Late phase reaction

Asthma is an extremely complex condition characterized by variable and reversible airways obstmction combiaed with nonspecific bronchial hypersensitivity (1 3). The cause of asthma, which is not always readily diagnosed (4), remains unknown. Days, if not weeks, ate needed to document the spontaneous reversal of the airways obstmction ia some patients. Asthmatics experience both an immediate hypersensitivity response and a delayed late-phase reaction, each mediated by a different pathway. Chronic asthma has come to be viewed as an inflammatory disease (5). The late-phase reaction plays a key role ia iaduciag and maintaining the inflammatory state which ia turn is thought to iaduce the bronchial hyperresponsiveness (6). The airways obstmction results from both contraction of airways smooth muscle and excessive bronchial edema. Edema, a characteristic of inflammatory states, is accompanied, ia this case, by the formation of a viscous mucus which can completely block the small airways. 

Bochner BS, Hudson SA, Xiao HQ, Liu MC. Release of both CCR4-active and CXCR3-active chemokines during human allergic pulmonary late-phase reactions. J Allergy Clin Immunol 2003 112(5) 930—934. 

From 4 to 8 hours after the initial exposure to an allergen, a late-phase reaction may occur, which is thought to be due to cytokines released primarily by mast cells and thymus-derived helper lymphocytes. This inflammatory response likely is responsible for persistent, chronic symptoms including nasal congestion. 

Intranasal corticosteroids effectively relieve sneezing, rhinorrhea, pruritus, and nasal congestion with minimal side effects (Table 79-4). They reduce inflammation by blocking mediator release, suppressing neutrophil che-motaxis, causing mild vasoconstriction, and inhibiting mast cell-mediated, late-phase reactions. 

In sensitized asthmatic individuals, antigen challenge generally causes a Type I (IgE-mediated) immediate hypersensitivity response by release of preformed mediators, including histamine, and prostaglandins, which are responsible for bronchoconstric-tion and increased vascular permeability. Between 2 and 8 hours after the immediate response, asthmatics experience a more severe and prolonged (late phase) reaction that is characterized by mucus hyper-secretion, bronchoconstriction, airway hyperresponsiveness to a variety of nonspecific stimuli (e.g., histamine, methacholine), and airway inflammation characterized by eosinophils. This later response is driven by leukotrienes, chemokines and cytokines synthesized by activated mast cells and Th2 cells. Both proteins and haptens have been associated with these types of reactions. 

Huh JC, Strickland DH, Jahnsen FL, Turner DJ, Thomas JA, Napoli S, Tobagus I, Stumbles PA, Sly PD, Holt PG Bidirectional interactions between antigen-bearing respiratory tract dendritic cells (DCs) and T cells precede the late phase reaction in experimental asthma DC activation occurs in the airway mucosa but not in the lung parenchyma. J Exp Med 2003 198 19-30. 

Allergic symptoms may be local or systemic and their manifestations may also vary. Local symptoms can manifest as a late phase reaction syndrome, which develops within 30 minutes (but may be delayed to six to eight hours). Changes characteristic for cell-mediated hypersensitivity, such as an inflam-... 

The activation of mast cells and T cells results in late-phase reactions. Both immediate hypersensitivity and late-phase reactions are evident in the skin of atopic as well as nonatopic individuals after the cross-linking of IgE-bound mast cells with an antibody against IgE. The atopic asthmatic could develop late-phase reaction even in the absence of mast cell-related immediate hypersensitivity reaction, which is mast cell-independent and HLA-dependent, suggesting the role of T cells by themselves in causing asthma symptoms in atopic asthmatics. 

Frew AJ, Corrigan CJ, Maestrelli P, Tsai JJ, et al. 1989. T lymphocytes in allergen-induced late-phase reaction and asthma. Int Arch Allergy Appl Immunol. 88 63-67. 

Observation time should be 24 h for expected early clinical reactions and 48 h for expected late-phase reactions (patients with AD). 

Type I hypersensitivity reactions usually occur within minutes to hours of exposure to an antigen in sensitized individuals. The immediate allergic response is initiated 5 to 30 minutes after allergen exposure and resolves in 30 to 60 minutes.This may be followed by the late-phase reaction, which is more severe and of greater duration. The late phase develops 4 to 6 hours after the initial response and may last up to 2 days. Neutrophils, eosinophils, macrophages, lymphocytes, basophils, and mast cells are involved in the late-phase inflammatory reaction, resulting in tissue damage. 

Charlesworth EN, Kagey-Sobotka A, Norman PS, Lichtenstein LM. Effect of cetirizine on mast cell-mediator release and cellular traffic during the cutaneous late-phase reaction. J Allergy Clin Immunol 1989 83(5) 905-12. 

This reaction shared the features of a delayed hypersensitivity reaction (exanthematous rash, positive patch test) and of a late phase reaction (CD4+ lymphocjdic infiltrate together with eosinophils). The authors emphasized the importance of skin testing in the diagnosis of delayed skin reactions to contrast media. 

Wershil, B.K., Wang, Z.S., Gordon, J.R. and Galli, S.J. (1991). Recruitment of neutrophils during IgE-dependent cutaneous late phase reactions in the mouse is mast cell-dependent. Partial inhibition of the reaction with antiserum against tumor necrosis factor-alpha. J. Clin. Invest. 87, 446-453. 

Anaphylactic reactions generally begin within 30 minutes but almost always within 2 hours of exposure to the inciting allergen. The risk of fatal anaphylaxis is greatest within the first few hours. After apparent recovery, anaphylaxis may recur 6 to 8 hours after antigen exposure. Because of the possibility of these late phase reactions, patients should be observed for at least 12 hours after an anaphylactic reaction. Fatal anaphylaxis most often results from asphyxia due to airway obstruction either at the larynx or within the lungs. Cardiovascular collapse may occur as a result of asphyxia in some cases, whereas in others cases cardiovascular collapse may be the dominant manifestation from the release of mediators within the heart muscles and coronary blood vessels. 

A number of other agents may be required for the treatment of anaphylactic reactions. Corticosteroids (hydrocortisone sodium succinate intravenously) are recommended to reduce the risk of late-phase reactions. Aminophylline may be used as adjunctive therapy for bronchospasm. Histamine (Hi) receptor blockers (such as diphenhydramine) may be administered to reduce some of the symptoms associated with anaphylaxis however, these agents are not effective as primary therapy. 

Administer hydrocortisone sodium succinate 100 mg intravenously (push) and 100 mg intravenously in saline every 2-4 h to block the late-phase reaction. 

Both immediate and late-phase reactions are observed after allergen exposure. The immediate reaction occurs within minutes, resulting in the rapid release of preformed mediators and newly generated mediators from the arachidonic acid cascade as the mast cell membrane is disturbed (Table 93-1). These mediators of immediate hypersensitivity include histamine, leukotrienes (LTs) C4, LTD4, LTE4, prostaglandin D2, tryptase, and kinins. In addition, the mast... 

P2 adrenoreceptor stimulants are used as first choice for the rapid relief of an acute asthmatic attack and maintenance treatment of chronic asthma. They are more effective in treatment of the immediate phase reaction than the late phase reaction. P2 adrenoreceptor stimulants are less effective in chronic bronchitis, possibly because in this disease bronchoconstriction is due to reflex stimulation of acetylcholine receptors following stimulation of local irritant receptors in lung tissue. 

Xanthines are a group of drugs that directly cause relaxation of bronchial smooth muscle and some central respiratory stimulation. They also have a slight diuretic effect. Xanthines are of principle use in the immediate phase reaction of asthma but also have some effect on the late phase reaction. They are used to treat severe acute asthma attacks and chronic asthma, in particular control of nocturnal asthma and early morning wheezing. Xanthines also have some use in chronic bronchitis. 

Corticosteroids are anti-inflammatory drugs that can be used in asthma to reduce airway hyper-responsiveness and to decrease bronchial oedema and mucus secretion. They are effective in the late phase reaction and reduce the intensity of allergic reactions. They are used in emergency treatment of severe acute attacks, for the treatment of mild to moderate attacks and prophylactically to prevent attacks. Corticosteroids can be useful in reducing acute exacerbations of chronic bronchitis. 

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