Chapter 3: Allergen immunotherapy: definition, indication, and reactions.

Specific allergen immunotherapy is the administration of increasing amounts of specific allergens to which the patient has type I immediate hypersensitivity. It is a disease modifying therapy, indicated for the treatment of allergic rhinitis, allergic asthma, and hymenoptera hypersensitivity. Specific IgE antibodies for appropriate allergens for immunotherapy must be documented. Indications for allergen immunotherapy include (1) inadequate symptom control despite pharmacotherapy and avoidance measures, (2) a desire to reduce the morbidity from allergic rhinitis and/or asthma or reduce the risk of anaphylaxis from a future insect sting, (3) when the patient experiences undesirable side effects from pharmacotherapy, and (4) when avoidance is not possible. Furthermore, patients may seek to benefit from economic savings of allergen immunotherapy compared with pharmacotherapy over time. Several studies have reported that immunotherapy in children with allergic rhinitis appears to prevent the development of new allergic sensitizations and/or new-onset asthma. Humoral, cellular, and tissue level changes occur with allergen immunotherapy including large increases in antiallergen IgG(4) antibodies, a decrease in the postseasonal rise of antiallergen IgE antibodies, reduced numbers of nasal mucosal mast cells and eosinophils, induction of Treg cells, and suppression of Th2 more than Th1 lymphocytes. There is a corresponding increase in IL-10 and transforming growth factor beta. In the United States, allergen immunotherapy is administered by the subcutaneous route in the physician's office, whereas primarily in some countries in Europe, it is administered for allergic rhinitis and asthma by the sublingual route by the patient at home.

Chapter 7: Nasal polyps.

Nasal polyps are inflammatory outgrowths of paranasal sinus mucosa caused by chronic mucosal inflammation that typically arise from the middle meatus and ethmoid region. The main symptoms of nasal polyps are perennial nasal congestion, nasal obstruction, and anosmia or hyposmia. Unlike patients with chronic rhinosinusitis (CRS) without nasal polyps who present with headache and facial pain, patients with nasal polyps typically do not complain of those symptoms. Nasal polyps appear as semitranslucent, pale gray growths in the nasal cavity in contrast to pink or erythematous adjacent mucosa. Nasal polyps occur more frequently in patients with persistent asthma, aspirin-exacerbated respiratory disease (AERD), CRS, and cystic fibrosis. Children with nasal polyps should be evaluated for cystic fibrosis. Churg-Strauss syndrome and ciliary dyskinesia also may be associated with nasal polyps. Nasal polyps have increased numbers of activated eosinophils, mast cells, and IgE. Staphylococcal superantigens may play a role in the Th2 type of chronic eosinophilic inflammation observed in nasal polyps. Dysfunction of the epithelial barrier in nasal polyps causing reduced levels of antimicrobial proteins has been described. Topical nasal steroids are the treatment of choice. They significantly decrease polyp size, nasal congestion, rhinorrhea, and increase nasal airflow. Short courses of oral steroids may be needed to reduce polyp size followed by maintenance therapy with intranasal steroids. Surgery is reserved for cases when polyps cause severe obstruction, recurrent sinusitis, and for patients who have failed medical therapy. Aspirin desensitization may decrease the requirement for polypectomies and sinus surgery in patients with AERD.

Chapter 8: Rhinosinusitis.

Rhinosinusitis is defined as inflammation of one or more of the paranasal sinuses and affects ∼16% of the population. Acute rhinosinusitis is defined as symptoms lasting <4 weeks and subacute rhinosinusitis is between 4 and 8 weeks. Chronic rhinosinusitis (CRS) is defined as symptoms lasting >8-12 weeks. CRS is divided into three groups: CRS with nasal polyps, CRS without nasal polyps, and allergic fungal rhinosinusitis. The sinus cavities are lined with pseudostratified ciliated columnar epithelial cells interspersed with mucous goblet cells. Cilia continuously sweep the mucous toward the ostial openings and are important in maintaining the proper environment of the sinus cavities. The frontal, maxillary, and anterior ethmoid sinuses drain into the ostiomeatal unit of the middle meatus. The posterior ethmoid sinuses and superior sphenoid sinuses drain into the sphenoethmoid recess of the superior meatus. Most acute sinus infections are caused by viruses and, therefore, it is not surprising that the majority of patients improve within in 2 weeks without antibiotic treatment. A bacterial infection should be considered if symptoms worsen or fail to improve within 7-10 days. Amoxicillin, trimethoprim-sulfamethoxazole, or doxycycline are first-line therapy. The Joint Task Force on Practice Parameters for Allergy and Immunology suggests assessing response to symptoms after 3-5 days of therapy and continuing for an additional 7 days if there is improvement. Combining an intranasal corticosteroid with an antibiotic reduces symptoms more effectively than antibiotics alone.

Chapter 22: Hereditary and acquired angioedema.

Hereditary angioedema (HAE) is an autosomal dominant disorder defined by a deficiency of functional C1 esterase inhibitor (C1-INH). Acquired angioedema (AAE) is caused by either consumption (type 1) or inactivation (type 2) of CI-INH. Both HAE and AAE can be life-threatening. The screening test for both conditions is complement component C4, which is low to absent at times of angioedema or during quiescent periods. A useful test to differentiate HAE from AAE is C1q protein, which is normal in HAE and low in AAE. There are three types of HAE: type 1 HAE is most common, occurring in ∼85% of patients and characterized by decreased production of C1-INH, resulting in reduced functional activity to 5-30% of normal. In type 2, which occurs in 15% of cases, C1-INH is detectable in normal or elevated quantities but is dysfunctional. Finally, type 3, which is rare and almost exclusively occurs in women, is estrogen dependent and associated with normal CI-INH and C4 levels. One-third of these patients have a gain-of-function mutation in clotting factor XII leading to kallikrein-driven bradykinin production. Although the anabolic steroid, danazol, is useful in increasing the concentration of C4 and reducing the episodes of angioedema in HAE and AAE, it has expected adverse effects. Fortunately, disease-specific therapies are available and include C1-INH enzyme for i.v. infusion either acutely or empirically, ecallantide, an inhibitor of kallikrein, and icatibant, a bradykinin B2-receptor antagonist, both approved for acute angioedema and administered, subcutaneously.

Lymphoid follicle cells in chronic obstructive pulmonary disease overexpress the chemokine receptor CXCR3.

RATIONALE: The mechanisms underlying formation of lung lymphoid follicles (LF) in chronic obstructive pulmonary disease (COPD) are unknown. The chemokine receptor CXCR3 regulates immune responses in secondary lymphoid structures elsewhere in the body and is highly expressed by Th1 lymphocytes in the airway in COPD. Because chemokine receptors control inflammatory cell homing to inflamed tissue, we reasoned that CXCR3 may contribute to LF formation in COPD. OBJECTIVES: We assessed the expression of CXCR3 and its ligands (IP-10/CXCL10, Mig/CXCL9, and ITAC/CXCL11) by LF cells in never-smokers, smokers without COPD, and subjects with COPD. METHODS: CXCR3, IP-10, Mig, and ITAC expression were assessed in lung sections from 46 subjects (never-smokers, smokers without COPD [S], and subjects with COPD in GOLD stages 1-4) by immunohistochemistry. MEASUREMENTS AND MAIN RESULTS: CXCR3-expressing T cells (CD8+ or CD4+) and B cells (CD20+) were topographically distributed at the follicle periphery and center, respectively. The percentage of immunohistochemically identified CXCR3+ cells increased progressively while proceeding from S through GOLD 3-4 (P < 0.01 for GOLD 3-4 vs. S). Moreover, the number of CXCR3+ follicular cells correlated inversely with FEV(1) (r = 0.60). The CXCR3 ligands IP-10 and Mig were expressed by several cell types in and around the follicle, including CD68+ dendritic cells/ macrophages, airway epithelial cells, endothelial cells, and T and B cells. CONCLUSIONS: These results suggest that LF form in the COPD lung by recruitment and/or retention of CXCR3-expressing T and B lymphocytes, which are attracted to the region through production of CXCR3 ligands IP-10 and Mig by lung structural and follicular cells.