Radiation recall reactions triggered by COVID-19 infection in a patient with buccal cancer; A clinical report and review of the literature

Abstract

A case of a patient who developed a radiation recall reaction (RRR) triggered by coronavirus disease 2019 (COVID-19) infection following surgery and chemoradiotherapy for carcinoma of the buccal mucosa is reported. A 75-year-old woman presented in October 2023 with pyrexia and erythema extending from the left cheek to the anterior chest area. In December 2021, she had undergone surgery to remove a carcinoma of the left buccal mucosa (pT2N0M0), followed by left comprehensive neck dissection for delayed cervical lymph node metastasis in June 2022, with subsequent adjuvant chemoradiotherapy. Her course was uneventful until September 2023, when she developed COVID-19. Twenty-three days after COVID-19 infection had been confirmed, she developed systemic pyrexia with erythema and a heat sensation from her left cheek to the left anterior chest. On presentation, her temperature was 39 ºC, and she had a mild sore throat. Erythema and a heat sensation were apparent from the left cheek to the neck and anterior chest, corresponding to the previously irradiated area. Laboratory tests showed a white blood cell count of 11,760/μl, and C-reactive protein of 16.0 mg/dl. Computed tomography did not show any obvious abscess formation or infection source. An RRR was diagnosed, and she was admitted for treatment with intravenous sulbactam/ampicillin and intravenous hydrocortisone sodium succinate. Five days after admission, the inflammatory reaction had improved, and she was discharged. Her subsequent course has been uneventful, with no flareup of the RRR. This case is presented along with a review of relevant literature.

Highlights

• •A radiation recall reaction (RRR) is a delayed complication of radiotherapy.
• •There have been several reports of RRRs triggered by COVID-19.
• •Most cases of COVID-19-associated RRRs have occurred after vaccination.
• •This is the first report of RRR after head and neck cancer treatment triggered by COVID-19 infection.

Introduction

A radiation recall reaction (RRR), first reported by D’Angio et al. in 1959, is a delayed complication of radiotherapy in which tissue damage occurs at the same site as the irradiation field due to the administration of anticancer agents or other drugs after the acute radiation damage has improved [1]. Its reported incidence is around 7 %, which varies in the literature [2]. Although its etiology is still unknown, it is considered to represent the development of an inflammatory reaction in a previously irradiated area, precipitated by drug administration.

During and after the recent coronavirus disease 2019 (COVID-19) pandemic, there have been several reports of COVID-19-associated RRR. Most cases of COVID-19-associated RRR have occurred after vaccination, but a very few cases triggered by COVID-19 infection have also been reported [3], [4], [5].

In this study, a case of a patient who developed an RRR triggered by COVID-19 infection following surgery and chemoradiotherapy for carcinoma of the buccal mucosa is reported.

Case study

A 75-year-old woman presented in October 2023 complaining of pyrexia and erythema extending from the left cheek to the anterior chest area. In December 2021, she had undergone surgery to remove a carcinoma of the left buccal mucosa (pT2N0M0), followed by left comprehensive neck dissection (levels 1–4) for delayed cervical lymph node metastasis (rN3bM0) in June 2022, with subsequent adjuvant chemoradiotherapy (weekly CPPD + 66.0 Gy). Since the adjuvant chemoradiotherapy, the patient had been monitored, and her course was uneventful, with no recurrence. In September 2023, she developed COVID-19, for which she was managed as an outpatient at home. In October 2023, 23 days after COVID-19 infection had been confirmed, she developed systemic pyrexia together with erythema and a heat sensation from her left cheek to the left anterior chest (Fig. 1).

Fig. 2.

Radiotherapy dose distribution. 3D skin rendering of the radiotherapy treatment was performed.

Fig. 3.

The patient’s medical history and course.

Fig. 1.

Photograph showing the patient’s facial appearance, frontal view, on day 1 of hospitalization. Erythema is seen from the left side of the cheek to the anterior thorax.

On presentation, her ECOG PS (performance status) was 0, and she was independent in activities of daily living. Her temperature was 39 ºC, and she had a mild sore throat. Erythema and a heat sensation were apparent from the left cheek to the neck and anterior chest, corresponding to the previously irradiated area (Grade 2 according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0). Laboratory tests were limited to white blood cell count which was 11,760/μl, and C-reactive protein was 16.0 mg/dl. Image diagnosis, panoramic radiography and computed tomography did not show any sign of the infection such as odontgenic/maxillofacial abscess. An RRR was diagnosed, and she was admitted for empiric treatment with antibiotics (intravenous sulbactam/ampicillin) and intravenous steroid (hydrocortisone sodium succinate 250 mg) therapy. Five days after admission, the inflammatory reaction had improved, and she was discharged. Her subsequent course has been uneventful, with no flareup of the RRR.

Discussion

Although several cases of COVID-19-associated RRR following vaccination against COVID-19 have been reported, there have been only three reported cases of RRR triggered by COVID-19 infection itself, making this the fourth such known case. This is the first report of an RRR triggered by infection with COVID-19 following treatment for head and neck carcinoma. Table 1 shows the reported cases of COVID-19 infection-related RRR to date of which we are aware [3], [4], [5].

Table 1.

Review of the literature: 4 cases of COVID-19 infection-related RRR.

Authors	Age (y)	Sex	Primary disease	Time to onset
Kurosaki et al.	78	f	lung cancer	9 days
Lazzari et al.	65	f	breast cancer	a few days
Ross et al.	64	f	breast cancer	a few days
Present case	75	f	buccal cancer	23 days

In general, the skin is most commonly affected location accounting for two-thirds of reported cases although an RRR can occur in many different types of tissue [6], [7], [8], [9], [10]. Its reported incidence varies in the literature, with Purkayastha et al. giving a figure of 6.5 % [2]. Based on the statistics cited in a number of published papers, McKay et al. estimated the incidence at 7 % [10]. Its etiology is still unknown, but the phenomenon is considered to represent the development of an inflammatory reaction in an area previously treated by radiotherapy due to the administration of a drug, and mechanisms including stem cell deficiency, keratinocyte necrosis, and hypersensitivity reaction to the trigger have also been proposed [9]. The timing at which RRR occur is also unclear. Camidge and Price reported that the median time to onset is around 40 days [9], whereas cases of RRR more than a decade post-irradiation have been reported. The time from irradiation to onset remains unknown [7], [11]. In the present patient, approximately one year had passed since radiation exposure. The minimum dose required for its development is also still unknown, but Scher et al. reported a figure of 20 Gy [12].

According to Camidge and Price, a skin reaction to drugs administered 7 days or more after radiotherapy should be regarded as an RRR, and they suggested that skin RRR occur from a few minutes to 14 days after intravenous administration of the trigger drug (median 3 days) and from 3 days to 2 months after oral administration (median 8 days) [9].

An RRR often appears after anti-cancer drug administration, with reported triggers including cytotoxic drugs, molecular targeted drugs, and immune checkpoint inhibitors [13]. However, cases of the occurrence of RRR due to the use of antibiotics or antivirals have also been reported [14], [15].

The symptoms of a skin RRR are skin erythema and desquamation, and in severe cases, necrosis of the skin. The severity of skin RRR is classified according to CTCAE version 5.0, and the present patient showed grade 2 dermatitis [16]. RRR are treated symptomatically. Withdrawal of the causal drug and the use of steroids, nonsteroidal anti-inflammatories, and antihistamines are believed to be effective [6], [8], [10], but if extensive dermatitis or skin necrosis is evident, then autologous skin transplant may be one treatment option. In the present case, since there was no clear pharmacological causal factor, and the presentation was atypical, with a high inflammatory reaction, intravenous antibiotics and steroids were administered for anti-inflammatory purposes.

As described above, RRR are usually triggered by chemotherapy drugs. However, there have been almost no reported cases of RRR precipitated by COVID-19 infection, and to the best of our knowledge, only three such cases have been reported [3], [4], [5]. In the case reported by Kurosaki et al., the patient developed an RRR 9 days after COVID-19 infection was confirmed, and other factors, including the patient’s vaccination history, were unknown [3]. The cases reported by Ross et al. and Lazzari et al. both occurred in patients who had not been vaccinated, both of whom were breast cancer patients who developed skin RRR a few days after infection with COVID-19 [4], [5]. In the previously reported cases of COVID-19-associated RRR, the reactions appeared within 10 days of COVID-19 infection, but in the present patient, RRR onset occurred 23 days after infection was confirmed. This somewhat longer time to onset might be related to the patient’s vaccination history. The COVID-19 virus infects the host via ACE-2 receptors. This reduces the number of ACE-2 receptors that display their typical action, increasing NF-ĸβ activity as a result, and this is known to promote the production of inflammatory cytokines such as IL-1β, IL-6, IL-12, and TNF−α⊡ This process may cause an RRR [17], [18], [19]. RRR is usually drug-induced (anticancer agent or other drugs) and the infections do not play any role in its incidence. There is possibility of similar reaction induced by COVID-19 infection although the exact mechanisms are not currently unknown. Elucidating the mechanism of COVID-19 infection-induced RRR could turn out to be groundbreaking in the future.

Conclusion

In this report, treatment of a patient with an RRR triggered by COVID-19 infection following chemoradiotherapy for carcinoma of the buccal mucosa was described. There have been only three reported cases of RRR triggered by COVID-19 infection itself, making this the fourth such known case. This is the first report of an RRR triggered by infection with COVID-19 following treatment for head and neck carcinoma.

Author statement

The work described has not been published previously except in the form of a preprint, an abstract, a published lecture, an academic thesis, or a registered report. The article is not under consideration for publication elsewhere. The article's publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out. If accepted, the article will not be published elsewhere in the same form, in English or in any other language, including electronically, without the written consent of the copyright-holder.

CRediT authorship contribution statement

Y Takada: Conceptualization, Investigation, Methodology, Project administration, Resources, Visualization, Writing-original draft, Writing-review and editing H Doi: Resources, Investigation, Methodology, Project administration, Visualization, Writing – review and editing. Y Kinoshita: Conceptualization, Investigation, Project administration, Resources, Validation, Visualization, Writing-original draft. M Kawaguchi: Conceptualization, Investigation, Project administration, Resources, Validation, Visualization, Writing-original draft. Y Numata: Conceptualization, Investigation, Project administration, Resources, Validation, Visualization, Writing-original draft. A Enomoto: Project administration, Resources, Supervision, Validation, Visualization, Writing-original draft, Writing-review and editing.

Consent

The patient gave written consent for the publication of personal and clinical details.

Ethical approval

Ethics approval was not required for this case study.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or non-profit sectors.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.