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SPECIAL ARTICLE |
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| Year : 2022 | Volume
: 67
| Issue : 6 | Page : 732-743 |
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| Diagnosis and management of urticaria in Indian settings: Skin allergy research society's guideline-2022 |
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Kiran Godse1, Anant Patil2, Abhishek De3, Nidhi Sharma4, Muralidhar Rajagopalan5, Bela Shah6, Sushil Tahiliani7, Mukesh Girdhar8, Vijay Zawar9, Prabhakar Sangolli10, DS Krupa Shankar11, Sandipan Dhar12
1 From the Department of Dermatology, D Y Patil Hospital, Navi Mumbai, Maharashtra, India
2 Department of Pharmacology, D Y Patil Hospital, Navi Mumbai, Maharashtra, India
3 Department of Dermatology, Calcutta National Medical College, Kolkata, West Bengal, India
4 Department of Dermatology, The Medicity, Medanta Hospital, Gurugram, Haryana, India
5 Department of Dermatology, Apollo Hospital, Chennai, Tamil Nadu, India
6 Department of Dermatology, BJ Medical College, Ahmedabad, Gujarat, India
7 Department of Dermatology, PD Hinduja Hospital, Mumbai, Maharashtra, India
8 Department of Dermatology, Max Super Speciality Hospital, Patparganj, Delhi, India
9 Department of Dermatology, Skin Diseases Centre, Nashik, Maharashtra, India
10 Consultant Dermatologist, Skin Care Centre, Rajajinagar, Bengaluru, Karnataka, India
11 Department of Dermatology, Mallige Hospital, Bengaluru, Karnataka, India
12 Department of Dermatology, Institute of Child Health, Kolkata, West Bengal, India
| Date of Web Publication | 23-Feb-2023 |
Correspondence Address:
Abhishek De
Department of Dermatology, Calcutta National Medical College, Flat Number 3 A, Arcadia 1 Dream Park Sonarpur Station Road, Kolkata - 700 103, West Bengal
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ijd.ijd_307_22
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 Abstract | | |
Urticaria is a common skin disorder. Chronic urticaria, i.e., the presence of symptoms for more than six weeks, is associated with a significant adverse impact on sleep, performance, quality of life, and financial status of the patients. Although several treatment options are available, the condition can be challenging to treat for many clinicians. Several updates have been published on the subject of urticaria and its management since the publication of an updated consensus statement in 2018 by Indian experts. The objective of this consensus statement is to summarize the updates and provide concise information, including classification, diagnosis, and management of urticaria. Understanding and elimination of the underlying eliciting trigger are essential in all possible cases. The goal of pharmacological treatment is to provide symptomatic relief. Second-generation nonsedating H1 antihistamine continue to be recommended as the first-line treatment, the dose of which can be increased up to four times in patients not responding satisfactorily, in the second step. The role of omalizumab, cyclosporine, H2 antihistamines, and other options is also discussed.
Keywords: Antihistamines, chronic urticaria, omalizumab, quality of life
How to cite this article:
Godse K, Patil A, De A, Sharma N, Rajagopalan M, Shah B, Tahiliani S, Girdhar M, Zawar V, Sangolli P, Shankar DK, Dhar S. Diagnosis and management of urticaria in Indian settings: Skin allergy research society's guideline-2022. Indian J Dermatol 2022;67:732-43 |
How to cite this URL:
Godse K, Patil A, De A, Sharma N, Rajagopalan M, Shah B, Tahiliani S, Girdhar M, Zawar V, Sangolli P, Shankar DK, Dhar S. Diagnosis and management of urticaria in Indian settings: Skin allergy research society's guideline-2022. Indian J Dermatol [serial online] 2022 [cited 2023 Mar 23];67:732-43. Available from: https://www.e-ijd.org/text.asp?2022/67/6/732/370288 |
| Introduction | |  |
Urticaria, also known as hives, is a common skin disorder across the world. It may present with or without angioedema. The hives/wheals disappear within 24 h, whereas the angioedema, if present may last up to 72 h.[1],[2] Angioedema can also be seen without urticaria in the settings of hereditary or acquired angioedemas; however, those situations are kept out of the scope of the present article.[3] Chronic urticaria (CU) is defined as the occurrence of hives daily or nearly daily, for six weeks or more. Considering the nature of the disease, CU can be challenging to treat. Although several options are available, treatment is not satisfactory for many patients. Guidelines, consensus statements, and international updates for the diagnosis and treatment of urticaria from different countries are available to aid practicing physicians in treating this challenging condition.[4],[5],[6],[7],[8],[9],[10],[11],[12]
For the first time in India in 2011, the Special Interest Group – Urticaria designated by IADVL (Indian Associations of Dermatologists, Venereologists and Leprologists) published a consensus statement on the management of urticaria.[13] An updated consensus statement for the diagnosis and treatment of urticaria by the Skin Allergy Society was published in 2018.[14] However, evidence related to basic research, pathophysiology, investigations, the role of biomarkers, and different management options in urticaria is dynamic and continues to evolve. This can be supported by the fact that only in “PubMed”, from 2019 till now, over 1250 articles with the word “Urticaria” in the title have been published [2019; 337; 2020;399; 2021;424; 2022;93]. The international EAACI/GA2LEN/EuroGuiDerm/APAAACI guidelines have been published recently.[6] Moreover, Collegium Internationale Allergologicum Update 2020,[5] Korean practice guidelines,[7],[8] and Taiwanese consensus[11] on the management of urticaria are also published recently. With the advent of emerging evidence, improved understandings, and accumulating clinical experience, there is a need to have an updated consensus statement for the diagnosis and management of CU in Indian settings.
The objective of this consensus statement is to summarize the available literature for the diagnosis and treatment of urticaria in today's context. A draft presentation was prepared based on the extensive literature search of articles retrieved from PubMed/Medline and Google Scholar. References of selected articles were also considered for discussion. Indian experts were invited to discuss these updates in urticaria. A draft word document of the consensus statement was prepared after two online meetings of experts and sent for review and comments via emails. Suggestions and comments of experts based on the evidence, and experience, were included in the final document.
Definition and classification of urticaria
Urticaria is a condition characterized by the development of wheals (hives), angioedema, or both. Wheal is a specific skin lesion for urticaria that has a central swelling of variable size and is surrounded by a zone of reflex erythema; it is usually associated with itching and is of a fleeting nature lasting less than 24 h. Angioedema, on the other hand, is characterized by a sudden, pronounced erythematous or skin-coloured swelling of the lower dermis and subcutis or mucous membranes; it is usually associated with pain, rather than itch, and its resolution is slower than that of wheals (can take up to 72 h).
Urticaria is broadly classified into two types: acute and CU, depending upon the duration of condition.[3] Urticaria with the presence of wheals and/or angioedema for less than and more than six weeks is called acute urticaria and CU, respectively.[2],[14],[15]
Acute urticaria is usually related to allergic reactions to drugs such as nonsteroidal antiinflammatory drugs (NSAIDs), foods, chemicals, or infections.[16],[17] CU is defined as wheals with or without angioedema occurring daily or almost daily for at least 6 weeks. Further subclassification of CU is given in [Table 1].[14] Based on the triggers/eliciting factors, CU is divided into two subtypes: chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU). CIndU is further classified into different subtypes [Table 1].[14],[15],[18]
CU, i.e., symptoms for more than six weeks, does not only cause physical impact but is also associated with considerable psychological and economic burden and poor quality of life[1],[5],[11],[19],[20],[21] due to chronic itching, wheals, and flare.
The prevalence of CU differs based on geographical areas. According to the results of a recent systematic review and meta-analysis, point prevalence of CU is more in Asian studies (1.4%) compared to Europe (0.5%) and Northern America (0.1%) with more rates in females than the male population.[22] The prevalence of CU in children is less than 1%.[23] Among children less than 15 years of age, there is no significant difference between males and females.[22]
CSU is a type of urticaria where any triggering factor is not found.[24] The disease is most common between the third and fifth decades of life.[25] CSU cases are often challenging to treat. Longer duration and severity of condition can be compounded by comorbidities, such as anxiety and depression, observed in over 30% of patients with CSU. Sleep disturbances, sexual dysfunction, impaired daily work, personal, leisure, and sports activities can adversely affect family, social, and professional life.[26],[27] Thus, the disease is associated with a significant direct (medical cost) and indirect (nonproductivity and loss of work cost) burden.[26]
CIndU constitutes up to 25% of CUs. These are more commonly seen in young adults. The symptoms are often restricted to areas exposed to specific stimuli. Sometimes, generalized symptoms are also seen. In these subgroups of CUs, wheals are induced by different types of physical stimuli. The inducing stimuli can be temperature (cold or heat), pressure, vibration, or sunlight. In a few patients, physical urticaria with more than one inducing agent can be seen. Mediator release from the activated mast cells results in symptoms of physical urticaria.[28] Cold urticaria (ColdU) is a common form of CIndU that occurs due to cold-induced formation of autoallergens and IgE to these autoallergens, causing a release of proinflammatory mediators from the mast cells. ColdU can be of typical and atypical types.[29] Solar urticaria is a rare type of photodermatosis, in which patients develop symptoms within seconds to minutes of exposure to light, most commonly ultraviolet-A or visible light.[30],[31]
Epidemiology and course of the disease
The lifetime prevalence of acute urticaria is about 20%.[6] Acute urticaria is more common than CU.[15] Point prevalence of CU ranges from 0.5 to 1% of the worldwide population of all age groups.[5],[14],[32] Its prevalence is more common in young people and middle-aged females. The disease may last for several years in many patients. In 25–75% of patients, the duration is more than 1 year.[26] According to a study from Germany, 72.2% of patients have CSU, whereas 19.7% have CIndU. The remaining 9.1% of patients have both.[33] In the Swedish registry, 89% of patients had CSU and 11% had CIndU.[34] Large Indian studies are not available to suggest a prevalence of these subtypes. CSU is a self-limiting disease with a variable duration that depends on multiple factors. About 21–47% of patients achieve remission within 1 year, whereas 34–45% of patients achieve remission within 5 years.[35]
Pathophysiology
CU is a mast-cell-driven disease.[36] The release of mediators after activation of mast cells results in stimulation of sensory nerves, vasodilation, increased vascular permeability, and extravasation of inflammatory cells, including basophils, eosinophils, and T cells.[5],[15] These changes result in the formation of wheals, itching, and angioedema. Endothelial cells mainly contribute to the important clinical features of CU.[37] High-affinity receptor IgE (FcεRI) plays an important role in the degranulation of skin mast cells responsible for clinical features seen in CSU.[37] Overall, two mechanisms have been postulated in causing mast cell degranulation in CSU; type I autoimmunity, i.e., autoallergy and type IIb autoimmunity. In the first type of autoimmunity, autoantigens crosslink IgE autoantibodies on the mast cells and basophils, causing the release of inflammatory mediators. In type IIb autoimmunity, autoantibodies (usually IgG/IgM) bind to antigen on a target cell and cause a release of mediators.[5] Adhesion molecules, TF, and P-selecting are commonly involved and upregulated biomarkers in CU skin, whereas in serum, upregulated markers include coagulation cascade, D-dimers, and MMP-9.[36]
Diagnosis
In acute urticaria, a supplementary workup is often not necessary as history provides clues to identify the trigger for symptoms. It identifies a convincing, inciting allergen. In CU, often, it is not easy to identify a trigger.[2] Several infections, including Helicobacter pylori, have been reported to have an association with CU.[38] Stress can also be associated with the onset of disease.[39] In patients with CU, up to 40% of patients have the possibility of autoimmune aetiology,[39] Thyroid autoimmunity is commonly associated with CU. According to the results of a recent meta-analysis of case control studies, patients with CU have a five-to-nearly seven times higher risk of positive antithyroid peroxidase antibodies. Hence, all patients with CU may be tested for thyroid autoimmunity.[40] In serum/plasma of some patients with solar urticaria, chromophores, i.e., “serum factor”, may be found.[30] A high total IgE level may represent high disease activity and longer disease duration.[41] Wheals usually develop after rewarming and disappear within an hour. Anaphylaxis can develop in these patients; diagnosis is based on the history narrated by the patient and cold stimulation test. Further investigations for underlying infections may be needed only if history demands it.[29] Skin biopsy may be required only in some cases for the confirmation of diagnosis and to rule out other diseases presenting with similar clinical features.[42] A study identified an allergen in 88% of cases with urticaria,[43] whereas in another study, 71% were positive for at least one allergen.[44] Despite this, we strongly feel that there is no high clinical relevance of the skin prick test.
We recommend following investigations in patients with CU [Table 2].
Although no specific triggers are known, a cross-sectional, questionnaire survey-based study reported worsening of CSU in 46% of patients after consumption of hot peppers (Capsicum spp.).[45] CSU patients frequently have elevated total IgE serum levels (up to 50%), but normal or very low total IgE levels may also be seen.[41] Total IgE is a useful marker for CSU. We recommend the use of this investigation in the routine diagnostic workup of CSU.[39]
Assessment of the severity of urticaria
Biomarkers for severity can be broadly divided into two types: clinical and serological markers.[46] Currently, there are no specific diagnostic biomarkers for CSU. Several patient-reported outcome measures are available for the assessment of disease activity/severity and response to treatment. The Urticaria Activity Score (UAS) is an easy-to-use method to assess the severity and response to treatment.[47] UAS7 measures the score, taking into account separate scores for wheals and itch (each is scored on a scale of 0–3) over 7 days. The Urticaria Control Test (UCT) can be useful for the evaluation of the control of the disease. Estimation of quality of life is also a useful measure for disease and treatment evaluation. However, during clinical practice, many clinicians do not use it. Being simple, convenient, and easy to use, we strongly recommend UAS7 for the assessment of the severity and treatment response. Basopenia and coagulation cascade activation can be useful biomarkers for disease activity and severity. However, their routine use cannot be recommended, considering the available limited evidence.[46]
Management
Management of CU can be divided into two aspects: general management and specific treatment.
General management
In all possible cases, identifying and eliminating the underlying cause(s) and/or trigger(s) is recommended. Unfortunately, for many patients, it takes more than a year to start effective management.[26] The reasons for the delay could be related to diagnosis or approaching physicians for treatment after using over-the-counter options.
a. Patient education
Patients should be educated and advised to avoid other known triggers, if possible. In cases where avoidance is not possible, they should be prepared to prevent or control an acute exacerbation using an appropriate pretreatment.[48] In patients with higher education, information and technology can be used for communication and educational purposes.[49],[50]
b. Treatment of infections and elimination of other triggers
H. pylori, ear infections, and other sources of infections should be ruled out. Tinea infection can also be associated with CU. In such cases, treatment of fungal infection with antifungal drugs is necessary.[51] A recent systematic review and meta-analysis suggested correlated Helicobacter pylori and CU.[38] Drugs such as NSAIDs may aggravate pre-existing CSU. Eliminations of such drugs wherever possible are suggested. Avoidance of triggers and symptomatic treatment remains the key principles of the effective management of CIndU.[28] Patients with ColdU should avoid exposure to cold.[29] Action spectrum and minimal urticarial dose should be determined. Other causes of photoreactions, i.e., polymorphic light eruption or porphyrias, should be excluded. Patients with solar urticaria should avoid sunlight exposure.[30]
c. Role of diet
Although evidence for a relationship between diet and CSU is not conclusive, it is not unusual to see patients commonly reporting food items as triggers for both acute and CU and asking for suggestions related to dietary modifications. In acute urticaria, the food items commonly implicated as triggers include nuts and shellfish. Many patients with CU unnecessarily avoid specific food items. The relationship between diet and exacerbation is not well established in CU. Dermatologists should help patients to identify if there is a reasonable association between symptoms and dietary items. Avoidance of pseudo allergens and histamine-releasing food items may help some patients with CU.[2]
Modified diets may be useful in some patients with antihistamine refractory CSU. However, currently, there are no tests that can identify such patients. Food item elimination, solely based on the history given by patients, may result in unnecessary restrictions and a risk of nutritional deficiencies. Food additives/artificial pseudo allergens should be eliminated. Dietary elimination of red meat, fish, and their products and natural pseudo allergens may be suggested. Before determining the effectiveness of elimination diets, they should be continued regularly for at least three weeks.[52]
Pharmacological treatment
a. Antihistamines
For symptomatic relief, pharmacological treatment is essential for CU patients. In both AU and CU, second-generation, nonsedating H1 antihistamines (nsAHs) are considered the mainstay of treatment.[3],[53] Sedating antihistamines adversely affect the quality of life due to impairment of sleep and performance.[54] As recommended by all currently available guidelines and a previous recommendation from the consensus statement,[14] second-generation nsAHs are recommended as the first-line treatment [Figure 1].
According to the findings of a recently published network meta-analysis, second-generation antihistamines such as olopatadine, fexofenadine, bilastine, rupatadine, and levocetirizine outperform placebo in CSU. The acceptability of these agents was not inferior as compared to placebo. Robust head-to-head clinical trials are necessary to estimate the superiority of one agent over the other in terms of efficacy and safety.[55] Considering such evidence, it is difficult to rate one nsAH over the other. Hence, we recommend that any nsAH can be used as the first-line treatment for the treatment of CSU.
A retrospective study reported that in CSU patients with nonsatisfactory responses to commonly used antihistamines (double dose or combined use), switching to bilastine helps to reduce symptoms and improve quality of life.[56] A recent small, randomized study from India showed better response with updosing of nsAH compared to a combination of second-generation and first-generation AH.[57] Bilastine has been shown to be useful in CSU refractory to levocetrizine.[58]
A single subtype of CU responds better to second-generation antihistamines. According to a single-centre, retrospective study, at standard doses, control of symptoms is seen in 38.83 and 56.32% of patients with mixed subtype and single subtype CU, respectively.[59]
In patients with nonsatisfactory results, the dose of nsAH can be increased up to four times. A prospective study reported the effectiveness of updosing with ebastine in different types of CU with no significant difference between factitious urticaria, CSU, cholinergic urticaria, and CSU with factitious urticaria in different doses. There was no increase in the incidence of adverse reactions with the escalation of doses from 10 to 40 mg.[60] A meta-analysis of randomized controlled trials has shown that intensive nsAH provides a higher reduction in the mean pruritus score than standard dose nsAH.[61]
Although there is no strong evidence, many clinicians in India give nonsedating AH such as bilastine and fexofenadine in the morning and minimally sedating antihistamine, e.g., levocetirizine, in the evening.[62],[63]
Over 25% of patients do not show satisfactory results with even higher doses of nsAH.[26] In such cases, third- and fourth-line treatments are required. Patients with high disease activity, high levels of C-reactive protein, and D-dimer predict low response to second-generation antihistamines.[64] Serum diamine oxidase can help in the prediction of the efficacy of antihistamines.[65]
Although many studies with updosing with nsAH are available, there is heterogeneity in the articles.[66]
b. Omalizumab
Omalizumab is a preferred and recommended option for nonresponding patients with updosing of nsAH as recommended in the second step. Low serum levels of total IgE are predictors of poor response.[64] In India, the cost of therapy with omalizumab is a challenge.[67] With the availability of biosimilars, the financial burden can be slightly eased out. However, it is still out of reach for many patients with CU.
Targeting IgE with biological agents (monoclonal antibodies) is an efficient measure for the treatment of CSU. Omalizumab, the IgE-targeted agent, is recommended for the treatment of CSU in patients not showing a satisfactory response to nsAH.[37],[68]
A recent systematic review and meta-analysis of 10 randomized controlled trials (n = 1620) including patients between 12 and 75 years of age, treated with omalizumab for 16–40 weeks, reported clinically meaningful improvements in both UAS7 and quality of life. Similarly, it can reduce the need for rescue medications.[69] Currently, it is the only biologic approved for CS in India. In adult patients with CSU, there is good evidence from randomized clinical trials as well as real-world studies with omalizumab demonstrating its efficacy and safety. There is little evidence in CIndU and in special populations.[68]
Omalizumab is useful in patients with CSU who are symptomatic despite treatment with H1 antihistamines.[69],[70] According to a recently published systematic review and network meta-analysis of 23 randomized clinical trials in adolescents or adults with CSU who did not achieve a satisfactory response to H1 antihistamines, ligelizumab (72 or 240 mg) and omalizumab (300 or 600 mg) can be effective options.[71]
According to the position statement on omalizumab from Indian experts, the recommended dose is 300 mg administered every 4 weeks in adults and adolescents equal or more than 12 years of age. Some patients may show a response to 150 mg. All patients receiving omalizumab should be observed for 2 h for anaphylactic reactions.[72]
Ligelizumab has been shown to provide numerically higher responses than omalizumab.[73] However, it is currently not available in India.
Markers of IgG-mediated autoimmunity including autologous serum skin test, basophil activation/histamine release assays, and low total IgE may be useful to predict a lesser chance of response to omalizumab. Autoallergy with higher IgE levels may suggest higher chances of response to omalizumab. Baseline total IgE levels have high prognostic relevance for response to omalizumab response with a threshold value of 18 IU/ml.[74]
Overall, omalizumab has been a landmark treatment option for patients with CSU. Based on its success, next-generation anti-IgE products are expected to arrive to expand the armamentarium of pharmacological treatment. Unmet needs in this area include easy availability of tools to identify potential candidates who will not respond and optimal duration of therapy. Although omalizumab is a promising treatment for CSU, new targets or biologics are still being evaluated to provide an effective treatment for those who do not get relief from it.[75],[76],[77]
A retrospective study showed that omalizumab does not increase the risk of COVID-19 infection; hence, it can be safely given to patients with CSU during COVID-19.[78]
A high total IgE level may suggest a high chance of responding to omalizumab treatment and a quick relapse after stopping omalizumab, whereas a low IgE, in contrast, may suggest Type IIb autoimmune CSU and a poor response to treatment with omalizumab. Differences in IgE in different cohorts may have different physicochemical properties, leading to differences in the responses to IgE-directed therapies.[41]
c. Cyclosporine
Cyclosporine is an option for patients with poor responses to updosed antihistamines up to four times. In India, considering the cost of cyclosporine, it is more commonly used by dermatologists than omalizumab. A positive histamine release assay is a predictor of good response cyclosporine.[64] The availability of this test is a challenge in India. A high total IgE level may suggest a poor response to cyclosporine, whereas a low IgE suggests a better chance of response to cyclosporine treatment.[41]
d. Other therapies
There is no strong evidence to suggest the role of topical corticosteroids in patients with urticaria. Systemic use of corticosteroids should be avoided as much as possible. If needed, prednisolone equivalent doses of 20–50 mg/day (0.5 mg/kg body weight per day) may be used in adults only as short-term (maximum of 10 days) therapy to control acute flares in certain situations. Long-term use of corticosteroids can cause severe adverse events; hence, such practice is strongly discouraged.
Shot course of oral corticosteroids may be required in some conditions [Table 3]. | Table 3: Conditions where a short course of oral corticosteroid may be required
Click here to view |
Strong evidence for H2-antagonists, montelukast, methotrexate, and dapsone is not available for the treatment of CU. These agents may still have relevance in some patients considering their affordability.[6] Montelukast at 10 mg/day may be effective for the treatment of CU. In India, a combination of montelukast with second-generation antihistamines is available. These combinations should not be used for updosing because there is no evidence of montelukast up-dosing. Autologous serum therapy may be tried in refractory cases [Table 4]. Evidence for potential benefit is low, but it has an advantage of low cost and a good safety profile.[14] | Table 4: Alternative options for the management of chronic urticaria apart from nsAH, omalizumab, and cyclosporine
Click here to view |
Third- and fourth-line therapies can control the disease in two-thirds of nsAH-resistant patients.[26]
Other therapies, including sulfasalazine, interferon, plasmapheresis, phototherapy, and intravenous immunoglobulins also do not have strong evidence.[6] We do not recommend these therapies until there is strong evidence for their use in patients with CU.
The severity of urticaria may change over a period of time. In some patients, spontaneous remission may be possible at any time. It is therefore recommended to re-evaluate the need to continue ongoing treatment or the requirement for an alternative therapy. Such re-evaluation may be done every 3–6 months focusing on the basic principle of providing treatment as much as required with as little as possible,[6] or when the patient has achieved a UCT score of 16. The principles of assessment and reassessment, adjustment, and action should be followed as appropriate during the treatment course.[6] [Figure 1] also shows step-up and step-down for nonresponding and stable patients.
Urticaria in pregnancy and lactation
Ideally, it is best to avoid all antihistamines in pregnancy, although major concerns, especially of teratogenicity and birth defects, are not reported with nsAH. Pregnancy Category B drugs suggest no evidence of harm to the foetus in animal studies, and the absence of well-controlled studies in humans to exclude harmful effects. A list of second-generation antihistamines in pregnancy category B is shown in [Table 5].[78],[79],[80],[81] Cyclosporine is embryotoxic in animal models. Hence, its use should be judged carefully. The long-term safety of omalizumab has not been established in pregnancy and lactation.[14]
Considering excretion of all H1-antihistamines in breast milk in low concentration, there is risk of sedation and impaired cognition-related problems with first-generation H1-antihistamines in nursing infants. Use of nsAH may be advised in nursing mothers, if necessary. There is no strong evidence for the safety of an increased dosage of nsAH during pregnancy and lactation.
Other treatment options
Vitamin D has been suggested to have an adjuvant role in CSU. Larger studies are required for more evidence and recommendation.[82]
Management of angioedema
Angioedema can be histamine-mediated or non-histamine-mediated. Histamine-mediated angioedema may have allergic, pseudo allergic, or idiopathic causes, whereas the other type, i.e., nonhistamine mediated is usually driven by bradykinin. It can also be hereditary, acquired, or caused by drugs like angiotensin-converting enzyme inhibitors. Bradykinin-mediated angioedema is usually self-limiting, but those with laryngeal involvement can lead to serious complications. Avoidance of known, specific triggers, if possible, remains the mainstay of angioedema management. For hereditary angioedema, drugs approved by the regulatory authority can be used.[3]
Urticaria in children
Because of the absence of high-quality evidence for many drugs, specific guidelines for the management of urticaria in children are not available. Considering the available evidence, same as in adults, nsAH antihistamines are the first line of treatment for CSU in children. Omalizumab can be used in adolescent patients who do not respond to nsAH updosing four times. Evidence regarding updosing of nsAHs and omalizumab in pediatric patients under 12 years of age with CSU is limited. Similarly, evidence for cyclosporine and montelukast is limited in children of all ages. Case series and case reports suggest a promising role of omalizumab and cyclosporine in children with CSU. However, large and well-designed randomized control trials are needed for convincing evidence for a strong recommendation. First-generation antihistamines are known to have more adverse events as compared to second-generation antihistamines.[24]
Kidney and liver disease
Recommendations for dose adjustments of second-generation antihistamines are given to patients with kidney and liver impairment [Table 6].[81],[83],[84],[85],[86] | Table 6: Recommendations for dose adjustments in kidney and liver disease
Click here to view |
Bilastine 20 mg given orally is well-tolerated in patients with renal impairment.[87] There are no well-designed studies for updosing in renally or hepatically impaired patients with CU.
Urticaria during the coronavirus disease (COVID-19) pandemic
COVID-19, due to significant morbidity and mortality, especially during the initial period of pandemic resulted in unprecedented challenges for everyone, including patients and healthcare practitioners of all specialties. Management of urticaria in COVID-19 patients should involve antihistamines. Short courses of low doses of prednisolone may be considered on a case-to-case basis.[88] A cross-sectional, international study reported less use of cyclosporine and systemic corticosteroids during the pandemic. However, use of antihistamines or omalizumab was not reduced.[89] It should be noted that CU has no effect on the course of COVID-19. However, in some patients, COVID-19 can cause an exacerbation of CU, especially in those with severe COVID-19.[89] COVID-19 vaccines have also been shown to be trigger urticaria in some patients.[90] Other relevant COVID-19-related information for dermatology practice has been published elsewhere.[91] Overall, CU management remains unchanged during the COVID-19 pandemic. First-line treatment with nsAH and updosing up to fourfold dose in patients with unsatisfactory response remains the same strategy. Steroids may be required in some cases. Omalizumab can be safely administered to patients with COVID-19. Care should be taken in case the patient requires an immunosuppressant.
| Conclusion | | |
CU causes significant impairment and impact on quality-of-life necessitating prompt diagnosis and effective treatment. Basic approach in the management of urticaria is to identify and eliminate the underlying cause/trigger, wherever possible. Patients should be educated about the nature of the disease and the need for long-term treatment in CU. The objective of treatment is to provide complete symptom relief to the patients. Second-generation nsAHs are recommended as first-line treatment of patients with CSU as well as CIndU. The dose of the nsAH can be increased up to four times in patients not showing an appropriate response to therapy. As a third step, omalizumab is recommended in patients not responding to updosing of nsAH. Cyclosporine can also be used instead. Patients should be informed about the possible risks and benefits of the provided treatment option.
Disclaimer
The consensus statement is only a set of recommendations and should not be regarded as legally binding. The statement is prepared considering currently available evidence. Individual variations in treatment may occur from patient to patient. Clinicians should provide treatment depending on the patient profile and involve patients in decision-making. Some of the treatment options discussed in the consensus statement may not be approved by the regulatory authorities. Before prescribing it, clinicians should explain the same to the patient.
The Skin Allergy Research Society will not be responsible either directly or indirectly for any legal claims.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Du-Thanh A. Chronic urticaria. Rev Prat 2021;71:293-97.  |
| 2. | Shao K, Feng H. Nutrition and urticaria. Clin Dermatol 2022;40:150-5. |
| 3. | Kanani A, Betschel SD, Warrington R. Urticaria and angioedema. Allergy Asthma Clin Immunol 2018;14(Suppl 2):59. |
| 4. | Bauer A, Dickel H, Jakob T, Kleinheinz A, Lippert U, Metz M, et al. Expert consensus on practical aspects in the treatment of chronic urticaria. Allergo J Int 2021;30:64–75. |
| 5. | Maurer M, Eyerich K, Eyerich S, Ferrer M, Gitermuth J, Hartmann K, et al. Urticaria: Collegium Internationale Allergologicum (CIA) Update 2020. Int Arch Allergy Immunol 2020;181:321–33. |
| 6. | Zuberbier T, Abdul Latiff AH, Abuzakouk M, Aquilina S, Asero R, Baker D, et al. The international EAACI/GA 2LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria. Allergy 2022;77:734-66. |
| 7. | Song WJ, Choi M, Lee DH, Kwon JW, Kim GW, Kim MH, et al. The KAAACI/KDA evidence-based practice guidelines for chronic spontaneous urticaria in Korean adults and children: Part 1. Definition, methodology and first-line management. Allergy Asthma Immunol Res 2020;12:563-78. |
| 8. | Choi JH, Lee DH, Song WJ, Choi M, Kwon JW, Kim GW, et al. The KAAACI/KDA evidence-based practice guidelines for chronic spontaneous urticaria in Korean adults and children: Part 2. Management of H1-antihistamine-refractory chronic urticaria. Allergy Asthma Immunol Res 2020;12:750-70. |
| 9. | Sanchez-Borges M, Ansotegui IJ, Baiardini I, Bernstein J, Canonica GW, Ebisawa M, et al. He challenges of chronic urticaria part 1: Epidemiology, immunopathogenesis, comorbidities, quality of life, and management. World Allergy Organ J 2021;14:100533. |
| 10. | Sanchez-Borges M, Ansotegui IJ, Baiardini I, Bernstein J, Canonica GW, Ebisawa M, et al. The challenges of chronic urticaria part 2: Pharmacological treatment, chronic inducible urticaria, urticaria in special situations. World Allergy Organ J 2021;14:100546. |
| 11. | Cho YT, Chan TC, Lee CH, Chou WY, Hsiao PF, Chen YJ, et al. Taiwanese dermatological association consensus for the definition, classification, diagnosis, and management of urticaria: A 2021 update. J Formos Med Assoc 2022;121:1191-203. |
| 12. | Sabroe RA, Lawlor F, Grattan CEH, Ardern-Jones MR, Bewley A, Campbell L, et al. British Association of Dermatologists guidelines for the management of people with chronic urticaria 2021. Br J Dermatol 2022;186:398-413. |
| 13. | Godse KV, Zawar V, Krupashankar D, Girdhar M, Kandhari S, Dhar S, et al. Consensus statement on the management of urticaria. Indian J Dermatol 2011;56:485-9. [ PUBMED] [Full text] |
| 14. | Godse K, De A, Zawar V, Shah B, Girdhar M, Rajagopalan M, et al. Consensus statement for the diagnosis and treatment of urticaria: A 2017 update. Indian J Dermatol 2018;63:2-15. [ PUBMED] [Full text] |
| 15. | Folci M, Ramponi G, Brunetta E. A comprehensive approach to urticaria: From clinical presentation to modern biological treatments through pathogenesis. Adv Exp Med Biol 2021;1326:111-37. |
| 16. | Khandzian M, Hacard F, Braire-Bourrel M, Jaulent C, Berard F, Nicolas JF, et al. NSAID urticaria: Similar management to acute urticaria. Rev Med Interne 2019;40:166-72. |
| 17. | Allegra A, Asero R, Giovannetti A, Isola S, Gangemi S. Urticaria and coronavirus infection: A lesson from SARS-CoV-2 pandemic. Eur Ann Allergy Clin Immunol 2021;53:51-4. |
| 18. | He L, Yi W, Huang X, Long H, Lu Q. Chronic urticaria: Advances in understanding of the disease and clinical management. Clin Rev Allergy Immunol 2021;61:424-48. |
| 19. | Stadler PC, Marsela E, Kammerer T, Frommherz LH, Clanner-Engelshofen B, French LE, et al. Impact of allergic reactions and urticaria on mental health and quality of life. Allergol Immunopathol (Madr) 2022;50:124-30. |
| 20. | Rani S, Singh S, Kumar D, Dabas S, Ritu K. Assessment of depression, anxiety, and stress in chronic urticaria and its correlation with disease severity. Ann Allergy Asthma Immunol 2022;128:330-31. |
| 21. | Costa C, Rosmaninho I, Portuguese Study Investigational Group. Chronic urticaria in the real-life clinical practice setting in Portugal: 2-years results from the non-interventional multicenter AWARE study. Acta Med Port 2022;35:12-9. |
| 22. | Fricke J, Avila G, Keller T, Weller K, Lau S, Maurer M, et al. Prevalence of chronic urticaria in children and adults across the globe: Systematic review with meta-analysis. Allergy 2020;75:423-32. |
| 23. | Caffarelli C, Paravati F, El Hachem M, Duse M, Bergamini M, Simeone G, et al. Management of chronic urticaria in children: A clinical guideline. Ital J Pediatr 2019;45:101. |
| 24. | Chang J, Cattelan L, Ben-Shoshan M, Le M, Netchiporouk E. Management of pediatric chronic spontaneous urticaria: A review of current evidence and guidelines. J Asthma Allergy 2021;14:187-99. |
| 25. | Licari A, Manti S, Leonardi S, Minasi D, Caffarelli C, Cardinale F, et al. Biologic drugs in chronic spontaneous urticaria. Acta Biomed 2021;92:e2021527. |
| 26. | Goncalo M, Gimenez-Arnau A, Al-Ahmad M, Ben-Shoshan M, Bernstein JA, Ensina LF, et al. The global burden of chronic urticaria for the patient and society. Br J Dermatol 2021;184:226-36. |
| 27. | Ates H, Firat S, Buhari GK, Keren M, Cifci B, Erkekol FO. Relationships between quality of life, sleep problems, and sleep quality in patients with chronic idiopathic urticaria. J Cosmet Dermatol 2022;21:4072-9. |
| 28. | Abajian M, Mlynek A, Maurer M. Physical urticaria. Curr Allergy Asthma Rep 2012;12:281-7. |
| 29. | Maltseva N, Borzova E, Fomina D, Bizjak M, Terhorst-Molawi D, Kosnik M, et al. Cold urticaria – What we know and what we do not know. Allergy 2021;76:1077-94. |
| 30. | Goetze S, Elsner P. Solar urticaria. J Dtsch Dermatol Ges 2015;13:1250-3. |
| 31. | Sabbah F, Hodak E, Levi A. Solar urticaria. Harefuah 2016;155:604-7. |
| 32. | Yuksekal G, Sevimli Dikicier B, Koku Aydın B, Yilmaz K, Altindis M, Koroglu M. Investigation of intestinal microbiome in chronic spontaneous urticaria patients. Int J Dermatol 2022;61:988-94. |
| 33. | Weller K, Maurer M, Bauer A, Wedi B, Wagner N, Schliemann S, et al. Epidemiology, comorbidities, and healthcare utilization of patients with chronic urticaria in Germany. J Eur Acad Dermatol Venereol 2022;36:91-9. |
| 34. | Tayefi M, Bradley M, Neijber A, Fastberg A, Ceynowa D, Eriksson M. Chronic urticaria: A Swedish registry-based cohort study on population, comorbidities and treatment characteristics. Acta Derm Venereol 2022;102:adv00624. |
| 35. | Balp MM, Halliday AC, Severin T, Leonard SA, Partha G, Kalra M, et al. Clinical remission of chronic spontaneous urticaria (CSU): A targeted literature review. Dermatol Ther (Heidelb) 2022;12:15-27. |
| 36. | Mostmans Y, De Smedt K, Richert B, Elieh Ali Komi D, Maurer M, Michel O. Markers for the involvement of endothelial cells and the coagulation system in chronic urticaria: A systematic review. Allergy 2021;76:2998-3016. |
| 37. | Maurer M, Khan DA, Elieh Ali Komi D, Kaplan AP. Biologics for the use in chronic spontaneous urticaria: When and which. J Allergy Clin Immunol Pract 2021;9:1067-78. |
| 38. | Cui YL, Zhou BY, Gao GC. A systematic review and meta-analysis of the correlation between Helicobacter pylori infection and chronic urticaria. Ann Palliat Med 2021;10:10584-90. |
| 39. | Hurtado-Avilés Hurtado-Avilés MG, Martínez-Reculez MGC, Vargas-Camaño ME, Castrejón-Vázquez MI. HuAutoimmunity in chronic urticaria. A historical and current perspective. Rev Alerg Mex 2022;69(Suppl 1):s69-80. |
| 40. | Tienforti D, Di Giulio F, Spagnolo L, Castellini C, Toraro M, Muselli M, et al. Chronic urticaria and thyroid autoimmunity: A meta-analysis of case-control studies. J Endocrinol Invest 2022;45:1317-26. |
| 41. | Altrichter S, Fok JS, Jiao Q, Kolkhir P, Pvatilova P, Romero SM, et al. Total IgE as a marker for chronic spontaneous urticaria. Allergy Asthma Immunol Res 2021;13:206-18. |
| 42. | López Mateos A, Sánchez Pujol MJ, Silvestre Salvador JF. Skin biopsy in chronic urticaria: When and where and what to look for? Actas Dermosifiliogr (Engl Ed) 2021;112:406-13. |
| 43. | Lote S, Gupta SB, Poulose D, Deora MS, Mahajan A, Gogineni JM, et al. Role of the skin prick test in urticaria patients. Cureus 2022;14:e21818. |
| 44. | Koirala S, Paudel U, Pokhrel DB, Parajuli S. Skin prick test positivity in chronic urticaria. J Nepal Health Res Counc 2021;18:615-18. |
| 45. | Turk M, Yilmaz I, Hawro T, Maurer M. Worsening of chronic spontaneous urticaria after intake of hot pepper. Asian Pac J Allergy Immunol 2021;39:25-30. |
| 46. | Asero R, Cugno M. Biomarkers of chronic spontaneous urticaria and their clinical implications. Expert Rev Clin Immunol 2021;17:247-54. |
| 47. | Zhang Y, Zhang H, Du S, Yan S, Zeng J. Advanced biomarkers: Therapeutic and diagnostic targets in urticaria. Int Arch Allergy Immunol 2021;182:917-31. |
| 48. | Grumach AS, Staubach-Renz P, Villa RC, Diez-Zuluaga S, Reese I, Lumry WR. Triggers of exacerbation in chronic urticaria and recurrent angioedema-prevalence and relevance. J Allergy Clin Immunol Pract 2021;9:2160-8. |
| 49. | Cherrez-Ojeda I, Vanegas E, Cherrez A, Felix M, Weller K, Magerl M, et al. How are patients with chronic urticaria interested in using information and communication technologies to guide their healthcare? A UCARE study. World Allergy Organ J 2021;14:100542. |
| 50. | Maurer M, Weller K, Magerl M, Maurer RR, Vanegas E, Felix M, et al. The usage, quality and relevance of information and communications technologies in patients with chronic urticaria: A UCARE study. World Allergy Organ J 2020;13:100475. |
| 51. | Godse KV, Zawar V. Chronic urticaria associated with tinea infection and success with antifungal therapy—a report of four cases. Int J Infect Dis 2010;14:e364–5. |
| 52. | Podder I, Jaiswal S, Das A. Dietary strategies for chronic spontaneous urticaria: An evidence-based review. Int J Dermatol 2021. doi: 10.1111/ijd. 15988. |
| 53. | Hon KL, Li JTS, Leung AKC, Lee VWY. Current and emerging pharmacotherapy for chronic spontaneous Urticaria: A focus on non-biological therapeutics. Expert Opin Pharmacother 2021;22:497-509. |
| 54. | Godse K, Bharrar P, Patil S, Nadkarni N, Gautam M. Updosing of nonsedating anti-histamines in recalcitrant chronic urticaria. Indian J Dermatol 2016;61:273-8. [ PUBMED] [Full text] |
| 55. | Phinvo P, Koompawichit P, Nochaiwong S, Tovanabutra N, Chiewchanvit S, Chuamanochan M. Comparative efficacy and acceptability of licensed dose second-generation antihistamines in chronic spontaneous urticaria: A network meta-analysis. J Allergy Clin Immunol Pract 2021;9:956-70.e57. |
| 56. | De A, Godse K, Dhoot D, Sarda A. Real-life experience of efficacy and safety of bilastine in the refractory cases of chronic spontaneous urticaria and its effect on the quality of life of patients. Indian J Dermatol 2021;66:159-64. [Full text] |
| 57. | Shah B, Dhoot D, Choudhary A, Jangid N, Mistry D, Shah S, et al. A comparative, three-arm, randomized clinical trial to evaluate the effectiveness and tolerability of bilastine vs fexofenadine vs levocetirizine at the standard dose and bilastine vs fexofenadine at higher than the standard dose (up-dosing) vs levocetirizine and hydroxyzine (in combination) in patients with chronic spontaneous urticaria. Clin Cosmet Investig Dermatol 2022;15:261-70. |
| 58. | Shah B, De A, Sarda A, Kocchar AM, Dhoot D, Deshmukh G, et al. Effect of bilastine on chronic spontaneous urticaria refractory to levocetrizine: Real world experience in India. Dermatol Ther 2021;34:e14557. |
| 59. | Mao M, Yuan Y, Xiao Y, Peng C, Chen X, Li J. Clinical difference between single subtype and mixed subtype chronic urticaria: A retrospective study. Indian J Dermatol Venereol Leprol 2022;88:171-6. |
| 60. | Qian T, Li S, Chen Q, Zhang D, Song Z, Hao F. Efficacy and safety of ebastine dose escalation in chronic urticaria: A prospective study. Dermatol Ther 2022;35;e15386. |
| 61. | Zhou P, Zeng S, Fu L, Chen H, Li L. Efficacy and safety of intensive nonsedating antihistamines for chronic spontaneous urticaria: A meta-analysis of randomized controlled trials. Int Arch Allergy Immunol 2022;183:796-803. |
| 62. | Layton D, Wilton L, Boshier A, Cornelius V, Harris S, Shakir SA. Comparison of the risk of drowsiness and sedation between levocetirizine and desloratadine: A prescription-event monitoring study in England. Drug Saf 2006;29:897-909. |
| 63. | Kawauchi H, Yanai K, Wang DY, Itahashi K, Okubo K. Antihistamines for allergic rhinitis treatment from the viewpoint of non-sedative properties. Int J Mol Sci 2019;20:213. |
| 64. | Fok JS, Kolkhir P, Church MK, Maurer M. Predictors of treatment response in chronic spontaneous urticaria. Allergy 2021;76:2965-81. |
| 65. | Chiang HL, Chen CH, Koo M, Tsai TY, Wu CH. Predictors of response to oral medications and low-histamine diet in patients with chronic urticaria. J Immunol Res 2022;2022:5243825. |
| 66. | Iriarte Sotés P, Armisen M, Usero-Barcena T, Rodriguez-Fernandez A, Otero Rivas MM, Gonzalez MT, et al. Efficacy and safety of up-dosing antihistamines in chronic spontaneous urticaria: A systematic review of the literature. J Investig Allergol Clin Immunol 2021;31:282-91. |
| 67. | Godse K, De A, Shah B, Girdhar M, Shankar K, Sarda A, et al. Management of chronic spontaneous urticaria: Real world Indian perspective. Indian J Skin Allergy 2022;1:11-6. |
| 68. | Wedi B, Traidl S. Anti-IgE for the treatment of chronic urticaria. Immunotargets Ther 2021;10:27-45. |
| 69. | Agache I, Rocha C, Pereira A, Song Y, Alonso-Coello P, Sola I, et al. Efficacy and safety of treatment with omalizumab for chronic spontaneous urticaria: A systematic review for the EAACI Biologicals Guidelines. Allergy 2021;76:59-70. |
| 70. | Yuan W, Hu S, Li M, Yang L, Liu L, Zheng M, et al. Efficacy and safety of omalizumab in Chinese patients with anti-histamine refractory chronic spontaneous urticaria. Dermatol Ther 2022;35:e15303. |
| 71. | Nochajwong S, Chuamanochan M, Ruengorn C, Awiphan R, Tovanabutra N, Chiewchanvit S. Evaluation of pharmacologic treatments for H1 antihistamine-refractory chronic spontaneous urticaria: A systematic review and network meta-analysis. JAMA Dermatol 2021;157:1316-27. |
| 72. | Godse K, Rajagopalan M, Girdhar M, Kandhari S, Shah B, Chhajed PN, et al. Position statement for the use of omalizumab in the management of chronic spontaneous urticaria in Indian patients. Indian Dermatol Online J 2016;7:6-11. [ PUBMED] [Full text] |
| 73. | Gimenez-Arnau A, Maurer M, Bernstein J, Staubach P, Barbier N, Hua E, et al. Ligelizumab improves sleep interference and disease burden in patients with chronic spontaneous urticaria. Clin Transl Allergy 2022;12:e12121. |
| 74. | Asero R. Clinical variables of severe chronic spontaneous urticaria from total IgE standpoint: A retrospective study. Eur Ann Allergy Clin Immunol 2022;54:30-3. |
| 75. | Martina E, Diotallevi F, Bianchelli T, Paolinelli M, Offidani A. Novel therapeutic approaches and targets for treatment of chronic urticaria: New insights and promising targets for a challenging disease. Curr Pharm Biotechnol 2021;22:32-45. |
| 76. | Metz M, Maurer M. Use of biologics in chronic spontaneous urticaria – beyond omalizumab therapy? Allergol Select 2021;5:89-95. |
| 77. | Wedi B. Emerging treatments for chronic urticaria. Expert Opin Investig Drugs 2022;31:281-90. |
| 78. | Koç Yıldırım S, Demirel Öğüt N, Erbagci E. Retrospective evaluation of patients with chronic spontaneous urticaria using omalizumab during the COVID-19 pandemic. J Cosmet Dermatol 2022;21:431-4. |
| 79. | Kar S, Krishnan A, Preetha K, Mohankar A. A review of antihistamines used during pregnancy. J Pharmacol Pharmacother 2012;3:105-8. [ PUBMED] [Full text] |
| 80. | Kar S, Krishnan A, Shivkumar PV. Pregnancy and skin. J Obstet Gynecol India 2012;62:268–75. |
| 81. | Davia I, del Cuvillo A, Mullol J, Jauregui I, Bartra J, Ferrer M, et al. Use of second generation H1 antihistamines in special situations. J Investig Allergol Clin Immunol 2013;23(Suppl 1):1-16. |
| 82. | Mohamed AA, Hussein MS, Salah EM, Eldemery A, Darwish MM, Ghaith DM, et al. Efficacy and safety of active vitamin D supplementation in chronic spontaneous urticaria patients. J Dermatolg Treat 2022;33:427-32. |
| 83. | |
| 84. | |
| 85. | |
| 86. | |
| 87. | Lasseter KC, Sologuren A, La Noce A, Dilzer SC. Evaluation of the single-dose pharmacokinetics of bilastine in subjects with various degrees of renal insufficiency. Clin Drug Investig 2013;33:665-73. |
| 88. | Abuelgasim E, Dona ACM, Sondh RS, Harky A. Management of urticaria in COVID-19 patients: A systematic review. Dermatol Ther 2021;34:e14328. |
| 89. | Kocaturk E, Salman A, Cherrez-Ojeda I, Criado PR, Peter J, Comert-Ozer E, et al. The global impact of the COVID-19 pandemic on the management and course of chronic urticaria. Allergy 2021;76:816-30. |
| 90. | Thomas J, Thomas G, Chatim A, Shukla P, Mardiney M. Chronic spontaneous urticaria after COVID-19 vaccine. Cureus 2021;13:e18102. |
| 91. | Manchanda Y, Das S, De A. Coronavirus disease of 2019 (COVID-19) facts and figures: What every dermatologist should know at this hour of need. Indian J Dermatol 2020;65:251-8. [Full text] |
[Figure 1]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6] |
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