key: cord-0792125-m0takok2
authors: Warren, Graham W.; Lim, Vun-Sin; Chowdhary, Mudit; Marwaha, Gaurav; Abd Elbadee, Osama Mostafa; Kirakli, Esra Korkmaz; Billiet, Charlotte; Marin, Alexandra Giraldo; Ramos, Monica; Suppli, Morten Hiul; McGinnis, Gwendolyn J.; Adjei, Alex A.
title: Brief Report: New Pulmonary Infiltrates Observed on Computed Tomography Based Image Guidance for Radiotherapy Warrant Diagnostic Workup for COVID-19.
date: 2021-06-22
journal: J Thorac Oncol
DOI: 10.1016/j.jtho.2021.06.005
sha: 46b78c2be204e1e0ecc0f153b9ccb60336ad18c0
doc_id: 792125
cord_uid: m0takok2

Introduction Screening for COVID-19 exposure, coupled with engaged decision making to prioritize cancer treatment in parallel with reducing risk of exposure and infection, is crucial in the management of COVID-19 during cancer treatment. Following two reported case studies of imaging findings during daily computed tomography (CT) -based image guided radiotherapy scans, a call for submission of anonymized case reports was published with the objective of rapidly determining if there was a correlation between the onset of new pulmonary infiltrates seen during radiotherapy and COVID-19. We hereby report the results of the aggregate analysis. Methods Data of deidentified case reports for patients who developed biochemically confirmed COVID-19 during radiotherapy were submitted through an online portal. Information requested included a patient’s sex, age, cancer diagnosis and treatment, and COVID-19 diagnosis and outcome. Coplanar CT-based imaging was requested to demonstrate the presence or absence of ground glass opacities or infiltrates. Results A total of 7 reports were submitted from Turkey, Spain, Belgium, Egypt, and the United States. Results and imaging from the patients reported by Suppli et al. and McGinnis et al. were included for a total of 9 patients for analysis. All patients were confirmed COVID-19 positive using polymerase chain reaction (PCR) based methods or nasopharyngeal swabs. Of the 9 patients analyzed, abnormalities consistent with ground glass opacities or infiltrates were observed in 8 patients. Conclusion This is the largest case series demonstrating the potential utility of CT-based image guidance during radiotherapy as a tool for identifying patients who need further workup for COVID-19. Considerations for reviewing image guidance for new pulmonary infiltrates, and immediate COVID-19 testing in patients who develop new infiltrates even without COVID-19 symptoms are strongly encouraged.

Screening for COVID-19 exposure, coupled with engaged decision making to prioritize cancer treatment in parallel with reducing risk of exposure and infection, is crucial in the management of COVID-19 during cancer treatment. Following two reported case studies of imaging findings during daily computed tomography (CT) -based image guided radiotherapy scans, a call for submission of anonymized case reports was published with the objective of rapidly determining if there was a correlation between the onset of new pulmonary infiltrates seen during radiotherapy and COVID-19.

We hereby report the results of the aggregate analysis.

Data of deidentified case reports for patients who developed biochemically confirmed COVID-19 during radiotherapy were submitted through an online portal. Information requested included a patient's sex, age, cancer diagnosis and treatment, and COVID-19 diagnosis and outcome.

Coplanar CT-based imaging was requested to demonstrate the presence or absence of ground glass opacities or infiltrates.

A total of 7 reports were submitted from Turkey, Spain, Belgium, Egypt, and the United States.

Results and imaging from the patients reported by Suppli et al. and McGinnis et al. were included for a total of 9 patients for analysis. All patients were confirmed COVID-19 positive using polymerase chain reaction (PCR) based methods or nasopharyngeal swabs. Of the 9 patients analyzed, abnormalities consistent with ground glass opacities or infiltrates were observed in 8 patients.

This is the largest case series demonstrating the potential utility of CT-based image guidance during radiotherapy as a tool for identifying patients who need further workup for COVID-19.

In the past year, the coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread to all corners of the globe. By mid-May 2021, global tracking through Johns Hopkins University estimates over 165 million cases worldwide including approximately 33 million cases in the United States, 25 million cases in India, 15 million cases in Brazil, and over 1 million cases in 25 other countries (1). Approximately 3.4 million deaths have already been attributable to COVID-19, and the COVID-19 pandemic is accelerating as 3 rd waves across multiple countries through early 2021. Although COVID-19 is most commonly associated with SARS, it can affect a wide spectrum of organ systems with significant effects on the lungs, heart, gastrointestinal tract, kidneys, circulatory system, immune system, and even the brain (2) (3) . Cancer treatment has been disrupted by the COVID-19 pandemic including delays in screening that may ultimately lead to substantial changes in survival patterns due to delays in starting or pauses of active treatment, as well as patient reticence to address medical issues for fear of contracting COVID-19 (4) (5) . Addressing COVID-19 during cancer treatment requires close coordination across health systems to accurately screen for COVID-19 exposure and infection, coupled with engaged decision making to prioritize cancer treatment in parallel with reducing risk of exposure (6) . Additionally, cancer patients who develop COVID-19 require careful consideration of the urgency to treat cancer while balancing the need to manage COVID-19 as well as risking exposure to other cancer patients.

Screening for COVID-19 in the general population is based upon assessing exposure, symptoms, and testing using polymerase chain reaction (PCR) or serologic antibody-based assays (7) . People suspected of infection can receive further testing including radiologic thoracic imaging to evaluate for the presence of pulmonary infiltrates. A recent Cochrane review across 34 studies suggested a pooled sensitivity of 89.9% and specificity of 61.1% for computed tomography (CT) based imaging (8). However, authors noted a high or unclear risk of bias. In April of 2020, 2 separate groups reported case studies of imaging findings during daily CT-based image guided radiotherapy scans (9-10). A subsequent call for submission of anonymized case reports was published to try and ascertain if similar findings were observed during radiotherapy (11) . Results of submissions are reported below.

A call for aggregation of deidentified case reports for patients who developed biochemically confirmed COVID-19 during radiotherapy was published in April of 2020 (11) . The primary objective J o u r n a l P r e -p r o o f was to determine whether there was a correlation between the onset of new pulmonary infiltrates seen during RT and a diagnosis of COVID-19. Submitting groups would send anonymized data through an online link. Data requested included a patient's sex, age, cancer diagnosis, histologic evaluation, cancer stage, chemotherapy agent, planned RT dose, completed RT dose, method of COVID-19 diagnosis, date of COVID-19 diagnosis relative to the start of RT, date of COVID-19 symptoms relative to the start of RT, any COVID-19 symptoms, and data related to patient care and outcome. Reporting for outcome was at the discretion of the submitting contributors as a free text field. Coplanar CT-based imaging was requested to demonstrate the presence or absence of ground glass opacities or infiltrates. Because of the expected variability of imaging quality among contributors and different institutional practices for daily image verification, there were no stipulations regarding select imaging and contributors were allowed to submit representative images at their own discretion. Because deidentified data were reported such that subjects could not be identified, this study is exempt as supported by the Code of Federal Regulations (CFR) section 45, part 46.

A total of 7 reports were submitted through the online portal representing cases from Turkey, Spain, Belgium, Egypt, and the United States. The case of patient 1 was subsequently published (12) and included in this report with author's permission under the Creative Commons Attribution License. Results and imaging from the patients reported by Suppli et al (9) and McGinnis et al. (10) were included for a total of 9 patients for analysis ( Table 1) . The 9 patients presented included 4 females and 1 patient with metastatic disease. All patients were confirmed COVID-19 positive using polymerase chain reaction (PCR) based methods or nasopharyngeal swabs. All 9 patients were diagnosed with lung cancer including 4 with squamous cell carcinoma and 5 with adenocarcinoma.

The cancer treatment characteristics and COVID-19 outcomes are reported in Table 2 .

Chemotherapy was used as a part of cancer treatment for 7 patients, and one patient was on a trial for immunotherapy in combination with stereotactic ablative radiotherapy (SABR). The planned course of radiotherapy was completed by 3 patients, with the remaining patients having treatment interrupted or discontinued. Symptoms were noted in 6 patients with fever the most common symptom present in all 6 patients. Hospitalization occurred in 7 patients, including one patient who was hospitalized without symptoms as a part of standard local policy. As of the date of data submission, deaths were reported in 2 patients. Figure 1 demonstrates CT findings submitted as screen shots for each patient. Images submitted by contributors were analyzed and it was decided to present representative axial images for consistency across all patients. Of 9 sets of patient images, abnormalities consistent with ground glass opacities or infiltrates were observed in 8 patients (Fig. 1B) . Only one patient (Patient 2) had no observable opacities or infiltrates on submitted images.

Initial reports suggest that lung cancer patients who develop COVID-19 have observable infiltrates or ground glass opacities that can be detected during CT-based image guidance for radiotherapy. Data do not support guidance on how to manage patients or whether radiotherapy procedures should be disrupted. Data further are insufficient to provide guidance on any COVID-19 outcomes. However, data do support the conclusion that new ground glass opacities or pulmonary infiltrates observed during CT-based image guidance warrant further diagnostic evaluation for COVID-19.

Screening patients during radiotherapy setup procedures has been discussed as a potentially useful tool for detecting . In a letter to the editor, analysis of temperature screening yielded a comparable detection rate as compared with CT screening at the time of radiotherapy setup, both approximately 0.5% (14) . A typical course of conventional radiotherapy could consist of 2-3 weeks for consultation and radiotherapy setup and 5-7 weeks for radiotherapy treatment. This results in 7-10 weeks of potential exposure time for a typical patient within a radiotherapy department. Patients can be exposed prior to or during treatment, and a single point of care assessment is likely to misrepresent risk over the entirety of treatment. For patients receiving daily or weekly CT-based image guidance, this would enable screening both at the time of radiotherapy setup with a CT simulation as well as repeated assessments for the 5-7 weeks of treatment.

Monitoring CT scans for changes suggesting ground glass opacities or infiltrates may not add any time or burden to treatment staff, but would require additional time for people responsible for image review. This could represent an added time burden for physicians. However, the reward for this added time could be an increased detection of COVID exposure and a secondary system for alerting clinicians and patients for dedicated COVID screening. Increased early detection is anticipated to reduce overall exposure within an oncology clinic and ultimately reduce impact on effective cancer treatment.

The objective of this aggregation of cases was to rapidly determine if there was a correlation between the onset of new pulmonary infiltrates seen during radiotherapy and COVID-19 (11) . The 9 J o u r n a l P r e -p r o o f cases presented suggest that there is a correlation and support consideration of further COVID-19 screening and workup for any patients exhibiting new infiltrates during the pandemic. There are several limitations to any interpretation beyond this conclusion. There were no data collected on patients who did not have COVID-19, thus limiting the ability to estimate any sensitivity or specificity for new pulmonary infiltrates. Though most patients exhibited symptoms, there are likely many COVID-19 positive patients who were asymptomatic and who were never screened for COVID-19.

It was recognized early that responses were anticipated to be multi-national and that submission of CT-based images used for radiotherapy would have a wide range of institution specific technical capability and standard practice procedures. For this reason, the request for images was liberal and did not require specific image quality or anatomical representation. While this limits the quality of interpretation, the observation that 8 of 9 patients demonstrated new observable pulmonary infiltrates across a spectrum of technical capability and practice strengthens the potential utility of CT-based image guidance as a potential screening tool for COVID-19. It is also important to note that method of COVID-19 detection was described as 'nasopharyngeal swabs' in 3 reports. While PCR was the likely method, it is possible that alternative tests such as rapid antigens using nasopharyngeal swabs were used, and potential variations in accuracy among different tests was not available.

To the authors knowledge, this is the largest case series demonstrating the potential utility of CT-based image guidance during radiotherapy as a tool for identifying patients who need further workup for COVID-19. It is anticipated that collecting a large structured dataset providing strong estimates of sensitivity, specificity, and with well-defined imaging criteria would take a moderately long time and limit access to information that could immediately benefit patients during the ongoing pandemic.

Two recommendations arise from these cases. First, radiation oncologists and radiotherapy departments should strongly consider reviewing image guidance for new pulmonary infiltrates, and consider immediate COVID-19 testing in patients who develop new infiltrates even without COVID-19 symptoms. Second, substantially more data are needed to determine the sensitivity and specificity of these findings as well as the temporal nature. While highly effective COVID 19 vaccines are available at the time of completing this report, there is significant variability in vaccine distribution and uptake across different countries, and it may take years before a substantial number of individuals are vaccinated globally to achieve herd immunity. It is ancitipated that COVID-19 infection may become endemic or seasonal, akin to the common influenzas. Thus, these findings are anticipated to remain relevant for several years. Submitted axial images are displayed for each patient. Images submitted were not altered for enhancement, but were formatted for size and fit within the figure. B. Areas with ground glass opacities or infiltrates are highlighted in yellow for each patient. Patient 2 had no observed infiltrates or ground glass opacities on any submitted images. Patient 1 (Kirakli et al. [12] ); patient 8 (Suppli et al. [9] ); patient 9 (10). 

How does coronavirus kill? Clinicians trace a ferocious rampage through the body, from the brain to toes

Extrapulmonary manifestations of COVID-19

COVID-19 and cancer. Science

COVID-19 and Cancer: Current Challenges and Perspectives. Cancer Cell

Treatment Guidance for Patients With Lung Cancer During the Coronavirus

Diagnostic Test Accuracy Group. Rapid, point-of-care antigen and molecular-based tests for diagnosis of SARS-CoV-2 infection. Cochrane Database Syst Rev

Rapid Detection of Asymptomatic Coronavirus Disease 2019 by Computed Tomography Image Guidance for Stereotactic Ablative Radiotherapy

A Call for Rapid Submission of Data for Aggregate Review: Can Daily Radiotherapy Imaging Be Used as a Potential Screen for Coronavirus Disease

RT Imaging as an Unintended COVID-19 Diagnostic Tool: Can be used for Screening before Thoracic RT?

The simulation-CT: Radiotherapy's useful tool in the race against COVID-19 pandemic. A serendipity approach

The use of simulation-CT's as a coronavirus disease 2019 screening tool during the severe acute respiratory syndrome coronavirus 2 pandemic

Writing -Original draft preparation, reviewing and editing, Visualization, Supervision Vun-Sin Lim: Methodology, Data curation, Project administration

Charlotte Billiet: Investigation, Resources

Investigation, Resources Monica Ramos: Investigation, Resources

Morten Hiul Suppli: Investigation, Resources

Investigation, Resources

Adjei: Conceptualization, Methodology, Writing -Original draft preparation, Supervision

J o u r n a l P r e -p r o o f