Post nirmatrelvir/ritonavir erythema multiforme in a patient with coronavirus disease infection

ABSTRACT

Erythema multiforme (EM), an immune-mediated skin condition, can occur after infection or following the use of medications. In this study, we describe a patient who developed EM after nirmatrelvir/ritonavir administration. An 81-year-old woman presented with fever and dyspnea. Laboratory investigations showed positive coronavirus disease (COVID-19) based on polymerase chain reaction assay, and she received a 5-day regimen of nirmatrelvir/ritonavir. We observed development of EM after this treatment and initiated prednisone (1 mg/kg) therapy, which led to rapid improvement. Our study is the first to report EM in a patient with COVID-19, who received nirmatrelvir/ritonavir and showed a favorable response.

Keywords:
COVID-19; Nirmatrelvir/ritonavir; Erythema multiforme

INTRODUCTION

Erythema multiforme (EM), an immune-mediated condition involving the skin and mucous membranes^1,2, has an estimated prevalence of less than 1%³. EM predominantly affects women and adults aged 20-40 years¹. The pathophysiology of this condition involves the production of immunocomplexes, which can be precipitated by infections or medications and injure small vessels in the skin and mucous membranes⁴. Lesions may be asymptomatic or may present with dysesthesia, and the mean duration varies from 1 to 4 weeks. EM is characterized by target lesions, which may present as macules, papules, or vesicles, mainly distributed on the hands, feet, knees, and elbows^1,5. Treatment involves withdrawal of the possible causative agent in addition to corticosteroid therapy¹.

Coronavirus disease (COVID-19), an infection caused by the severe acute respiratory syndrome coronavirus 2⁶ may present with cutaneous manifestations⁷. Antiviral medications, including nirmatrelvir/ritonavir are approved for treatment in patients at risk of adverse clinical evolution⁸.

In this article, we describe a patient who developed EM after nirmatrelvir/ritonavir administration.

CASE REPORT

We searched the MEDLINE database via PubMed without any time restrictions. The following descriptors (bold), synonyms, natural language, and Boolean operators were used to cross-check the databases: MEDLINE (Medical Subject Headings [MeSH]: search strategy (nirmatrelvir/ritonavir), (COVID-19), and (erythema multiforme). The search was performed on January 19, 2023.

An 81-year-old woman was admitted for evaluation of cough, fever, and mild dyspnea, which required supplemental oxygen inhaler use. COVID-19 polymerase chain reaction assay showed positive results 3 days after the onset of symptoms. Nirmatrelvir/ritonavir therapy was initiated 4 days after onset of symptoms and was continued for 5 days. An acute cutaneous eruption of reddish annular macules suggestive of EM was observed on the patient’s arms the day following completion of the medication regimen (Figures 1 and 2). Histopathological examination of the lesions was not performed. Prednisone (1 mg/kg) therapy was initiated, which led to rapid improvement.

FIGURE 1:
Photograph showing an erythematous maculopapular “target” lesion.

FIGURE 2:
Photograph showing a macular “target” lesion.

DISCUSSION

To our knowledge, this is the first report of EM that showed a positive outcome in a patient with COVID-19, who was treated with nirmatrelvir/ritonavir.

Previous studies have reported EM after COVID-19 and lopinavir/ritonavir administration⁹. Likewise, EM associated with COVID-19 has been described in the medical literature, both in patients aged <30 years and in those aged >55 years⁷.

Our patient did not undergo histopathological examination; however, the temporal relationship between the appearance of the lesion after medication initiation and improvement after discontinuation of therapy reinforces the contribution of nirmatrelvir/ritonavir to EM in this case. The Naranjo Adverse Drug Reaction Probability Scale¹⁰ score in our patient was 5, which indicates a probable adverse reaction and strengthens our suspicion.

We could not differentiate whether EM was due to a viral infection or secondary to the use of the aforementioned medications in our patient, which serves as a limitation of this study.

CONCLUSIONS

In this case report, we describe a rare skin reaction following the use of nirmatrelvir/ritonavir. Our findings will serve as guidelines for early detection of this complication and can aid with the establishment of the most suitable treatment in such cases.

ACKNOWLEDGMENTS

We thank the patient and family.

REFERENCES

• ¹ Samim F, Auluck A, Zed C, Williams PM. Erythema multiforme. A review of epidemiology, pathogenesis, clinical features, and treatment. Dent Clin North Am. 2013;57(4):583-96.
• ² Nesbit SP, Gobetti JP. Multiple recurrence of oral erythema multiforme after secondary herpes simplex: report of case and review of literature. J Am Dent Assoc. 1986;112(3):348-52.
• ³ Huff JC, Weston WL, Tonnesen MG. Erythema multiforme: a critical review of characteristics, diagnostic criteria, and causes. J Am Acad Dermatol. 1983;8(6):763-75. Available from: https://doi.org/10.1016/s0190-9622(83)80003-6
  » https://doi.org/10.1016/s0190-9622(83)80003-6
• ⁴ Watanabe R, Watanabe H, Sotozono C, Kokaze A, Iijima M. Critical factors differentiating erythema multiforme majus from Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Eur J Dermatol. 2011;21(6):889-94.
• ⁵ Williams PM, Conklin RJ. Erythema multiforme: A review and contrast from Stevens-Johnson syndrome/toxic epidermal necrolysis. Dent Clin North Am . 2005;49(1):67-76.
• ⁶ Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020;382(8):727-33.
• ⁷ Bennardo L, Nisticò SP, Dastoli S, Provenzano E, Napolitano M, Silvestri M, et al. medicina Erythema Multiforme and COVID-19: What Do We Know? Medicina (Kaunas). 2021;57(8):828. Available from: https://doi.org/10.3390/medicina57080828
  » https://doi.org/10.3390/medicina57080828
• ⁸ Agência Nacional de Vigilância Sanitária (Brasil). Anvisa aprova uso emergencial do medicamento Paxlovid para Covid-19. Brasília, DF: Anvisa, 30 mar. 2022. Disponível em: Disponível em: https://www.gov.br/anvisa/pt-br/assuntos/noticiasanvisa/2022/anvisa-aprova-uso-emergencial-do-medicamento-paxlovid-paracovid-19 Acesso em: 17 out. 2022.
  » https://www.gov.br/anvisa/pt-br/assuntos/noticiasanvisa/2022/anvisa-aprova-uso-emergencial-do-medicamento-paxlovid-paracovid-19
• ⁹ Pupo Correia M, Fernandes S, Filipe P. Cutaneous adverse reactions to the new oral antiviral drugs against SARS-CoV-2. Clin Exp Dermatol. 2022;47(9):1738-40.
• ¹⁰ Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30(2):239-45. https://doi.org/10.1038/clpt.1981.154
  » https://doi.org/10.1038/clpt.1981.154

• All authors were involved in the critical review of the manuscript for important intellectual content.
• Financial Support: This study did not use funding from any specific source.

Publication Dates

• Publication in this collection
  02 June 2023
• Date of issue
  2023

History

• Received
  19 Jan 2023
• Accepted
  19 Apr 2023