Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2797_Библиотеки_им_академика_М_И_Перельмана
.pdf
122 Textbook of Diagnostic and Therapeutic Procedures in Allergy
Viral (upper respiratory tract), bacterial
(urinary tract), fungal and parasitic
Penicillin and cephalosporins
Children: cow’s milk, egg, peanut, tree nuts,
soy and wheat
Adult: shellfish, tree nuts and peanut
Hymenoptera: bees, wasps, hornets and
imported fire ants
Triatoma: kissing bug
Bedbugs, fleas and mites (papular urticaria)
Healthcare and rubber industry workers,
patients with spina bifida and patients with
multiple surgeries
Narcotics, muscle relaxants, beta-lactam
antibiotics, vancomycin, and radiocontrast
media
Pseudoallergic and allergic
https://t.me/medicina_free
Photo 2. Angioedema. Source: James Heilman, MD, CC BY-SA 3.0 via Wikimedia Commons; https://commons.wikimedia.
org/wiki/File:Angioedema2010.JPG.
Classification
Urticaria is categorized by its chronicity. Acute urticaria is defined by hives lasting less than 6 weeks,
whereas chronic urticaria is defined by hives that recur most days for 6 weeks or longer (Figure 1)
(Kaplan et al. 2009). Approximately 40% of patients with chronic urticaria have accompanying
angioedema, whereas 10% have angioedema as their sole manifestation (Saini 2014). The average
duration of chronic urticaria is 2–5 years but can last longer if there is concurrent angioedema
(Zuberbier et al. 2010).
Approximately 25% of patients with chronic urticaria have an underlying physical trigger
which is termed chronic inducible urticaria (CIndU). This type of urticaria is further categorized
according to the nature of the inciting stimulus. In the remaining 75% of cases, no specific trigger
can be identified, and is termed chronic spontaneous urticaria (CSU). Of these, approximately
30–40% have serological evidence of IgG autoantibodies against IgE or the high-affinity IgE
receptor (FcεR1) or circulating IgE autoantibodies to various self-antigens, including thyroid
peroxidase (TPO) (Kaplan et al. 2009). Consequently, it is sometimes referred to as “chronic
autoimmune urticaria.”
Figure 1. Classification of Urticaria According to EAACI/GA2LEN/WAO 2013 Guideline. Source: Murat Borlu, Salih
Levent Cinar and Demet Kartal. (2017). Chronic Inducible Urticaria Part I. DOI: 10.5772/68069 CC BY 3.0 via Wikimedia
Commons.
Acute and Chronic Urticaria/Angioedema 123
https://t.me/medicina_free
More than two-thirds of cases of new-onset urticaria prove to be acute. However, the lesions
of acute and chronic urticaria are identical in appearance, therefore it is not possible to differentiate
between the two at the onset (Kaplan 2002).
Pathophysiology
Urticaria is mediated by the degranulation of cutaneous mast cells in the superficial dermis and,
to a lesser extent, by basophils. When mast cells and basophils are activated through IgE or
non-IgE-mediated mechanisms, they release histamine and vasodilatory mediators, such as
prostaglandins, leukotrienes, tryptase, platelet-activating factor and kinins. Within 4–8 hours of
mast cell activation, inflammatory cytokines are secreted, resulting in a delayed inflammatory
response. Consequently, a skin biopsy typically shows a perivascular infiltrate of cells comprised
of CD4+ lymphocytes, monocytes, neutrophils, eosinophils and basophils, similar to the infiltrate
seen in late-phase IgE-mediated reactions (Ying et al. 2002). Angioedema associated with urticaria
is also mediated by cutaneous mast cells, but it involves mast cells in deeper tissue layers, including
the deep dermis and subcutaneous tissues.
Etiology
Acute Urticaria
Acute urticaria is more likely to have an identifiable etiology compared with chronic urticaria.
Common etiologies include infections, drugs, foods, insect stings/bites and latex (Table 1). Acute
urticaria may develop during or following a viral (e.g., upper respiratory infection) or bacterial
infection (e.g., urinary tract infection), particularly in children. In fact, infections are associated with
over 80% of cases of urticaria in some pediatric series (Sackesen et al. 2014; Mortureux et al. 1998;
Imbalzano et al. 2016; Minciullo et al. 2014) and likely involve the immune complex formation
and/or complement activation. Parasitic infections can also result in acute urticaria and are usually
associated with prominent eosinophilia.
Urticaria caused by allergic (IgE-mediated) reactions typically occurs within minutes to
2 hours of exposure to the culprit allergen. Among drugs, beta-lactam antibiotics (penicillin and
cephalosporin) are the most common culprits. Among foods, cow’s milk, egg, peanut, tree nuts, soy
and wheat are frequently implicated in children, whereas shellfish, tree nuts and peanuts are most
often implicated in adults (Wang and Sampson 2011). Allergic reactions to insects can involve either
their stings, such as Hymenoptera (bees, wasps, hornets, and imported fire ants) or their bite, such as
Triatoma (kissing bug). On the other hand, the bite of bedbugs, fleas and mites can result in papular
urticaria, characterized by clusters of pruritic papules that persist for days to weeks. Exposure
Type Examples
Infections Viral (upper respiratory tract), bacterial (urinary tract), fungal and parasitic
Drugs (IgE-mediated) Penicillin and cephalosporins
Foods Children: cow’s milk, egg, peanut, tree nuts, soy and wheat
Insect bites/stings Hymenoptera: bees, wasps, hornets and imported re ants
Latex Healthcare and rubber industry workers, patients with spina bida and patients with
Drugs (non-IgE-mediated) Narcotics, muscle relaxants, beta-lactam antibiotics, vancomycin, and radiocontrast media
NSAIDs Pseudoallergic and allergic
Table 1. Common etiologies of acute urticaria.
Adult: shellsh, tree nuts and peanut
Triatoma: kissing bug
Bedbugs, eas and mites (papular urticaria)
multiple surgeries
124 Textbook of Diagnostic and Therapeutic Procedures in Allergy
https://t.me/medicina_free
to latex may cause urticaria in sensitized individuals, namely healthcare and rubber industry
workers, patients with spina bifida or those who have undergone multiple surgeries (Sussman and
Beezhold 1995).
Drugs can also cause mast cell degranulation through non-IgE-mediated mechanisms. Commonly
implicated drugs include narcotics, muscle relaxants, beta-lactam antibiotics, vancomycin and
radiocontrast media.
NSAIDs can cause urticaria by two distinct mechanisms: pseudoallergic and allergic.
Pseudoallergic reactions are nonimmunologic reactions related to the drug’s cyclooxygenase-1
(COX-1)-inhibiting properties (Grattan 2003). As a result, affected individuals will react to both
aspirin and COX-1 NSAIDs. Allergic reactions, on the other hand, are IgE-mediated. They are
elicited by a specific NSAID in a susceptible individual. Of note, there have been no known cases
of IgE-mediated reactions to aspirin.
Chronic Urticaria
Chronic Inducible Urticaria
Chronic inducible urticaria (CIndU) is a type of chronic urticaria that occurs in response to specific
triggers, such as heat, cold, friction, pressure, exercise, vibration and sunlight (Magerl et al. 2016).
The duration of individual wheals is often brief (minutes to hours), except for delayed-pressure
urticaria. Current evidence suggests that IgE binding to the high-affinity IgE receptor (FcεRI)
on skin mast cells plays important in the pathogenesis of CIndU (Maurer et al. 2018). Moreover,
symptoms can be passively transferred through serum IgE to healthy individuals in cold urticaria,
solar urticaria and symptomatic dermatographism. Mast cells may also be activated through
IgE-independent pathways. A recent area of interest is the role of transient receptor potential (TRP)
channels, a group of ion channels that serve as cellular sensors for a variety of physical and chemical
stimuli (Freichel et al. 2012).
Symptomatic dermatographia is the most common CIndU (Maurer et al. 2018). Individuals
with this condition develop itchy, linear wheals after firm stroking the skin (Photo 3). Symptomatic
dermatographia is clinically distinct from the more common “simple” dermatographia, which
involves linear wheals without the itch.
Cold urticaria is the second most frequent CIndU (Maurer et al. 2018). It is characterized by
pruritic wheals and/or angioedema after exposure to cold temperatures (Photo 4). Triggers include
contact with cold objects, cold liquids and cold air. Wheals typically appear within minutes and can
last for one hour. Extensive cold contact (i.e., swimming in cold water) may result in anaphylaxis.
Cholinergic urticaria is characterized by small, 1–3 mm punctate wheals (Photo 5). It is induced
by an elevation of core body temperature. Exercise and hot environments are the most common
triggers. The lesions are typically short-lived and localized to the trunk and extremities. Cholinergic
urticaria must be differentiated from exercise-induced urticaria/anaphylaxis, in which exercise is the
only trigger, and passively raising the core body temperature does not induce symptoms.
Exercise-induced urticaria/anaphylaxis is a disorder in which symptoms occur only in
association with physical exertion. Symptoms range from flushing and mild hives in the early stage of
exercise to life-threatening laryngeal edema and vascular collapse. In a subset of patients, symptoms
develop only if exercise takes place within a few hours of eating; in most cases, only if a specific
food to which the patient is sensitized to is eaten. This unique disorder is termed food-dependent,
exercise-induced anaphylaxis. The foods most implicated are wheat, other grains, shellfish and tree
nuts (Beaudouin et al. 2006). Cofactors that can precipitate exercise-induced urticaria/anaphylaxis
include infections, NSAIDs, alcohol and stress.
Delayed-pressure urticaria/angioedema is characterized by erythematous swelling of the
skin approximately 4–6 hours after the application of pressure. The amount of pressure needed to
Acute and Chronic Urticaria/Angioedema 125
Photo 2: Angioedema
Source: James Heilman, MD, CC BY-SA 3.0 via Wikimedia Commons;
https://commons.wikimedia.org/wiki/File:Angioedema2010.JPG
https://t.me/medicina_free
Photo 3. Symptomatic Dermatographia. Source: Mysid, Public domain, via Wikimedia Commons; https://commons.
wikimedia.org/wiki/File:Dermatographic_urticaria.jpg.
Photo 4. Cold urticaria. Source: Templeton8012, CC BY-SA 3.0 via Wikimedia Commons; https://commons.wikimedia.
Photo 5. Cholinergic Urticaria. PKeMcG, CC BY 3.0, via Wikimedia Commons; https://commons.wikimedia.org/wiki/
induce symptoms varies among individuals. Symptoms are often described as burning and pain
instead of pruritus, and the swelling may be accompanied by arthralgias (Greaves 2000). Common
triggers include wearing tight clothing, sitting for prolonged periods on a hard surface and carrying
heavy bags.
More rare forms of CIndU include vibratory, solar and heat. Vibratory urticaria/angioedema
involves itching and swelling following a vibratory stimulus. Common triggers include lawn
mowing, power tools and horseback riding. Solar urticaria involves urticaria following direct
exposure to sunlight. Limited exposure provokes only itching while more prolonged exposure leads
to wheals. Heat urticaria involves urticaria following direct contact with a warm stimulus.
org/wiki/File:Cold_urticaria3.jpg.
File:WP_20120924_8.jpg.
126 Textbook of Diagnostic and Therapeutic Procedures in Allergy
https://t.me/medicina_free
Chronic Spontaneous Urticaria
The etiology of CSU is unknown. Two prominent hypotheses are the autoimmune theory and the
cellular defect theory.
Autoimmune Theory
Approximately 30–40% of individuals with CSU have serological evidence of IgG autoantibodies
against IgE, the high-affinity IgE receptor (FcεR1) or circulating IgE autoantibodies to various
self-antigens, such as thyroid peroxidase (TPO) (Kaplan and Greaves 2009). In 1986, Grattan et al.
reported a case series of seven out of 12 patients with chronic urticaria in whom autologous serum
injected intradermally produced a wheal-and-flare response (Grattan et al. 1986). This became
known as the autologous serum skin test (Sabroe et al. 1999). Further evidence in support of the
autoimmune theory is based on the increased prevalence of autoimmune disorders among patients
with CSU, in particular thyroid disease, vitiligo, rheumatoid arthritis, systemic lupus erythematosus,
Sjogren syndrome, celiac disease and Type 1 diabetes mellitus. Antinuclear antibodies are also more
prevalent than in the general population.
Cellular Defect Theory
The cellular defect theory proposes that individuals with CSU have defects in basophil trafficking,
signaling and function. For example, it has been shown that blood basophils are reduced in patients
with CSU, a finding attributed to increased migration of basophils to the skin (Saini 2009). In
addition, blood basophils in CSU patients have a reduced ability to release histamine upon IgE
receptor activation (Kern and Lichtenstein 1976).
Differential Diagnosis
Several dermatologic conditions can be confused with urticaria. Common mimickers include
drug eruptions, atopic dermatitis, contact dermatitis, insect bites, erythema multiforme, bullous
pemphigoid, mastocytoma, pityriasis rosea and viral exanthems. A skin punch biopsy should be
obtained to rule out urticarial vasculitis whenever individual urticarial lesions persist beyond
24 hours, are painful, have accompanying petechial or purpuric characteristics or leave residual
pigmentation (Zuberbier et al. 2022). An elevated CRP/ESR or the presence of systemic symptoms,
such as fever or arthralgias, should also raise suspicion for vasculitis.
Urticaria pigmentosa presents with brownish-red cutaneous lesions that become erythematous,
pruritic and edematous within 5 minutes after gentle stroking (Photo 6). This physical finding is
called Darier’s sign (Soter 2000). Urticaria pigmentosa is commonly associated with cutaneous
mastocytosis in children, whereas it is commonly associated with systemic mastocytosis in adults.
In patients with isolated angioedema without urticaria, bradykinin-mediated angioedema should
be considered. Measurement of complement component 4 (C4) constitutes a good screening test.
Low C4 levels should prompt further evaluation for hereditary or acquired C1 inhibitor deficiency.
Diagnostic Investigations
Prior to any investigations, one should first verify that the lesions are truly urticarial in nature,
preferably through direct observation, or high-quality photographs. Once the diagnosis of urticaria
is confirmed, the duration of symptoms determines the next steps of evaluation.
Acute and Chronic Urticaria/Angioedema 127
https://t.me/medicina_free
Photo 6. Urticaria Pigmentosa. Source: James Heilman, MD, CC BY-SA 3.0 via Wikimedia Commons; https://commons.
wikimedia.org/wiki/File:UriticariaPigmentosa.jpg.
Acute Urticaria (< 6 Weeks)
The evaluation of acute urticaria consists primarily of careful history taking, with an emphasis on
trying to identify triggering factors. Routine investigations are “not” recommended due to the short
duration and self-limiting nature of the disease. One notable exception is when the clinical history
is highly suggestive of an IgE-mediated reaction; in this case, skin testing or allergen-specific IgE
testing (if commercially available) of the suspected culprit is appropriate.
For foods, commercial extracts of cow’s milk, egg, peanut, tree nuts, soy, fish and shellfish
are generally reliable for skin prick tests; in contrast, extracts to fruits and vegetables are often
inadequate because the allergen can be labile and altered during processing. In such cases,
prick-by-prick testing with fresh foods yields more accurate results. Intradermal skin testing on
foods should “never” be performed, as it carries a risk of inducing anaphylaxis.
Unfortunately, the diagnosis of drug allergy is more challenging, as validated skin testing
has been established for only a limited number of drugs (penicillin, other beta-lactam antibiotics,
neuromuscular blockers and local anesthetics) and in vitro tests remain investigational. When
interpreting skin tests or allergen-specific IgE tests, one must be mindful that a positive test is
only indicative of sensitization, not the allergy. Therefore, obtaining an accurate clinical history is
critically important.
Although infections constitute a common cause of acute urticaria, obtaining cultures or
serologies is generally not recommended. One notable exception is when a parasitic infection is
suspected, in which case stool examination for ova and parasites may be warranted.
Chronic Urticaria (> 6 Weeks)
Chronic Inducible Urticaria
Although clinical history will often suffice to establish the diagnosis of chronic inducible urticaria,
provocation testing (Figure 2) and threshold testing (Figure 3) can help confirm the diagnosis and
assess disease severity. Prior to testing, oral antihistamines should be discontinued for the appropriate
withholding period.
128 Textbook of Diagnostic and Therapeutic Procedures in Allergy
https://t.me/medicina_free
Figure 2. Chronic inducible urticaria provocation tests. Source: Magerl et al. 2016.
Symptomatic Dermographism
Provocation testing is commonly performed by stroking the skin with a clean, firm object such
as a wooden tongue blade. Commercially available dermographometers provide a more uniform
method of testing using defined pressure settings. The FricTest [Moxie, Berlin (Germany)] can
simultaneously test four trigger strengths (Photo 7). A test is considered positive if a wheal develops
within 10 minutes of provocation.
Acute and Chronic Urticaria/Angioedema 129
https://t.me/medicina_free
Figure 3. Chronic inducible urticaria threshold tests. Source: Magerl et al. 2016.
Cold Urticaria
Provocation testing involves placing an ice cube melting in a plastic bag on the volar surface of
the forearm for 5 minutes. The test is considered positive if there is a wheal 10 minutes after the
removal of the ice cube. Patients with a positive test should subsequently undergo threshold testing
130 Textbook of Diagnostic and Therapeutic Procedures in Allergy
Source: James Heilman, MD, CC BY-SA 3.0 via Wikimedia Commons;
https://commons.wikimedia.org/wiki/File:UriticariaPigmentosa.jpg
https://t.me/medicina_free
Photo 7. FricTest Dermographometer. Source: https://medelink.ca/product/frictest-4/.
Photo 8. TempTest. Source: https://medelink.ca/allergy/sub-page-temptest/.
if possible. This is performed via the TempTest [Courage and Khazaka in Cologne (Germany)], an
element-based temperature exposure device that provides a continuous gradient of temperatures
ranging from 4 to 44°C (Photo 8).
Cholinergic Urticaria and Exercise-Induced Urticaria/Anaphylaxis
Provocation testing helps confirm the diagnosis of cholinergic urticaria and distinguish it from
exercise-induced urticaria/anaphylaxis. The first step involves an exercise challenge (treadmill
or stationary bicycle) sufficiently intense to cause sweating for at least 15 minutes. The test is
considered positive if it results in hives. In such a case, the next step is to perform a passive heat
challenge to exclude exercise-induced anaphylaxis. The patient’s body is placed in a hot water bath
(42°C) until the core body temperature rises by 1°C. A positive test for both the exercise challenge
and passive heat challenge is diagnostic of cholinergic urticaria, whereas a positive test for only the
exercise challenge is diagnostic of exercise-induced urticaria/anaphylaxis.
Delayed-Pressure Urticaria/Angioedema
The traditional provocation test is the “sandbag test,” where a 15-lb sandbag is attached to a strap
and hung from the shoulder for 15 minutes. The site is then observed for the next 24 hours for
evidence of erythematous swelling. In research settings, weighted rods or a dermographometer are
used instead.
Heat Urticaria
Provocation testing is conducted by applying a test tube containing warm water at 44°C to the volar
forearm for 5 minutes. The test is considered positive if a wheal develops within a few minutes after
the removal of the heated object.
Acute and Chronic Urticaria/Angioedema 131
https://t.me/medicina_free
Solar Urticaria
Provocation testing involves placing light sources that emit specific wavelengths of ultraviolet A
and ultraviolet B 10 to 15 cm from the patient’s back or buttocks. Clinical response is assessed every
10 minutes for up to an hour. Most patients with solar urticaria react to a specific wavelength.
Vibratory Urticaria/Angioedema
A vortex mixer is placed in contact with the patient’s forearm for 5 minutes at 1,000 rpm. The test is
considered positive if the area becomes erythematous, pruritic and edematous.
Chronic Spontaneous Urticaria
A comprehensive clinical history is crucial to the diagnostic evaluation of CSU. This includes
associated signs and symptoms, duration of individual lesions and accompanying angioedema.
Before establishing the diagnosis of CSU, one must exclude the possibility of a more serious
systemic disease. Potential red flags include fever, weight loss, arthralgias, abdominal pain and
bone pain.
Certain triggers can aggravate CSU in a subset of patients. These include physical factors,
NSAIDs, alcohol, stress and concomitant infections. In addition, some patients report aggravation
of symptoms with spicy or fermented foods. This may be related to the histamine content or
histamine-releasing properties of these foods.
Considering that the etiology of CSU is unknown in most cases, extensive investigations
are not recommended. Nonetheless, a limited workup consisting of CBC with differential,
ESR/CRP and TSH may be considered to rule out certain underlying causes (Zuberbier et al. 2022;
Bernstein et al. 2014). For example, eosinophilia should prompt evaluation for a parasitic infection.
Significant elevations in ESR or CRP should prompt investigation for a rheumatological, infectious
or neoplastic disease. An abnormal TSH should prompt evaluation for thyroid disease. In contrast to
acute urticaria, skin testing and allergen-specific IgE testing are not indicated, as chronic urticaria is
rarely caused by IgE-mediated reactions.
Investigational Tests
Investigational tests include the autologous serum skin test (ASST), tests of basophil activation and
assays for antibodies to IgE or the high-affinity mast cell receptor (FcεR1α). The validity of these
tests has not been fully established, therefore they are not recommended outside of research settings.
ASST
The ASST is an in vivo test to detect basophil histamine-releasing activity from the patient’s serum.
It involves intradermally injecting a patient with his/her serum. A wheal-and-flare reaction at the
site of injection within 30 minutes constitutes a positive test (Grattan et al. 1986). However, its
clinical usefulness remains doubtful. For example, one study found positive ASSTs in 56% of
healthy controls (Taskapan et al. 2008). In addition, the positivity of the ASST persists in patients
with CSU, even when their disorder is in clinical remission (Fusari et al. 2005). Finally, the ASST
has not demonstrated clinical utility in identifying patients who respond differently to treatment
(Lapolla et al. 2012).
Basophil Histamine Release Assay (BHRA)
The basophil histamine release assay is an in vitro test in which a patient’s serum is incubated with
donor basophils. The cells are centrifuged, and the supernatant is recovered. Using a quantitative
enzyme immunoassay, histamine released into the supernatant is measured and compared to
Соседние файлы в папке Библиотека им академика М.И. Перельмана