As mentioned above, RR syndromes refer to an inflammatory process occurring within a previous irradiated volume, following a triggering factor that could be chemicals (drugs), environmental (ultraviolet light) or biological (virus) [21]. Among drugs, chemotherapy, antibiotics, antimetabolites, vaccines have been involved in this process [22]. Interestingly, in this pandemic time, this phenomenon has been reported after a antiCovid-19 vaccine administration and few cases have been described due to Covid-19 infection [18, 19, 20]. Even if skin is reported as the most involved site, RR has been detected in other organs such as lung, oesophagus, small intestine muscle, central nervous system, and head and neck, depending on variations in tissue tolerance and local repairing mechanism. Timing between the end of radiation therapy and the recall phenomenon is variable ranging between 7 days and 15 years as appropriate by the published reports. Moreover, no absolute radiation dose thresholds have been related. To this concern, Yeo et al recorded a skin reaction occurring only in the irradiated skin involved in the highest radiation doses (from 18.7 to 21.5 Gy), but no reasonable relation with time and dose were estabilished [23]. Neither fractionation schedules seem to influence this phenomenon. However, due to the its wide spectrum in severity grade, RR syndromes have been aslo graded according to Common Terminology Criteria for Adverse Events version 3.0 [24].
Concerning the lung involvement as in RRP, a first report was presented in 1976 by McInerney in a pediatric patient who had been given adriamycin [25]. Long after, several renew anticancer drugs as Taxanes or gemcitabine have been accounted too. Ding X et al recorded a RRP in eight on twenty patients receiving several cycles of consolidation chemotherapy with Taxanes after lung radiation [26]. Moreover, Schwarte et al described a severe RRP in a patient who had received as salvage chemotherapy with gemcitabine after RT on mediastinum for esophageal cancer [27]. In addition Min Wang more recently described a RRP after lung radiotherapy triggered by Sintilimaban, an anti-PD-L1 immunochekpoini-inhibitor [28].
Now, in this Covid-19 pandemic new scenarios have been observed with some difficulties in the differential diagnosis when lung is involved [29]. In this pandemic time, several RR syndromes have been renewed. Soyer et al has described an acute skin reactions in two irradiated patients underlying the vaccination anti Covid-19 with differing timelines of RT and vaccinations administration [19]. A case of RRP has been shown after Covid 19 vaccination by Shinada et al. In this case, an acute pneumonitis developed in a previously irradiated field after the vaccination a year later the last dose of irradiation [30].
Another RRP triggered by Covid-19 vaccination supply has been described by Steber et al in an oligometastatic non-small cell lung cancer patient who had previously received local consolidation radiotherapy to the right lung and mediastinum. In this case, the patient complained of pneumonitis with symptoms similar to Covid-19 pneumonia like dry cough, low-grade fever, and shortness of breath. Pneumonitis radiological findings were found inside the previous irradiated lung volume through the beams pathway. This patient developed symptoms of pneumonitis within three to five days of his first administration of the coronavirus disease 2019 (Covid-19) vaccine injection [18].
A suspected case of RRP has been shown by Kuroaski et al [20]. Authors described a suspected case of a 78-year-old woman who had received definitive radiation therapy for small cell lung cancer three and a half years before the Covid-19 infection, developing a rapid decline in respiratory status. She died but autopsy was not performed. Chest radiograph revealed a strong shadow at the prior irradiation site reminding the phenomenon of radiation recall. Also our case could be considered emblematic of radiation recall pneumonitis triggered by a well-documented Covid-19 infection in a patient survivor and then healed. Due to the absence of histological proven samples, its mechanism has not been understood yet. To this concern, several hypotheses have been addressed. A biological hypothesis indicates the effect of a triggered inflammatory reaction among the cells remaining in the irradiation field after radiation therapy as a “remembered reaction” [21]. Another theory is based on a radiation induced depletion of normal tissue stem cells leading to a limited capacity to proliferate and maintain the tissue functional and morphologic integrity [31]. Thus, triggering insulting agents may produce sufficient cell damage unable to be restored in that irradiated area. Thus, a reasonable hypothesis to be considered is the hypersensitivity mechanism based on the effect of radiation therapy in lowering the normal tissue inflammatory response threshold so that it can be more sensitive to the following triggering factors [32]. In the case of lung radiation, it is well known that radiation induces a lung injury involving the alveolar-capillary barrier damage, the activation of resident platelets and macrophages responsible for an initial inflammatory cascade. Then follows the neutrophils recruitment and degranulation leading to an orchestrated cytokine storm. Among them, interleukin-1, interleukin-6, platelet derived growth factor-b, tumour necrosis factor α, and transforming growth factor- β are involved, all responsible for the fibrosis event in the chronic phase [33]. After radiation, it has been postulated that these cells continue to secrete low levels of cytokines. Then the intervention of a triggering agent might yield to an upregulation of these cytokines, causing a recall reaction. As for the pulmonary damage induced by Covid-19 virus, its affinity is well established for lung tissue and its effect, which could lead to acute lung injury (ALI) and adult respiratory distress symptoms. (ARDS) [34, 35]. Thus, a combination of lung injury caused by Covid-19 virus in a previous irradiated lung volume could explain the RT mild effect findings on a CT scan of the chest indicating a radiation recall pneumonitis. This possible mechanism could fit the theory of a “remembered reaction” involving the immune memory system. This paper shows one of the first clear relationship between a documented COVID-19 and RRP, with a specific reactivation of an inflammatory process in the previous irradiated fields. In our case, the combination of a previous repaired radiation induced lung injury reactivated by Covid 19 lung damage as a remembered reaction could have been a reasonable hypothesis.