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      Injuries From Asymptomatic COVID-19 Disease: New Hidden Toxicity Risk Factors in Thoracic Radiation Therapy

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          Abstract

          In the near future, among the many upheavals caused by the coronavirus disease 2019 (COVID-19) outbreak, the thoracic radiation oncology community might have to face a new unexpected risk factor for patients undergoing radiation therapy (RT) for thoracic malignancies. The major challenge will especially concern patients with asymptomatic COVID-19. Although we may expect that for symptomatic cases the RT strategy will be similar to the current management of RT patients with a pre-existing lung condition, 1 a different scenario can be envisaged for patients who have contracted COVID-19 without apparent symptoms. Common signs of COVID-19 include fever and dry cough or respiratory symptoms; however, infection can be asymptomatic. In a study investigating the infection exposure before and after the lockdown in the population from a north Italian village, about 43% of the confirmed infections detected were asymptomatic and never developed symptoms during the survey period. 2 Similarly, a comprehensive screening of the Icelandic population conducted by the National University Hospital of Iceland and the deCODE genetics biopharmaceutical company indicated that 43% of the participants who tested positive reported having no symptoms. 3 At the time we are writing, the spread of COVID-19 has taken on pandemic proportions, with nearly 6 million confirmed cases and 350,000 persons dead (https://coronavirus.jhu.edu/map.html). It could be estimated that asymptomatic or undiagnosed infections far exceed tens of millions of people worldwide. This cumulative number is expected to increase until a vaccine for COVID-19 is developed and available for large-scale human use. Recent studies, some in the form of case reports, refer to computed tomography (CT) imaging abnormalities, even in recovered asymptomatic COVID-19 patients. The analysis of the positive cases from the cruise ship Diamond Princess revealed that 73% were asymptomatic, of whom 54% had lung opacities on CT, usually showing a prevalence of ground glass opacity (GGO) over consolidation. 4 A comparable prevalence of abnormal chest x-ray in asymptomatic and minimally symptomatic patients was reported by a radiologic center in the first Italian COVID-19 epicenter. 5 An unsuspected COVID-19 case undergoing CT for other pathologies showed numerous foci of GGO suggestive of COVID-19; the patient was subsequently diagnosed with a nasopharyngeal swab test. 6 Another case report by McGinnis et al demonstrated bilateral GGOs detected after CT image guidance performed as part of the routine setup and delivery of curative RT treatment in a patient who was ultimately asymptomatic for COVID-19. 7 In symptomatic patients, longitudinal CT studies showed diffuse lesions with extensive multifocal involvement; abnormalities were bilateral in most cases and progressed rapidly after symptom onset. 8 , 9 Lesions were particularly evident in the lower lobes, posterior lung fields, and peripheral lung zones. Various combinations of pure GGOs, GGOs plus reticular or interlobular septal thickening, and GGOs plus consolidation were common. These mixed patterns of GGO peaked during illness and became the second most prevalent pattern thereafter. Long-term follow-up analyses are clearly required to determine whether the reticulation represents irreversible fibrosis, thus clarifying the transient or permanent nature of CT changes noted in asymptomatic COVID-19 survivors. In addition, concerns exist for COVID-19 carriers on direct and indirect involvement of other organs, with the cardiovascular system being particularly affected. 10 Notably, it is still controversial whether asymptomatic COVID-19 carriers are mainly young people 2 , 11 ; 47% of the Icelandic infected persons were less than 40 years old (https://www.covid.is/data). All these findings suggest that in the future there could be a non-negligible proportion of patients, possibly of young age, in need of thoracic RT and with undiagnosed pre-existing cardiopulmonary damage from asymptomatic COVID-19. This might represent an additional hidden comorbidity for radiation-induced injury. COVID-19 per se does not modify the dose constraints for patients receiving thoracic RT as long as pulmonary function can be considered adequate. However, future studies might provide the rationale for adjustments based on sufficient solid information. Indeed, as most clearly pointed out in a study by Defraene et al, a higher baseline lung density was prognostic for a higher susceptibility to radiation-induced damage in patients with lung cancer treated by RT. 12 As a result, dosimetric limits of standard thoracic RT practice commonly considered safe may not be equally safe for this new patient population. Radiation-induced lung injury is the major dose-limiting factor in thoracic RT, especially for lung and esophageal cancer. 13 Radiation pneumonitis, with a clinical spectrum that may vary from no symptoms to a potentially life-threatening condition, is a common acute morbidity after RT for intrathoracic malignancies. Density changes of lung parenchyma with extended areas of GGO may be evident on posttreatment CT, even in cases of asymptomatic radiation pneumonitis. In addition, radiologic density changes are considered a relevant driver for symptomatic late lung complications, especially when the affected volume becomes important. Similarly, a large spectrum of cardiac toxicities has been reported as an important and feared complication of thoracic RT. The most frequent types of radiation damage to the heart reported in the literature are pericarditis, valvular defects, coronary artery disease, cardiomyopathy, and a significant increase in mortality due to cardiac disease. 14 Furthermore, subclinical lung damage could be indirectly responsible for secondary cardiac damage.15, 16, 17 In clinical practice, radiation treatment planning is performed according to prediction models for different radiation-induced toxicities. 18 In particular, in the last decades, research efforts have aimed at determining factors that contribute to radiation pneumonitis development. Age, cardiac comorbidities, the concomitant or sequential use of chemotherapeutic agents, and irradiation of the heart or inferior part of the lungs are some of the factors found to significantly increase the risk of lung toxicity. 13 , 19 Furthermore, the analysis of cardiac events identified age, cardiac comorbidities, and chemotherapy as concomitant risk factors for heart toxicity. 14 A new risk factor is henceforth likely to emerge for a nonnegligible percentage of patients in the already complex scenario of the identification of patient-specific susceptibility to radiation-induced toxicity. Notably, the identification of areas of GGO on thoracic planning CT possibly caused by asymptomatic COVID-19 should be an additional issue to take into account in RT planning optimization for thoracic malignancies in the post–COVID-19 era. Hence, radiation-related research is called to focus effort on identifying the interplay of the effects of COVID-19 with radiation-induced injury by disentangling established pathophysiological pathways from the influence of new subclinical damage induced by asymptomatic COVID-19. A reasonable approach would imply a comprehensive, interinstitutional strategy of data collection in the near term to gather data about mixed interactions between COVID-19–related and –unrelated conditions. Such information could be obtained from both quantitative imaging studies (eg, treatment planning CT or ventilation/perfusion imaging) and specific biomarkers (including N-terminal pro-B-type natriuretic peptide and troponins). This step would enable medium- to long-term action for toxicity analysis and normal tissue complication probability modeling able to include the changes caused by the pandemic. In addition to patients with lung and esophageal cancer, those with breast cancer and mediastinal Hodgkin lymphoma treated with chemo-RT may play a pivotal role in probing the impact of COVID-19 effects on radiation-induced cardiopulmonary morbidities, due to the high rate of patients with long survival and the relatively lower average age at diagnosis. The combined treatment modality therapy, indeed, implies the risk of long-term side effects, including pulmonary function decline. 20 The sequelae from a possible case of COVID-19, even if asymptomatic, may decrease lung compliance of patients with lymphoma or breast cancer, thus reducing the patient’s reserve needed to deal with future cardiopulmonary stresses. As for the toxicity analysis, a promising ally could be a radiomic-based approach, in which quantitative features are extracted from lung images, thus facilitating higher-order characterization of complex changes in the healthy parenchyma. Furthermore, one could argue that the dose-mass histogram (DMH)–based metrics of the lungs may provide better prediction performance compared with the parameters extracted from the more common dose-volume histograms. Indeed, the DMH would intrinsically account for patient-specific spatial patterns of baseline density variations and therefore could be proficiently used to provide more robust dose-limiting constraints. In summary, the COVID-19 pandemic might have altered on a large scale the risk profile of thoracic RT treatments for a nonnegligible fraction of unaware patients. The radiation oncology community should be called on to adequately account for the potential occurrence of these new pretreatment conditions.

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          Most cited references 12

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          Is Open Access

          Nondosimetric risk factors for radiation-induced lung toxicity.

          The decision to administer a radical course of radiotherapy (RT) is largely influenced by the dose-volume metrics of the treatment plan, but what are the patient-related and other factors that may independently increase the risk of radiation lung toxicity? Poor pulmonary function has been regarded as a risk factor and a relative contraindication for patients undergoing radical RT, but recent evidence suggests that patients with poor spirometry results may tolerate conventional or high-dose RT as well as, if not better than, patients with normal function. However, caution may need to be exercised in patients with underlying interstitial pulmonary fibrosis. Furthermore, there is emerging evidence of molecular markers of increased risk of toxicity. This review discusses patient-related risk factors other than dosimetry for radiation lung toxicity.
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            Association between pulmonary fibrosis and coronary artery disease.

            Pulmonary fibrosis and atherosclerosis have many similarities at the histopathologic level. Moreover, fibrotic lung diseases exhibit systemic effects and have the potential to affect the vasculature beyond the lung. The existence of a relationship between the two, however, has not been studied. To investigate whether fibrotic lung disorders may predispose to atherosclerosis, we conducted a cross-sectional study of 630 patients referred for lung transplantation evaluation at a university hospital. We compared the prevalence of angiographic coronary artery disease (CAD) in patients with fibrotic vs nonfibrotic lung diseases. Fibrotic lung diseases were associated with an increased prevalence of CAD compared with nonfibrotic diseases after adjustment for traditional risk factors (odds ratio, 2.18; 95% confidence interval, 1.17-4.06). The magnitude and significance of this association were maintained when only nongranulomatous fibrotic disease or its subset, idiopathic pulmonary fibrosis, was examined. The strength of the relationship between fibrotic disorders and CAD increased when multivessel disease was analyzed (odds ratio, 4.16; 95% confidence interval, 1.46-11.9). No significant association was detected for granulomatous fibrotic disorders (odds ratio, 1.56; 95% confidence interval, 0.47-5.16; P =.47), although this subgroup had fewer cases of CAD for analysis. These findings support an association between fibrotic lung disorders and CAD. Further research is necessary to confirm this relationship and to explore the pathologic processes underlying, and potentially linking, these 2 conditions.
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              • Record: found
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              CT characteristics allow identification of patient-specific susceptibility for radiation-induced lung damage.

              There is a huge difference in radiosensitivity of lungs between patients. The present study aims to identify and quantify patient-specific radiosensitivity based on a single pre-treatment CT scan.
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                Author and article information

                Journal
                Int J Radiat Oncol Biol Phys
                Int. J. Radiat. Oncol. Biol. Phys
                International Journal of Radiation Oncology, Biology, Physics
                Elsevier Inc.
                0360-3016
                1879-355X
                2 September 2020
                1 October 2020
                2 September 2020
                : 108
                : 2
                : 394-396
                Affiliations
                []Institute of Biostructures and Bioimaging, National Research Council, Napoli, Italy
                []Medical Radiation Physics and Nuclear Medicine, Karolinska University Hospital, Stockholm, Sweden
                []Department of Radiation Oncology, Karolinska University Hospital, Stockholm, Sweden
                Author notes
                []Corresponding author: Laura Cella, PhD
                Article
                S0360-3016(20)31342-0
                10.1016/j.ijrobp.2020.06.055
                7462877
                © 2020 Elsevier Inc. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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                Oncology & Radiotherapy

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