . . . . . . . . . . . . . . . . . 456
Pulmonary Function Testing . . . . . . . . . . . . 457
Peak Expiratory Flow Rate . . . . . . . . . . . . 457
Spirometry . . . . . . . . . . . . . . . . . . . . 462
Pulmonary Function Tests
in Children Under 12 Months to 6–7 Years . . . 464
Medicolegal Aspects of Immunoallergic Testing . 466
Pediatricians and Diagnostic Whereabouts . . 467
References . . . . . . . . . . . . . . . . . . . . . 467
XIV Contents
7 Atopic Dermatitis
The First Clinical Manifestation of Atopy . . . . . 473
Skin Immunopathophysiology . . . . . . . . . . . 474
The Role of Skin Surface Barrier . . . . . . . . 474
Skin Immune System . . . . . . . . . . . . . . . . . 475
Relationships Between Skin
and Immune System . . . . . . . . . . . . . . . 475
Pathogenesis . . . . . . . . . . . . . . . . . . . . . 479
Genetics . . . . . . . . . . . . . . . . . . . . . . 479
Immune Dysfunctions . . . . . . . . . . . . . . . . 481
Cell-Mediated Immunity . . . . . . . . . . . . . 481
Humoral Immunity: Role of IgE Antibodies . . 483
Role of T Lymphocytes . . . . . . . . . . . . . . 487
Langerhans Cells . . . . . . . . . . . . . . . . . 490
Interleukins and AD . . . . . . . . . . . . . . . 491
IgE and Histamine-Releasing Factors . . . . . . 492
A Concluding Pathogenic Hypothesis . . . . . 493
Biochemical Dysfunctions . . . . . . . . . . . . . . 493
Additional Biochemical
or Pharmacophysiological Anomalies . . . . . 495
Additional Pathogenic Factors . . . . . . . . . . . 495
Role of Infections . . . . . . . . . . . . . . . . . 495
Role of Food Factors . . . . . . . . . . . . . . . 497
Role of Food Additives . . . . . . . . . . . . . . 497
Role of Aeroallergens . . . . . . . . . . . . . . . 497
Pathophysiology of Itching . . . . . . . . . . . . . 499
Irritant Effects . . . . . . . . . . . . . . . . . . 500
Clinical Presentation . . . . . . . . . . . . . . . . . 500
Additional Clinical Features . . . . . . . . . . . 502
Complications . . . . . . . . . . . . . . . . . . . . 506
Additional Complications . . . . . . . . . . . . 507
Association with Other Atopic Diseases . . . . 507
Association with Nonatopic Diseases . . . . . . 508
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . 508
Differential Diagnosis . . . . . . . . . . . . . . 509
Management . . . . . . . . . . . . . . . . . . . . . 512
General and Local Hygienic
and Preventive Measures: Acute Phase . . . . . 512
Local Aspecific Cutaneous Treatment . . . . . . 515
Medical Treatment . . . . . . . . . . . . . . . . 516
Specific Antiallergic Measures . . . . . . . . . . 521
Additional Measures to Be Suggested
to Parents . . . . . . . . . . . . . . . . . . . . . 521
Antiasthmatic Measures . . . . . . . . . . . . . 522
Relationships Between AD and FA . . . . . . . . . 522
Epidemiology . . . . . . . . . . . . . . . . . . . 523
Pathophysiology . . . . . . . . . . . . . . . . . 523
Pathogenesis . . . . . . . . . . . . . . . . . . . . . 523
Experimental Studies . . . . . . . . . . . . . . 523
Clinical Studies . . . . . . . . . . . . . . . . . . 524
Clinical Presentation . . . . . . . . . . . . . . . . . 525
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . 526
Treatment . . . . . . . . . . . . . . . . . . . . . . . 527
Course and Prognosis . . . . . . . . . . . . . . . . 527
Pediatricians and AD . . . . . . . . . . . . . . . 529
References . . . . . . . . . . . . . . . . . . . . . 529
8 Other Allergic Skin Disorders
A Skin Panorama . . . . . . . . . . . . . . . . . . . 539
Urticaria-Angioedema Syndrome . . . . . . . . . 539
Etiopathogenesis . . . . . . . . . . . . . . . . . 540
Pathogenesis of Hereditary Angioedema . . . . 544
Pathogenesis of Urticaria . . . . . . . . . . . . 545
Clinical Presentation . . . . . . . . . . . . . . . 547
Physical Urticaria . . . . . . . . . . . . . . . . . 548
Diagnosis . . . . . . . . . . . . . . . . . . . . . 553
Treatment . . . . . . . . . . . . . . . . . . . . . 557
Prevention . . . . . . . . . . . . . . . . . . . . . 558
Allergic Contact Dermatitis . . . . . . . . . . . . . 558
Etiopathogenesis . . . . . . . . . . . . . . . . . 559
Etiological Agents . . . . . . . . . . . . . . . . 561
Clinical Presentation . . . . . . . . . . . . . . . 567
Types of ACD . . . . . . . . . . . . . . . . . . . 567
Diagnosis . . . . . . . . . . . . . . . . . . . . . 571
Treatment . . . . . . . . . . . . . . . . . . . . . 574
Protein Contact Dermatitis . . . . . . . . . . . . . 576
Phytodermatitis . . . . . . . . . . . . . . . . . . . 577
Allergic Photodermatitis . . . . . . . . . . . . . . 577
Contact Dermatitis by Seawater Organisms . . 579
Allergic Vasculitis . . . . . . . . . . . . . . . . . . 580
Immunopathogenesis . . . . . . . . . . . . . . 581
Clinical Presentation . . . . . . . . . . . . . . . 582
Prominent Vasculitis Syndromes in Children . 583
Diagnosis . . . . . . . . . . . . . . . . . . . . . 587
Treatment . . . . . . . . . . . . . . . . . . . . . 588
Pediatricians and Other Cutaneous Allergies . 588
References . . . . . . . . . . . . . . . . . . . . . 589
9 Food Allergy
One Allergy, Several Allergies . . . . . . . . . . . . 595
Pathogenesis . . . . . . . . . . . . . . . . . . . . . 596
Immune Mechanisms . . . . . . . . . . . . . . 596
In Utero Sensitization . . . . . . . . . . . . . . 600
Postnatal Sensitization . . . . . . . . . . . . . . 601
Immunology of the Gastrointestinal Tract . . . . . 602
GALT Regulation of Effector Functions . . . . 609
Oral Tolerance: Experimental Data . . . . . . . 611
Oral Tolerance: Factors that Condition
Its Induction and Maintenance . . . . . . . . . 613
Cow’s Milk Allergy . . . . . . . . . . . . . . . . . . 616
Clinical Manifestations . . . . . . . . . . . . . . . 616
Systemic Manifestations . . . . . . . . . . . . . 618
Gastrointestinal Manifestations . . . . . . . . . 619
Respiratory Manifestations . . . . . . . . . . . 622
Other Food-Induced Manifestations . . . . . . 622
Allergy to Other Foods . . . . . . . . . . . . . . . . 625
Allergy to Single Foods . . . . . . . . . . . . . 625
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . 636
Diagnostic Elimination Diets . . . . . . . . . . 637
Food Challenge Test . . . . . . . . . . . . . . . 640
Challenge Procedure . . . . . . . . . . . . . . . 640
Contents XV
Evaluation of Food Challenge Testing . . . . . . . 644
Dietary Treatment . . . . . . . . . . . . . . . . . . 647
Allergy to Single Foods . . . . . . . . . . . . . 663
Diet Duration . . . . . . . . . . . . . . . . . . . 669
Prevention of FA . . . . . . . . . . . . . . . . . 670
Medical Treatment . . . . . . . . . . . . . . . . 671
Acquisition of Oral Tolerance . . . . . . . . . . . . 671
FA-Caused Death . . . . . . . . . . . . . . . . . . . 678
Oral Allergy Syndrome . . . . . . . . . . . . . . . 679
Bird-Egg Syndrome . . . . . . . . . . . . . . . . . 682
Pediatricians and FA . . . . . . . . . . . . . . . 682
References . . . . . . . . . . . . . . . . . . . . . 682
10 Pseudoallergy and Food Immunotoxicology
Allergy and Pseudoallergy . . . . . . . . . . . . . 697
Pseudoallergy to Food Additives . . . . . . . . . . 699
Pharmacological Reactions . . . . . . . . . . . . . 710
Enzymatic Reactions . . . . . . . . . . . . . . . . . 714
Metabolic Reactions . . . . . . . . . . . . . . . . . 715
Toxic Reactions . . . . . . . . . . . . . . . . . . . . 715
Anaphylactoid Reactions . . . . . . . . . . . . . . 718
Immunotoxicology . . . . . . . . . . . . . . . . . . 718
Food Immunotoxicology . . . . . . . . . . . . 720
Pediatricians, Pseudoallergy,
and Immunotoxicology . . . . . . . . . . . . . 721
References . . . . . . . . . . . . . . . . . . . . . 721
11 Asthma
Pediatric Asthma . . . . . . . . . . . . . . . . . . . 725
Defense Mechanisms in the Airways . . . . . . . . 727
Genetic Factors . . . . . . . . . . . . . . . . . . . . 729
Pathogenesis . . . . . . . . . . . . . . . . . . . . . 732
Role of Immune Inflammation . . . . . . . . . 732
Role of the Inflammatory Cells . . . . . . . . . 737
The Role of IgE . . . . . . . . . . . . . . . . . . 749
Role of the Mediators . . . . . . . . . . . . . . 750
Role of Cytokines . . . . . . . . . . . . . . . . . 751
Airway Remodeling . . . . . . . . . . . . . . . . . 752
Role of Bronchial Hyperreactivity . . . . . . . 756
Endogenous Factors . . . . . . . . . . . . . . . 757
Main Exogenous Factors . . . . . . . . . . . . . 765
Predisposing Factors . . . . . . . . . . . . . . . . . 765
Anatomical and Physiological Predisposing
Factors . . . . . . . . . . . . . . . . . . . . . . . 765
Predisposing or Etiological Factors . . . . . . . 767
Drugs to Be Used and Routes of Administration . 772
Routes of Administration . . . . . . . . . . . . 772
Age Ranges for Inhalant Therapy . . . . . . . . 777
Dosages for the Very Young . . . . . . . . . . . 778
Drugs to Be Used . . . . . . . . . . . . . . . . . 778
Bronchiolitis . . . . . . . . . . . . . . . . . . . . . 793
Asthma . . . . . . . . . . . . . . . . . . . . . . . . 802
Clinical Presentation . . . . . . . . . . . . . . . . . 805
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . 805
Severe Asthmatic Attack – Status Asthmaticus 808
Treatment . . . . . . . . . . . . . . . . . . . . . . . 812
Treatment of Acute Asthma Attack . . . . . . . 812
Treatment of Status Asthmaticus . . . . . . . . 814
Treatment of Episodic, Frequent, Chronic
and Other Forms of Asthma . . . . . . . . . . . 822
Death by Asthma . . . . . . . . . . . . . . . . . 838
Prevention . . . . . . . . . . . . . . . . . . . . . 842
Preventive Therapy . . . . . . . . . . . . . . . . 842
Outcome . . . . . . . . . . . . . . . . . . . . . . 847
Present and Future Prospects . . . . . . . . . . . . 848
Anti-IgE . . . . . . . . . . . . . . . . . . . . . . 848
Leukotriene Modifiers . . . . . . . . . . . . . . 848
Other Pediatric Allergic Lung Disease . . . . . . . 850
Extrinsic Allergic Alveolitis . . . . . . . . . . . 850
Allergic Bronchopulmonary Aspergillosis . . . 851
Pediatricians and Pediatric Asthma . . . . . . . 853
References . . . . . . . . . . . . . . . . . . . . . 853
12 Allergic Rhinitis
The Airway Entrance . . . . . . . . . . . . . . . . . 875
Nasal Immunology . . . . . . . . . . . . . . . . . . 878
Immunopathology . . . . . . . . . . . . . . . . 879
Etiological Factors . . . . . . . . . . . . . . . . . . 886
Anatomical–Physiological Factors
Differentiating Children from Adults . . . . . . 889
Classification . . . . . . . . . . . . . . . . . . . 889
Seasonal Allergic Rhinitis . . . . . . . . . . . . . . 889
Perennial Allergic Rhinitis . . . . . . . . . . . . . 894
Treatment . . . . . . . . . . . . . . . . . . . . . . . 897
Identification and Elimination
of Principal Allergens . . . . . . . . . . . . . . 897
Antihistamines . . . . . . . . . . . . . . . . . . 897
Anticholinergics . . . . . . . . . . . . . . . . . 901
Cromones . . . . . . . . . . . . . . . . . . . . . 901
Corticosteroids . . . . . . . . . . . . . . . . . . 901
Anti-LT . . . . . . . . . . . . . . . . . . . . . . 903
Specific Immunotherapy . . . . . . . . . . . . . 903
Prevention . . . . . . . . . . . . . . . . . . . . . 903
Quality of Life . . . . . . . . . . . . . . . . . . . 903
Pediatricians and Allergic Rhinitis . . . . . . . 905
References . . . . . . . . . . . . . . . . . . . . . 905
13 Specific Immunotherapy
Specific Therapy for Pediatric Asthma
and Rhinitis . . . . . . . . . . . . . . . . . . . . . . 911
SIT Efficacy: Clinical Effects . . . . . . . . . . . . . 916
SIT Efficacy: Immunological Effects . . . . . . . . 920
Considerations Before Initiating SIT . . . . . . . . 927
General Criteria of SIT Execution . . . . . . . . . 927
Treatment Chronology . . . . . . . . . . . . . . . . 929
Adverse Reactions . . . . . . . . . . . . . . . . . . 932
Treatment of Local and Systemic Reactions . . 935
Comparison Between SIT
and Pharmacotherapy . . . . . . . . . . . . . . 937
XVI Contents
Present and Future Perspectives . . . . . . . . . . 938
Present Perspectives . . . . . . . . . . . . . . . 939
Comparison of Traditional (SC) SIT
and Other Routes . . . . . . . . . . . . . . . . . 943
Future Perspectives . . . . . . . . . . . . . . . . 943
Long-Term Perspectives . . . . . . . . . . . . . 950
Pediatricians and SIT . . . . . . . . . . . . . . 951
References . . . . . . . . . . . . . . . . . . . . . 951
14 Eye Allergy and Immunology
Eye Disorders . . . . . . . . . . . . . . . . . . . . . 961
Pathophysiology . . . . . . . . . . . . . . . . . 961
Ocular Immunology . . . . . . . . . . . . . . . . . 962
Conjunctiva-Associated Lymphoid Tissue . . . 962
Immune Functions . . . . . . . . . . . . . . . . 966
Allergic Conjunctivitis . . . . . . . . . . . . . . . . 968
Vernal Keratoconjunctivitis . . . . . . . . . . . . . 972
Atopic Keratoconjunctivitis . . . . . . . . . . . . . 977
Giant Papillary Conjunctivitis . . . . . . . . . . . 978
Ocular Contact Allergy . . . . . . . . . . . . . . . 980
Acute Edematous Conjunctivitis . . . . . . . . . . 981
Blepharitis . . . . . . . . . . . . . . . . . . . . . . 981
Keratitis . . . . . . . . . . . . . . . . . . . . . . . . 981
Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . 982
New Therapeutic Perspectives . . . . . . . . . . . . 984
Pediatricians and Eye Allergy . . . . . . . . . . 985
References . . . . . . . . . . . . . . . . . . . . . 985
15 Other Allergic Otorhinolaryngological
Diseases
Von Waldeyer’s Ring . . . . . . . . . . . . . . . . . 991
Nasal-Associated Lymphoid Tissue . . . . . . . . . 991
Tonsil Immunology . . . . . . . . . . . . . . . . . 993
Otitis Media with Effusion . . . . . . . . . . . . . . 998
Immunopathology . . . . . . . . . . . . . . . 1000
Pathogenesis . . . . . . . . . . . . . . . . . . 1002
Clinical Presentation . . . . . . . . . . . . . . 1005
Diagnosis . . . . . . . . . . . . . . . . . . . . 1006
Treatment . . . . . . . . . . . . . . . . . . . . 1007
Sinusitis . . . . . . . . . . . . . . . . . . . . . . . 1009
Pathophysiology . . . . . . . . . . . . . . . . 1010
Allergic Sinusitis . . . . . . . . . . . . . . . . 1014
Relationship Between Asthma,
Allergic Rhinitis, and Sinusitis . . . . . . . . . 1015
Clinical Presentation . . . . . . . . . . . . . . 1016
Diagnosis . . . . . . . . . . . . . . . . . . . . 1017
Treatment . . . . . . . . . . . . . . . . . . . . 1019
Pediatricians and ORL Diseases . . . . . . . . 1021
References . . . . . . . . . . . . . . . . . . . . 1021
16 Allergy and Central Nervous System
and Other Allergies
Introduction . . . . . . . . . . . . . . . . . . . . 1029
Migraine and Allergy . . . . . . . . . . . . . . . . 1029
Psychological and Neurological Factors
and Allergic Disease . . . . . . . . . . . . . . 1033
Chronic Fatigue Syndrome . . . . . . . . . . . . 1037
Clinical Presentation of Other Systems . . . . . . 1042
Clinical Ecology . . . . . . . . . . . . . . . . . 1046
Pediatricians, Migraine, and Other Allergies 1048
References . . . . . . . . . . . . . . . . . . . . 1049
17 Allergy to the Venom of Hymenoptera
and Other Insects
Historical Data . . . . . . . . . . . . . . . . . . . 1055
Characteristics of Hymenoptera . . . . . . . . . 1056
Genetic and Environmental Factors . . . . . . 1060
Etiopathogenesis . . . . . . . . . . . . . . . . 1062
Clinical Presentation . . . . . . . . . . . . . . 1062
Diagnosis . . . . . . . . . . . . . . . . . . . . 1064
Treatment . . . . . . . . . . . . . . . . . . . . 1066
Biting Insect Allergy . . . . . . . . . . . . . . . . 1068
Prevention . . . . . . . . . . . . . . . . . . . . 1070
Pediatricians and Insect Allergy . . . . . . . . 1070
References . . . . . . . . . . . . . . . . . . . . 1071
18 Autoimmune Diseases
Dysregulation of the Immune System . . . . . . 1075
Etiopathogenesis . . . . . . . . . . . . . . . . . . 1077
Etiopathogenetic Mechanisms . . . . . . . . . 1079
Juvenile Rheumatoid Arthritis . . . . . . . . . . 1085
Etiopathogenesis . . . . . . . . . . . . . . . . 1085
Drugs of Tomorrow . . . . . . . . . . . . . . . 1099
Inflammatory Bowel Disease . . . . . . . . . . . 1100
Etiopathogenesis . . . . . . . . . . . . . . . . 1102
Ulcerative Colitis . . . . . . . . . . . . . . . . 1105
Crohn’s Disease . . . . . . . . . . . . . . . . . 1105
Autoimmune Hematological Disorders . . . . . . 1110
Autoimmune Lymphoproliferative Syndrome 1110
Autoimmune Neutropenia . . . . . . . . . . . 1110
Diabetes . . . . . . . . . . . . . . . . . . . . . 1111
Systemic AIDs . . . . . . . . . . . . . . . . . . . . 1117
Systemic Lupus Erythematosus . . . . . . . . 1117
Juvenile Dermatomyositis . . . . . . . . . . . 1124
Juvenile Scleroderma . . . . . . . . . . . . . . 1127
Pediatricians and Autoimmune Diseases . . . 1131
References . . . . . . . . . . . . . . . . . . . . 1131
Contents XVII
19 Allergic and Pseudoallergic Reactions
to Drugs
Pediatric Drug-Induced Disorders . . . . . . . . 1147
Etiopathogenesis . . . . . . . . . . . . . . . . . . 1148
Predisposing Factors . . . . . . . . . . . . . . 1155
Clinical Presentation . . . . . . . . . . . . . . . . 1158
Clinical Features . . . . . . . . . . . . . . . . 1159
Additional Drug-Induced
Reactive Syndromes . . . . . . . . . . . . . . 1182
Characterization of Various Drugs
and Categories of Drugs . . . . . . . . . . . . 1184
Uncommon Reactions to Drugs . . . . . . . . 1190
Diagnosis . . . . . . . . . . . . . . . . . . . . . . 1190
Skin Test Indications and Application . . . . 1194
Challenge Testing . . . . . . . . . . . . . . . . 1196
Treatment . . . . . . . . . . . . . . . . . . . . . . 1196
Drug-Related Deaths . . . . . . . . . . . . . . . . 1197
Prevention . . . . . . . . . . . . . . . . . . . . . . 1197
Pediatricians and Drug-Induced Allergies
and Pseudoallergies . . . . . . . . . . . . . . 1197
References . . . . . . . . . . . . . . . . . . . . 1198
20 Anaphylaxis
Historical Outline . . . . . . . . . . . . . . . . . . 1205
Physiopathology . . . . . . . . . . . . . . . . 1206
Histopathology . . . . . . . . . . . . . . . . . 1207
Pathogenesis . . . . . . . . . . . . . . . . . . . . 1207
Risk Factors . . . . . . . . . . . . . . . . . . . . . 1210
Anaphylactoid Reactions . . . . . . . . . . . . 1221
Others . . . . . . . . . . . . . . . . . . . . . . 1221
Clinical Presentation . . . . . . . . . . . . . . . . 1222
Diagnosis . . . . . . . . . . . . . . . . . . . . . . 1225
Immediate Treatment . . . . . . . . . . . . . . . 1228
Pediatricians and Anaphylaxis . . . . . . . . . 1236
References . . . . . . . . . . . . . . . . . . . . 1236
21 Malnutrition and the Immune System
Immunological Effects of Child Malnutrition . . 1243
Protein-Energy Malnutrition . . . . . . . . . . . 1244
Micronutrient Deficiency . . . . . . . . . . . . . 1249
Vitamin Deficiency . . . . . . . . . . . . . . . 1249
Trace Element Deficiency . . . . . . . . . . . 1251
Essential Fatty Acid Deficiency or Excess . . . . . 1253
Other Causes of Malnutrition . . . . . . . . . . . 1255
Immunological Effects
of Neonatal Malnutrition . . . . . . . . . . . . 1257
Clinical Presentation . . . . . . . . . . . . . . 1259
Diagnosis . . . . . . . . . . . . . . . . . . . . 1260
Treatment . . . . . . . . . . . . . . . . . . . . 1260
Pediatricians, Malnutrition, and the Immune
System . . . . . . . . . . . . . . . . . . . . . . 1261
References . . . . . . . . . . . . . . . . . . . . 1261
22 Primary Immunodeficiencies
A World in Motion . . . . . . . . . . . . . . . . . 1265
Immunodeficiency and Atopy . . . . . . . . . . . 1265
Immunodeficiencies Associated with Hyper-IgE 1269
Immunodeficiency with Autoimmunity . . . . . 1270
Primary Immunodeficiencies . . . . . . . . . . . 1270
Predominantly B-Cell Immunodeficiency . . . . 1276
X-Linked Agammaglobulinemia
or Bruton Tyrosine Kinase Deficiency . . . . 1276
Gene Deletion for H Chains . . . . . . . . . . 1277
k and l Chain Deficiency . . . . . . . . . . . . 1277
Selective Ig Deficiency . . . . . . . . . . . . . 1279
Selective Antibody Deficiency
with Normal Ig Isotypes . . . . . . . . . . . . 1281
Selective Deficiency of Other Igs . . . . . . . 1281
Common Variable ID . . . . . . . . . . . . . . 1281
Not-X-Linked Hyper-IgM . . . . . . . . . . . 1282
Transient Hypogammaglobulinemia
of Infancy . . . . . . . . . . . . . . . . . . . . 1282
Combined T-Cell and B-Cell Deficiency . . . . . 1283
T–B+ SCID . . . . . . . . . . . . . . . . . . . . 1283
IL7R Deficiency . . . . . . . . . . . . . . . . . 1286
T–B– SCID . . . . . . . . . . . . . . . . . . . . 1286
T+B– SCID . . . . . . . . . . . . . . . . . . . . 1289
IL2 Deficiency (IL2Ra-Chain Gene Mutations) 1290
X-Linked Hyper-IgM (or Hyper-IgD)
or CD154 Deficiency Syndrome (XHIgMS) . . 1290
Purine-Nucleoside Phosphorylase Deficiency 1293
HLA Deficiency . . . . . . . . . . . . . . . . . 1294
CD3g, CD3d, CD3e, CD3z Deficiency . . . . . 1295
ZAP-70 Deficiency
or Selective CD8 Deficiency . . . . . . . . . . 1295
TAP-2 Deficiency . . . . . . . . . . . . . . . . 1296
NFAT Deficiency . . . . . . . . . . . . . . . . 1296
NK-Cell Deficiency . . . . . . . . . . . . . . . 1296
Undifferentiated SCID . . . . . . . . . . . . . 1297
Predominantly T-Cell Defects . . . . . . . . . . . 1297
Primary CD4 T-Cell Deficiency . . . . . . . . 1297
Primary CD7 Deficiency . . . . . . . . . . . . 1297
Primary CD45 Deficiency . . . . . . . . . . . 1297
Multiple IL Defects . . . . . . . . . . . . . . . 1298
Nezelof Syndrome . . . . . . . . . . . . . . . 1298
Fas (CD95) Deficiency . . . . . . . . . . . . . 1298
Other Well-Defined ID Syndromes . . . . . . . . 1298
Wiskott-Aldrich Syndrome . . . . . . . . . . 1298
Ataxia-Telangiectasia . . . . . . . . . . . . . . 1301
DiGeorge Syndrome . . . . . . . . . . . . . . 1303
X-Linked Lymphoproliferative Syndrome . . 1305
Hyper-IgE Syndrome . . . . . . . . . . . . . . 1305
Chédiak-Higashi Syndrome . . . . . . . . . . 1307
Griscelli Disease . . . . . . . . . . . . . . . . 1307
Phagocyte Deficiency . . . . . . . . . . . . . . . . 1307
Chronic Granulomatous Disease . . . . . . . 1307
Leukocyte Adhesion Deficiency . . . . . . . . 1312
Deficiency of Multiple Leukocyte Integrins . 1314
Glucose-6-Phosphate-Dehydrogenase
Deficiency . . . . . . . . . . . . . . . . . . . . 1314
XVIII Contents
Myeloperoxidase Deficiency . . . . . . . . . . 1314
Specific Granule Deficiency . . . . . . . . . . 1315
Neutropenia . . . . . . . . . . . . . . . . . . . 1315
Shwachman Syndrome . . . . . . . . . . . . . 1316
Leukocyte Mycobactericidal Defect . . . . . . 1317
Complement Deficiency . . . . . . . . . . . . . . 1318
C1 Deficiency . . . . . . . . . . . . . . . . . . 1318
C1q Deficiency . . . . . . . . . . . . . . . . . 1319
C4 Deficiency . . . . . . . . . . . . . . . . . . 1319
C2 Deficiency . . . . . . . . . . . . . . . . . . 1320
C3 Deficiency . . . . . . . . . . . . . . . . . . 1320
C5 Deficiency . . . . . . . . . . . . . . . . . . 1320
C6 Deficiency . . . . . . . . . . . . . . . . . . 1320
C7 Deficiency . . . . . . . . . . . . . . . . . . 1320
C8 Deficiency . . . . . . . . . . . . . . . . . . 1321
C9 Deficiencies . . . . . . . . . . . . . . . . . 1321
C1 Inhibitor Deficiency . . . . . . . . . . . . . 1321
Factor I Deficiency . . . . . . . . . . . . . . . 1321
Factor H Deficiency . . . . . . . . . . . . . . . 1321
Factor D Deficiency . . . . . . . . . . . . . . . 1321
Properdin Deficiency . . . . . . . . . . . . . . 1321
Children with RRIs . . . . . . . . . . . . . . . 1322
Immunodeficiency . . . . . . . . . . . . . . . 1324
Clinical Presentation . . . . . . . . . . . . . . 1327
Diagnosis and Differential Diagnosis . . . . . 1327
Treatment . . . . . . . . . . . . . . . . . . . . . . 1333
Antibody Deficiency . . . . . . . . . . . . . . 1333
T-Cell PID . . . . . . . . . . . . . . . . . . . . 1333
Bone Marrow Transplantation . . . . . . . . . 1335
Children with RRIs . . . . . . . . . . . . . . . 1340
Pediatricians, PID and RRIs . . . . . . . . . . 1341
References . . . . . . . . . . . . . . . . . . . . 1342
23 Pediatric AIDS
Twenty-Five Years of Science . . . . . . . . . . . . 1359
HIV . . . . . . . . . . . . . . . . . . . . . . . . . . 1359
Etiopathogenesis . . . . . . . . . . . . . . . . . . 1363
Pediatric HIV Infection . . . . . . . . . . . . . . 1371
Pathogenesis of HIV Transmission in Childhood 1375
Clinical Presentation . . . . . . . . . . . . . . . . 1380
Diagnosis . . . . . . . . . . . . . . . . . . . . 1387
Treatment . . . . . . . . . . . . . . . . . . . . . . 1394
Outcome . . . . . . . . . . . . . . . . . . . . . . . 1410
Current Implications . . . . . . . . . . . . . . . . 1410
Pediatricians and HIV-Positive Children . . . 1416
References . . . . . . . . . . . . . . . . . . . . 1416
24 Prevention of Allergic Disorders
Preventing Atopic March: A Priority . . . . . . . 1433
Primary Prevention . . . . . . . . . . . . . . . . 1434
Role of Diet . . . . . . . . . . . . . . . . . . . . . 1434
Prenatal Role of Diet . . . . . . . . . . . . . . 1434
Role of Postnatal Diet . . . . . . . . . . . . . 1435
Role of Allergen Avoidance . . . . . . . . . . . . 1442
Immune Interventions . . . . . . . . . . . . . 1444
Dietary Prevention
and Environmental Measures . . . . . . . . . . . 1444
Secondary Prevention . . . . . . . . . . . . . . . 1460
Avoiding Allergen Contacts . . . . . . . . . . 1460
Airborne Allergens . . . . . . . . . . . . . . . 1460
Preventing Allergen Entry
or Mast Cell Degranulation . . . . . . . . . . . . 1485
Modifying the State
of Sensitization Using Available Aids . . . . . 1485
Mad Cow Disease . . . . . . . . . . . . . . . . 1479
Transgenic Foods . . . . . . . . . . . . . . . . 1479
Hygiene Hypothesis . . . . . . . . . . . . . . 1480
Tertiary Prevention . . . . . . . . . . . . . . . 1486
New Frontiers . . . . . . . . . . . . . . . . . . . . 1487
References . . . . . . . . . . . . . . . . . . . . 1490
Appendices . . . . . . . . . . . . . . . . . . . . 1505
References not indicated . . . . . . . . . . . . 1553
Subject Index . . . . . . . . . . . . . . . . . . . 1555
Figure Credits . . . . . . . . . . . . . . . . . . . 1615
