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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_4518_Библиотеки_им_академика_М_И_Перельмана
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7 Allergy andImmunology
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• Allergen extracts are formulated (both aqueous and tablet) and delivered sublingually
• Evidence shows duration of benet of at least 2years after a 3-year
treatment duration.
• Can be continued during pregnancy—no increased risk of adverse
events, nor increased incidence of atopic disease in offspring
– Differences between SCIT and SLIT
Safety:
• Fatal reactions from SCIT occur at rate of 1in 2–2.5 million → 3.4
deaths/year.
• Between 2006 and 2009, six possible reported anaphylaxis, none resulting in fatalities
• Studies show a marginally better risk prole for SLIT compared to
SCIT, but FDA still mandates epi-pen prescription with rst SLIT dosing and must occur in physician’s ofce.
Efcacy:
• A 2007 Cochrane meta-analysis showed that immunotherapy reduced
medication use, decreased clinical symptoms, and improved quality
of life.
• Efcacy has been shown to last as long as 3years post-immunotherapy
cessation.
• Quality of evidence showing that SCIT is more efcacious than SLIT
is weak.
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Dosing
• Optimum SCIT maintenance dose is 5–20μg of major allergen.
Optimum SLIT maintenance dose not elucidated, but median monthly
dosing is 49× that of SCIT.
Cost
• Several FDA-approved SLIT tablets available (grass pollen, dust mites
and ragweed)
• Cost of SCIT varies dramatically according to insurance plans, while
SLIT varies between practices.
– Insurance companies covered 60–100% of cost for SCIT.Medicare
had a at 80% coverage—average cost for year of treatment ~$800
– SLIT cost ranged from $500 to 2100 depending on the allergy prac-
tice surveyed and number of antigens treated.
• When loss of productivity and travel expense is added into the cost of
SCIT, SLIT may be comparable in cost and more convenient for the
patient.
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A. Del Signore et al.
– Complications
Typically secondary to
• Presence, severity, control status of asthma
Dosing—inadvertent mistakes in antigen selection or concentration
calculation
• Accelerated dosing schedules
• Treatment during peak pollen season
• Extensive sensitivity to allergen
Local
• SCIT: induration, wheal
• SLIT: oral itching, irritation
Systemic
• SCIT: coughing, wheezing, shortness of breath, urticarial, anaphylaxis
• SLIT: Gastrointestinal—i.e., abdominal pain, nausea, vomiting
• Biologics for allergic rhinitis
– Omalizumab: recombinant humanized monoclonal anti-IgE antibody →
forms complexes with free IgE → blocks interaction with receptors on mast
cells and basophils
Profound reductions
• Nasal eosinophils
• IgE receptors on dendritic cells
• T and B cells
– Onset of action: typically 7–14days
– Clinical benet shown in seasonal AR and perennial AR
– Typically recommended for patient with refractory AR
– Well tolerated with low rate of anaphylaxis
– Combinatory therapy: omalizumab + immunotherapy increases safety and
decreases symptom and rescue medication usage compared to either therapy
alone. Can be used as pretreatment for allergy immunotherapy to reduce risk
of systemic reaction
– Disadvantage: Costly and not FDA approved for sole diagnosis of AR
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Severe Manifestations ofAllergic Response
Anaphylaxis
– Denition
• Immediate, severe, whole body, life-threatening, immunologic reaction characterized by the contraction of smooth muscle and dilatation of capillaries
– Epidemiology
– Approximately 1000 deaths per year in the United States
– One of every 3000 patients suffers an anaphylactic reaction in US hospitals
every year.
– Risk of death is twofold:
airway edema—asphyxiation
hypotension—Shock/Organ Failure
– Causes: Food (e.g., peanuts) > idiopathic > insect stings (e.g., bees) > medica-
tions (e.g., beta-lactam antibiotics)
– Treatment
– Epinephrine: alpha- and beta-agonist
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Adult dose: 0.3–0.5cm3 (1:1000) IM or SC
Pediatric dose: 0.01mg/kg (1:1000) IM or SC
May repeat dose in 10–15min
10% dose reduction with concomitant monoamide oxidase inhibitors
(MAOI) and tricyclic antidepressants (TCA)
– Antihistamine: H1 and H2 antagonists
Effect on symptoms, i.e., hives, but no effect on hypotension, shock, or
airway obstruction
H1 blocker: diphenhydramine 1mg/kg IV or IM
H2 blocker: ranitidine or cimetidine via IV push
– Steroids:
Typically used in asthmatic patients
Benecial for late-phase reactions
Prednisone 40mg PO
Dexamethasone 20mg IV
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– Bronchodilators:
Beta-agonist: Albuterol to break bronchospasm or overcome
beta-blockade
Anticholinergic: Ipratropium
– Dopamine: useful for maintenance of blood pressure
Initial dose 1μg/kg/min IV and titrate to 20μg/kg/min
Doses below 10μg typically act as beta-agonist
Angioedema
• Hereditary angioedema
– Classication
Type I: 80%—secondary to decreased production of C1-esterase inhibitor
(C1-INH)
Type II: 20%—normal or elevated functionally impaired C1-INH
– Importance of C1-INH
Complement cascade: C1-INH prevents activation of C1
A. Del Signore et al.
• Preventing activation of C4, C3, C5
• Decrease capillary permeability, uid extravasation, edema
Kallikrein/kinin system: C1-INH inactivates
• Factor XII, plasmin, kallikrein
• Prevents kininogen to be converted to bradykinin
• Decrease vasodilation, non-vascular smooth muscle contraction, edema
– Symptoms: edema of one of the following organs:
Skin
GI tract
Respiratory tract
– Clinical presentation
Symptoms associated with trauma, medical procedures, emotional stress,
menstruation, infections, medication use (i.e., ACE inhibitors)
Typically, symptoms last 2–5days with spontaneous resolution.
Non-pitting skin edema
Facial area involvement (lips, eyelids, tongue)
Laryngeal involvement must be ruled out.
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– Testing:
C1-INH levels
C1q levels
C2 and C4 levels—typically markedly decreased/undetectable
Genetic screening: autosomal dominant trait
– Management
Genetic counseling
Intravenous C1 esterase inhibitor (both prophylactic and for acute attacks)
Ecallantide—potent plasma kallikrein inhibitor thereby blocking conversion of kininogen to bradykinin (acute attacks)
Icatibant—blocks B2 receptor binding site for bradykinin (acute attacks)
Attenuated androgens, i.e., danazol, stanozolol
Trial of antihistamines, glucocorticoids, epinephrine
• Although some reports suggest no response
Intubation if airway involved
Cessation of any offending agents, i.e., ACE inhibitors
• Acquired angioedema
Secondary to increased destruction or metabolism of C1-INH
Typically noted in patients with rheumatologic disorders, B cell lymphoproliferative disease, IgG autoantibodies against C1-INH
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• ACE inhibitor therapy induced
– Associated with 0.1–0.5% of patients
– No sex predominance
– Onset may occur during rst week to as far as several years post initiation.
– Symptom resolution with 24–48h
– Typically with normal C1-INH levels and function
– Treatment: discontinue ACE-I, and start antihistamines, anticholinergics, and
corticosteroids.
Further Reading
1. Skoner DP. Allergic rhinitis: denition, epidemiology, pathophysiology, detection, and
diagnosis. J Allergy Clin Immunol. 2001;108(1 Suppl):S2–8. Research Support, Non- U.S.Gov’t Review.
2. Cox L, Nelson H, Lockey R, Calabria C, Chacko T, Finegold I, etal. Allergen immunotherapy:
a practice parameter third update. J Allergy Clin Immunol. 2011;127(1 Suppl):S1–55. Practice
Guideline.
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3. Boulet LP, Turcotte H, Laprise C, Lavertu C, Bedard PM, Lavoie A, etal. Comparative degree
and type of sensitization to common indoor and outdoor allergens in subjects with allergic
rhinitis and/or asthma. Clin Exp Allergy. 1997;27(1):52–9. Comparative Study.
4. Corey JP, Gungor A, Karnell M. Allergy for the laryngologist. Otolaryngol Clin N Am.
1998;31(1):189–205. Review.
5. Krouse JH, Altman KW.Rhinogenic laryngitis, cough, and the unied airway. Otolaryngol
Clin N Am. 2010;43(1):111–21, ix–x. Review.
6. Squillace SP.Environmental control. Otolaryngol Head Neck Surg. 1992;107(6 Pt 2):831–4.
7. Compalati E, Ridolo E, Passalacqua G, Braido F, Villa E, Canonica GW.The link between
allergic rhinitis and asthma: the united airways disease. Expert Rev Clin Immunol.
2010;6(3):413–23. Review.
8. Togias A.Rhinitis and asthma: evidence for respiratory system integration. J Allergy Clin
Immunol. 2003;111(6):1171–83; quiz 84. Review.
9. Smith LJ.Pharmacology and safety of the leukotriene antagonists. Clin Rev Allergy Immunol.
1999;17(1–2):195–212. Review.
10. Venarske D, deShazo RD. Molecular mechanisms of allergic disease. South Med
J. 2003;96(11):1049–54. Review.
11. Brozek JL, Bousquet J, Baena-Cagnani CE, Bonini S, Canonica GW, Casale TB, etal. Allergic
Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol.
2010;126(3):466–76. Practice Guideline Research Support, Non-U.S.Gov’t.
12. Barnes PJ.Mechanisms and resistance in glucocorticoid control of inammation. J Steroid
Biochem Mol Biol. 2010;120(2–3):76–85. Review.
13. Scichilone N, Arrigo R, Paterno A, Santagata R, Impellitteri S, Braido F, etal. The effect of
intranasal corticosteroids on asthma control and quality of life in allergic rhinitis with mild
asthma. J Asthma. 2011;48(1):41–7. Randomized Controlled Trial.
14. Bousquet J, Van Cauwenberge P, Bachert C, Canonica GW, Demoly P, Durham SR, et al.
Requirements for medications commonly used in the treatment of allergic rhinitis. European
Academy of Allergy and Clinical Immunology (EAACI), Allergic Rhinitis and its Impact on
Asthma (ARIA). Allergy. 2003;58(3):192–7.
15. Modgill V, Badyal DK, Verghese A. Efcacy and safety of montelukast add-on therapy in
allergic rhinitis. Methods Find Exp Clin Pharmacol. 2010;32(9):669–74. Comparative Study
Randomized Controlled Trial.
16. Ramey JT, Bailen E, Lockey RF.Rhinitis medicamentosa. J Investig Allergol Clin Immunol.
2006;16(3):148–55. Review.
17. Incorvaia C, Masieri S, Berto P, Scurati S, Frati F.Specic immunotherapy by the sublingual
route for respiratory allergy. Allergy, Asthma Clin Immunol. 2010;6(1):29.
18. Kaliner MA. Omalizumab and the treatment of allergic rhinitis. Curr Allergy Asthma Rep.
2004;4(3):237–44. Review.
19. Walker SM, Varney VA, Gaga M, Jacobson MR, Durham SR.Grass pollen immunotherapy:
efcacy and safety during a 4-year follow-up study. Allergy. 1995;50(5):405–13. Clinical Trial
Randomized Controlled Trial Research Support, Non-U.S.Gov’t.
20. Seiberling K, Hiebert J, Nyirady J, Lin S, Chang D.Cost of allergy immunotherapy: sublingual
vs subcutaneous administration. Int Forum Allergy Rhinol. 2012;2(6):460–4.
21. Wise SK, Schlosser RJ. Subcutaneous and sublingual immunotherapy for allergic rhinitis:
what is the evidence? Am J Rhinol Allergy. 2012;26(1):18–22. Review.
22. Bahceciler NN, Cobanoglu N. Subcutaneous versus sublingual immunotherapy for allergic
rhinitis and/or asthma. Immunotherapy. 2011;3(6):747–56. Review.
23. Nzeako UC, Frigas E, Tremaine WJ.Hereditary angioedema: a broad review for clinicians.
Arch Intern Med. 2001;161(20):2417–29. Review.
24. Wise SK, Lin SY, Toskala E, etal. International consensus statement on allergy and rhinology:
allergic rhinitis. Int Forum Allergy Rhinol. 2018;8:108–352.
A. Del Signore et al.
Chapter 8
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Systemic, Infectious, andInammatory
Diseases
AnsleyM.Roche andZaraM.Patel
Pearls
• Wegener’s granulomatosis is the most common granulomatous disease to affect
the upper airway with necrotizing granulomas and small- and medium-vessel
vasculitis.
• Behcet’s syndrome is a relapsing and remitting autoimmune disease with a triad
of oral or genital ulcers, iritis/uveitis, and progressive sensorineural hearing loss.
• Paget’s disease, also known as osteitis deformans, is an autosomal dominant
idiopathic, chronic, and at times progressive disease of the bone, with osteolytic
and osteoblastic changes that affect the axial skeleton.
Genetics
Genetic Transmission
• Genotype: genetic constitution of an organism, set of alleles that determine
expression of a trait/phenotype
• Phenotype: observable characteristics of an organism controlled by a specic
genotype and environmental factors
• Allele: corresponding form of a gene found on each chromosome
• Homozygosity: two identical alleles at an autosomal gene locus
• Heterozygosity: two different alleles at an autosomal gene locus
A. M. Roche (*)
Department of Surgery, Division of Otolaryngology - Head and Neck Surgery, Yale School of
Medicine, New Haven, CT, USA
e-mail: ansley.roche@yale.edu
Z. M. Patel
Otolaryngology - Head and Neck Surgery, Stanford Medicine, Palo Alto, CA, USA
e-mail: zmpatel@stanford.edu
© Springer Nature Switzerland AG 2023
F. Y. Lin, Z. M. Patel (eds.), ENT Board Prep,
https://doi.org/10.1007/978-3-031-26048-3_8
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A. M. Roche and Z. M. Patel
Mendelian Inheritance
• Autosomal dominant inheritance: gene traits expressed in heterozygotes, 50%
chance of passing gene to next generation. Penetrance—percentage of individu-
als with a genotype that express a phenotype, can be complete or incomplete.
Expressivity—variations in phenotype among individuals carrying a particular
genotype.
• Autosomal recessive inheritance: homozygous state is expression of disease; het-
erozygous state implies carrier status. Transmission of disease with two heterozygous parents is 25%; 50% chance of offspring being carriers, e.g., ataxia
telangiectasia.
• Sex-linked inheritance: can be either Y- or X-linked. Most commonly X-linked—
mother transmits to offspring 50% of time. Male offspring homozygous for disease; female offspring are carriers.
Non-Mendelian Inheritance Patterns
• Mitochondrial inheritance: maternal mitochondria inherited through ovum;
maternal inheritance.
• Dynamic mutation: e.g., trinucleotide repeat—Fragile X, CAG repeat
(Huntington’s disease, spinocerebellar ataxia, Friedreich’s ataxia). CAG translates to glutamine=“polyQ.” Autosomal dominant presentation, demonstrates
anticipation—earlier onset, more severe onset as disease is transmitted to subsequent generations.
• Genetic imprinting: expression depends on parent of origin, one active copy,
one inactive copy; inactive allele is highly methylated, e.g., Angelman syndrome and Prader-Willi syndrome—both involve the same region of chromosome 15 (Angelman misses maternal copy, Prader-Willi misses
paternal copy).
• Mosaicism: presence of two or more genetically different cell lines within one
individual, can be somatic or germline.
• Uniparental disomy: inheritance of two copies of one chromosome (or part of
chromosome) from one parent; none from the other parent. Can be isodisomy
(meiosis II error) or heterodisomy (meiosis I error). Also a cause of Angelman
and Prader-Willi syndrome.
Cancer Genetics
• Regulation of cell growth: proto-oncogenes—genes that normally act to regulate
cell growth and differentiation, execution of mitogenic signals. Single mutation
can lead to oncogene.
8 Systemic, Infectious, andInammatory Diseases
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• Tumor suppressor gene (TSG): encodes proteins that have a dampening/repres-
sive effect on cell growth, may promote apoptosis; majority are recessive.
• Two-hit hypothesis: both alleles of TSG must be mutated for a cell to become
cancerous.
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Oncogenes Classied Based onFunction
• Growth factor: int-2, c-Sis
• Growth factor receptor: epidermal growth factor receptor (EGFR), e.g., erb-b2
receptor tyrosine kinase 2 (HER2/neu)
• Protein kinases: c-raf (RAF proto-oncogene serine/threonine-protein kinase)
• Intracellular signal transduction protein: ras
• Transcription regulators: myc
Genes Involved inHead andNeck Squamous Cell
Carcinoma (SCC)
• p53: tumor suppressor gene involved in cell cycle regulation and apoptosis.
Mutation found in 50–66% of head and neck SCC. Located on chromosome
17p13.1. Binds cyclin-dependent kinins and arrests cell replication in G1. If
DNA repair mechanisms fail, induces apoptosis
• p16 and p21: tumor suppressor proteins; suppress cyclin and cyclin-dependent
kinase pathways
• Cyclin D1: protein that promotes progression through cell cycle
• bcl-2: oncogene that inhibits apoptosis, counteracts p53
• RET: proto-oncogene, cell surface tyrosine kinase receptor involved in signal
transduction pathways for cell growth, associated with MEN II
• HPV oncogenesis
– E6 viral oncoprotein associates with TSG p53
– E7 oncoprotein associates with TSG pRB
Circulatory
Hereditary Hemorrhagic Telangiectasia or HHT
(Osler- Weber-Rendu Syndrome)
• Autosomal dominant.
• Multiple telangiectasias of the skin and mucosa, lack of normal vascular
smooth muscle.
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• Patients present with recurrent epistaxis, pulmonary, gastrointestinal, and CNS
bleeds due to large and small arteriovenous malformations.
• Curaçao diagnostic criteria:
– Recurrent epistaxis
– Numerous telangiectases of hands, lips, face, intranasal—blanching
– AVMs/telangiectases in one or more internal organs
– Family history of HHT (rst-degree relative meeting these criteria or genetic
testing)
• Treatment: manage anemia/acute bleeds; recurrent laser or bipolar cautery, pos-
sible septal dermoplasty for epistaxis.
A. M. Roche and Z. M. Patel
Kawasaki Disease (Mucocutaneous Lymph Node Syndrome)
Medium-vessel vasculitis, usually presents <5years of age, rare in adults
Acute febrile illness of childhood, most common cause of acquired heart disease
in children
• Symptoms and diagnosis: Clinical diagnosis—must have fever >5days and have
4–5 of following symptoms: (1) acute non-purulent cervical lymphadenopathy
>1.5cm, typically unilateral, (2) erythematous desquamative rash of palms and
soles, (3) truncal rash, (4) bilateral painless conjunctivitis, and (5) mucositis
characterized by erythema of the tongue (strawberry tongue—protuberance of
papillae), lips, and oral cavity
• Workup: may have elevated CRP, ESR, and ferritin; thrombocytosis; chest radio-
graph with reticulogranular pattern; echocardiogram with pericardial effusion;
coronary artery dilation; abdominal ultrasound demonstrating acalculous cholecystitis. Seven percent to 20% develop coronary artery aneurysms, MI within
2–12 weeks of disease onset, facial palsy reported but rare, resolves in
1–12weeks, due to ischemic injury to nerve
• Treatment: (1) Immunoglobulin, (2) high-dose aspirin
Giant Cell Arteritis (Temporal Arteritis/Horton Disease/
Cranial Arteritis)
Granulomatous large-vessel vasculitis, commonly involves supercial temporal and
ophthalmic arteries but can involve any large vessel; thrombi contain microabscesses. More common in females, presents >50years of age
• Symptoms: jaw claudication, persistent throbbing pre-auricular pain, prominent
and tender artery, low-grade fever, possible visual disturbances—ipsilateral
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