Urticaria is treated with intravenous dexamethasone 10 mg and intravenous diphenhydramine 25 mg and resolves rapidly. She is dismissed home and continues with cetirizine 10 mg twice daily and famotidine 20 mg twice daily. 

The patient continues to improve, and respiratory symptoms, fever, and headache resolve by day 14 of the illness. By day 21, urticarial lesions are improved, although more mild migratory lesions continue to appear intermittently (Figure 2 and 3). Angioedema does not recur. Cetirizine is reduced to her usual dosage of 10 mg daily.

Figure 2. Migratory lesions continue to appear intermittently on day 21 of COVID-19 infection.
Credit: Kimberly M. Beckstrom, APRN, DNP, CNP
Figure 3. Timeline of COVID-19 symptoms and urticaria resolution.
Credit: Kimberly M. Beckstrom, APRN, DNP, CNP

Fifty-one days after the onset of urticaria, she receives the Pfizer-BioNTech COVID-19 vaccine. The vaccine was initially well-tolerated with only mild tenderness at the injection site. However, 48 hours after administration, she has a recurrence of generalized urticaria. No other significant vaccine-related reactions occur. The urticarial lesions spontaneously resolve within 24 hours and she continues on daily cetirizine.


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An allergy specialist is consulted for further evaluation. Several etiologies are considered, such as autoimmune conditions, mast cell defects, food-related allergies, and infectious causes. Because symptom onset immediately preceded her positive SARS-CoV-2 PCR test and she developed associated mild viral symptoms, it is felt that urticaria was a presenting symptom of her COVID-19 infection. The working diagnosis was chronic urticaria secondary to COVID-19 infection. She is cleared to receive the second dose of the Pfizer-BioNTech COVID-19 vaccine and similarly 48 hours after administration she had a recurrence in generalized urticaria but no other vaccine-related reactions. The urticarial lesions spontaneously resolve within 24 hours and she continues on daily cetirizine.

Discussion

SARS-CoV-2 is primarily spread by respiratory droplets, with an incubation period of up to 14 days.1,2 It is an RNA virus that invades host cells through the angiotensin-converting enzyme 2 (ACE2) receptor found on lung alveolar epithelial cells, small intestine enterocytes, vasculature, as well as endocrine, cardiac, and neurologic systems.3 The clinical features of COVID-19 disease are varied and typically include fever, dry cough, dyspnea, sore throat, fatigue, myalgia, headache, hyposmia, and hypogeusia.2 Less common symptoms have also been demonstrated, including diarrhea, nausea and vomiting, and cutaneous manifestations.2,4-7

Although the primary target of the virus is the upper respiratory mucosa, recent findings suggest that ACE2 receptors are also found in the skin, which may explain some of the cutaneous manifestations in COVID-19 infections.8 The pathogenesis of COVID-19-related urticaria remains unclear, although it is theorized that the virus sets off a state of mast cell activation leading to histamine release.7,9,10

Cutaneous manifestations in COVID-19 were first reported in a case series of 88 patients in Italy.7 In the study, 18 (20%) developed skin findings, including erythematous rash (14 patients), widespread urticaria (3 patients), and varicella-like vesicles (1 patient). The trunk was the most often involved region of the body.7 Several other case reports have described other dermatologic manifestations, including maculopapular rash, chilblain-like acral pattern, livedo reticularis-like pattern, vasculitic pattern, and urticarial eruptions in patients with COVID-19, sometimes co-existing with or preceding other classical symptoms of COVID-19.4,10 These cases highlight the importance of early recognition of cutaneous symptoms in the diagnosis of COVID-19 to limit the spread of the disease.

Urticaria is one of the most common skin manifestations of COVID-19 reported to date.4 One of the largest case series of patients with COVID-19 and urticaria (N=73) found that the trunk was most often affected, and pruritus was present in 97% of patients.11 Urticaria was associated with more severe disease and occurred concomitantly with other symptoms in the majority of cases.11 None of the patients with urticaria died.  

While most cases of urticaria in patients with COVID-19 resolve within 10 days, treatment of refractory urticaria in patients with COVID-19 can be challenging.12 Patients are typically treated with oral antihistamines, alone or in conjunction with other medications.13 For refractory pruritus and persistent lesions, doses of second-generation H1-antihistamines as high as 4 times the standard dose may be needed.13 The addition of an H2-receptor antagonist antihistamine (eg, famotidine) or leukotriene modifier (eg, montelukast) may also be considered for persistent symptoms.13

While systemic glucocorticoids are effective in controlling symptoms, administration beyond a few weeks is not warranted for a condition that typically has an excellent long-term prognosis given the significant adverse effects of long-term steroid use.13 However, glucocorticoids may be considered as short-term additive therapy for severe symptoms refractory to 1 or more antihistamines at maximum doses.14 The routine use of topical corticosteroids and topical antihistamines is not recommended as they typically do not hasten recovery or result in sustained improvement and may cause skin atrophy or contact sensitization.15  

Conclusion

While most patients with COVID-19 present with respiratory symptoms, several organs may be affected with multiple possible dermatologic findings. Cutaneous manifestations of COVID-19 are increasingly reported, with urticaria being one of the most common skin symptoms. This case underscores the need for early recognition of cutaneous symptoms in the diagnosis of COVID-19 to control the spread of the disease. Treatment of urticaria is aimed at controlling symptoms and typically includes oral antihistamines, leukotriene inhibitors, and oral corticosteroids.

Kimberly M. Beckstrom, APRN, DNP, CNP, practices at Mayo Family Northeast Clinic and Community Health and is an instructor in Surgery and Family Medicine at Mayo Clinic College of Medicine and Science, Rochester, Minnesota.

References

1. Lauer SA, Grantz KH, Bi Q, Jones FK, et al. The incubation period of coronavirus disease 2019 (COVID-19) from publicly reported confirmed cases: estimation and application. Ann Intern Med. 2020;172(9):577-582. doi:10.7326/M20-0504

2. Centers for Disease Control. COVID-19: clinical care guidance. Updated February 16, 2021. Accessed May 3, 2021. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html

3. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203(2):631-637. doi:10.1002/path.1570

4. Algaadi SA. Urticaria and COVID-19: a review. Dermatol Ther. 2020;33(6):e14290. doi:10.1111/dth.14290

5. Galván Casas C, Català A, Carretero Hernández G, et al. Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases. Br J Dermatol. 2020;183(1):71-77. doi:10.1111/bjd.19163

6. Goyal P, Choi JJ, Pinheiro LC, et al. Clinical characteristics of COVID-19 in New York City. N Engl J Med. 2020;382(24):2372-2374. doi:10.1056/NEJMc2010419

7. Recalcati S. Cutaneous manifestations in COVID-19: a first perspective. J Eur Acad Dermatol Venereol. 2020;34(5):e212-e213. doi:10.1111/jdv.16387

8. Li MY, Li L, Zhang Y, Wang XS. Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues. Infect Dis Poverty. 2020;9(1):45. doi:10.1186/s40249-020-00662-x

9. Abasaeed Elhag SA, Ibrahim H, Abdelhadi S. Angioedema and urticaria in a COVID-19 patient: A case report and review of the literature. JAAD Case Rep. 2020;6(10):1091-1094. doi:10.1016/j.jdcr.2020.07.042

10. Sachdeva M, Gianotti R, Shah M, et al. Cutaneous manifestations of COVID-19: report of three cases and a review of literature. J Dermatol Sci. 2020;98(2):75-81. doi:10.1016/j.jdermsci.2020.04.011

11. Galván Casas C, Català A, Carretero Hernández G, et al. Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases. Br J Dermatol. 2020;183(1):71-77. doi:10.1111/bjd.19163

12. Sachdeva M, Gianotti R, Shah M, Bradanini L, et al. Cutaneous manifestations of COVID-19: report of three cases and a review of literature. J Dermatol Sci. 2020;98(2):75-81. doi:10.1016/j.jdermsci.2020.04.011

13. Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy. 2018;73(7):1393-1414. doi:10.1111/all.13397

14. Pollack CV Jr,  Romano TJ. Outpatient management of acute urticaria: the role of prednisone. Ann Emerg Med. 1995;26(5):547-551. doi:10.1016/S0196-0644(95)70002-1

15. Barinol C, Dehours  E, Mallet J, Houze-Cerfon CH, Lauque D, Charpentier S. Levocetirizine and prednisone are not superior to levocetirizine alone for the treatment of acute urticaria: a randomized double-blind clinical trial. Ann Emerg Med. 2018;71(1):125-131.e1. doi:10.1016/j.annemergmed.2017.03.006