key: cord-0712094-2anqedib
authors: Lazzari, Grazia; Chiara Resta, Elda; Magli, Michelle; D'Ettorre, Ernesto; Silvano, Giovanni
title: Are there overlapping clinical features between thoracic radiotherapy side effects and covid-19 pneumonia? radiation pneumonitis outside the radiation ports : three case reports
date: 2020-09-25
journal: Clin Transl Radiat Oncol
DOI: 10.1016/j.ctro.2020.09.007
sha: 16b62911fb683d8d5965c0b302a1baa9e6c8f3fe
doc_id: 712094
cord_uid: 2anqedib

Respiratory involvement of Covid-19 infection, presenting as a mild flu-like illness to potentially lethal acute respiratory distress syndrome is the main clinical manifestation in adults. Chest imaging shows a pictorial fashion of images due to the severity and stage of the disease, starting from focal nodular or mass-like opacities with air bronchogram to areas of ground glass consolidation or whited out lung. However, at the Covid-19 pandemic time, CT findings could yield confounding reporting in case of cancer patients previously treated with thoracic radiotherapy (tRT) due to atypical radiation pneumonitis occurring outside the radiation ports. Hypersensitivity pneumonitis and radiation induced bronchiolitis obliterans organizing pneumonitis (RT-BOOP) are accounted in this report.

Severe pneumonia is the main clinical manifestation of Covid-19 pandemic in adults leading to fatal events which are overloading the healthcare system worldwide. [1] Studies have assessed the mandatory role of the Computed Tomography (CT) scan in diagnosis of Covid-19 patients with false negative Real-Time (RT) PCR results. Sensitivity of 98% in detecting and monitoring this disease combined with the bronchoalveolar lavage (BAL) fluid which is an optimal tool in improving the detection accuracy of virus have been reported. [2] Chest CT images per protocol should describe pulmonary lesions in terms of distribution, quantity, shape, pattern, density, and concomitant signs. [3] However, at the Covid-19 pandemic time, CT findings could yield misinterpretations in reporting diagnosis in cancer patients previously treated with thoracic radiotherapy. It is well acknowledged that chest CT is the preferred imaging technique able to detect radiation pneumonitis which is the main side effect of tRT. Typical features due to pulmonary fibrosis are unilateral and share a parenchymal involvement corresponding to the radiation treatment fields and the distribution of different doses to the lungs. [4] Recently these concepts have been widely pointed out by Ippolito E et al who have highlighted several points useful in the differential diagnosis among Covid-19 pneumonia features and radiation pneumonitis pictures. [5] Interestingly these points refer to the "classical " radiation induced lung injury (RILI) pictures. These syndromes are rare clinical situations which share a febrile flu-like syndrome or respiratory failure illness like Covid-19 pneumonia. In contrast to classic radiation pneumonitis, in these cases, CT scan images provide findings which do not correspond to the radiation ports and mimic the wide pictorial fashion of features shown in Covid-19 pneumonia. These similarities make it difficult to correctly diagnose among these diseases as occurred in our experience on three cases of atypical radiation induced pneumonitis developed few months after RT off during the Covid-19 pandemic time.

A 66 years old man affected by a SCLC in the right lung in stage pT2 pN1 M0, after lobectomy, received adjuvant RT with 50 Gy on a limited lung volume including the right hilum with 3dimensional conformal external beam (3D-CRT) and four photons fields radiotherapy. One month radiotherapy off, he returned to our observation complaining of fever, severe dyspnea with oxygen saturation < 70 % requiring C-PaP and ventilation in an intensive care unit. Anemia, neutrophilic leukocytosis with lymphopenia, high levels of D-Dimer, fibrinogen and IL-6 were recorded. Chest CT images and radiography ( Fig. 1 A, B ) described pleural effusion in the right lung with an air bronchogram, massive bilateral alveolar thickening and diffuse ground-glass opacities evolving into a whited out lung. Patient died with an acute respiratory distress syndrome (ARDS). Autopsy described alveolar disruption with hyaline membranes due to fibrin deposits and serous fluid.

Pneumocytes exfoliation, platelets clots with microthrombi and loads of giant macrophages and neutrophils were also found. The serology for Covid-19 was negative, so a diagnosis of Hypersensitivity pneumonitis was given.

A 45 years old woman, after breast conserving surgery due to intraductal carcinoma of the left breast, pTis N0, received adjuvant therapy with tamoxifen and postoperative RT 50 Gy on the residual breast with 3D-CRT and two photon tangential fields. Two months later RT, she presented with a febrile flulike syndrome with cough and mild dyspnea. High Erythrocyte Sedimentation Rate (ESR) and leukocytosis were found. The CT scan images showed in both lungs several nodular opacities associated to a vessel sign and air bronchogram. Swab and BAL were negative for Covid-19 infection.

Symptoms ameliorated after steroid therapy. Chest CT scan images ( Fig. 2 A, B) showed a completely remission of findings. Multinodular RT-BOOP was the final diagnosis.

A 70 years old man, affected by Adenocarcinoma of the left lung in stage pT3 pN2 M0 after upper lobectomy, received sequential adjuvant chemotherapy and radiotherapy 50,4 Gy on left mediastinum with 3D-CRT consisting of five photon fields. Three months radiotherapy off, he showed a mild flulike syndrome with cough and fever lasting one day. Leukocytosis with neutrophilia , lymphopenia and elevated ESR were accounted.

Chest CT scan images (Fig.3 A, B) recorded in the posterior right inferior lobe a single peripheral air-space infiltrate with a bronchus signs inside a slight reticular pattern area. Covid-19 swab and serology test were negative. After steroids and antibiotic therapy CT scan images resulted in a resolution of the inflammatory process. The final diagnosis was focal nodular RT-BOOP.

Although Covid-19 is an acute resolved disease in most of the population, it can also be deadly providing more than 2% case fatality rate as registered in Northern Italy at the beginning of March 2020. [6] Respiratory involvement, presenting as mild flulike illness to potentially lethal ARDS or fulminant pneumonia is the dominant clinical manifestation of Covid-19 in adults although more other organs could be involved as heart, vessels, NCS, depending on the ACE-2 cell receptors expression. [7] By postmortem autopsies in these patients, destruction of lung alveolar structure with exfoliated I-II pneumocytes, giant macrophages, fibrinous exudate in alveolar cavities, thrombosis in micro vessels, pulmonary tissue hemorrhage and interstitial fibrosis have been described. [8] Studies have assessed the key role of the CT scan in diagnosis of Covid-19 patients with false negative RT-PCR results showing a 98% sensitivity in detecting and monitoring this disease. [1, 2] As reported in many series, CT images could manifest different pictorial features according to the disease severity and course, varying from focal or massive bilateral GGO and consolidation as the predominant findings to a "whited out lung". [9] BAL fluid may improve diagnosis with detection accuracy of the virus.

However in patients who have received thoracic radiotherapy as in our cases, similar findings could be an expression of several atypical pneumonitis occurring as side effect of chest radiation due to radiation induced lung injury (RILI). While the "classic" RILI signs recall the paths of radiation fields, [5] unusual pneumonitis features displayed outside the radiation ports are described in atypical RILI showing a similarity with Covid-19 pneumonia signs. This similarity is present in to autopsies reports too. On the contrary, BAL fluid shows an inflammatory pattern and negative result for bacterial, mycobacterial, fungal and viral pathogens; neither a viral cytopathic effect in BAL cells is found. The Hypersensitivity pneumonitis and RT-BOOP are evocated to this concern as occurred in our experience.

The Hypersensitivity pneumonitis had been recorded many years ago in women treated with conventional tangential fields tRT for breast cancer who developed pneumonitis signs outside the radiation fields with diffused interstitial bilateral pneumonia evolving into a "whited out lung". [10] This event is accounted in the "sporadic " RILI which occurs in approximately 10% of thoracic RT and sometimes is associated with ARDS. [11] RT-BOOP syndrome is a migratory pneumonitis showing findings commonly seen outside the radiation fields observed mainly in breast cancer patients few months after adjuvant tRT off with an incidence of 1.8-2.9%. [12] Several cases have been also recorded in lung cancer RT [13] .

From all the reported series, a spectrum of CT findings in RT-BOOP have been described getting from focal nodular or mass-like opacities to areas of consolidation resembling pneumonia or patchy ground glass infiltrates. Interestingly, in nodular opacities, either a feeding vessel or bronchus sign like an air bronchogram have been identified as characteristic signs. [14] Likewise Covid-19 pneumonia, an immunologically mediated mechanism due to an overactive immune system triggered by radiation has been postulated also in these post radiation pneumonia.

[15] Given these similarities and the exceptional rarity of these events, to recognize and differentiate these entities from COVID-19 pneumonia is now a big challenge for radiologists who are beginning to familiarize with this infectious disease. Sharing informations may be useful to solve the question.

In our experience, the anamnesis of a prevoius tRT togheter to the negativity of Covid-19 tests and BAL fluid were helpful to exclude the viral infection.

In conclusion, because CT imaging pictures are not specific in Covid-19 pneumonia, a diagnostic doubt should alert radiologists to hypothesis of atypical radiation induced pneumonitis in cancer patients previously treated with thoracic RT. Diagnosis of Hypersensitivity pneumonitis and RT-BOOP should be taken into account.

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. Fig. 1 B. Chest radiography indicating the evolution of the process into a whited out lung. 

A Comprehensive Literature Review on the Clinical Presentation, and Management of the Pandemic Coronavirus Disease 2019 (COVID-19)

Chest CT for typical 2019-nCoV pneumonia: relationship to negative RT PCR testing

Use of chest CT in combination with negative RT-PCR assay for the 2019 novel coronavirus but high clinical suspicion

Effects of radiation therapy on the lung: radiologic appearances and differential diagnosis

COVID-19 and radiation induced pneumonitis: Overlapping clinical features of different diseases

Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy

Renin-angiotensin system blockers and the COVID-19 pandemic

A pathological report of three COVID-19 cases by minimally invasive autopsies

Chest CT manifestations of new coronavirus disease 2019(COVID-19): a pictorial review

Radiation-Induced Lung Injury: A Hypersensitivity Pneumonitis?

Radiation-Induced Lung Injury. Assessment and Management

Radiation-induced bronchiolitis obliterans organizing pneumonia (BOOP) syndrome in breast cancer patients is associated with age

Occurrence of BOOP outside radiation field after radiation therapy for small cell lung cancer

Bronchiolitis obliterans organizing pneumonia syndrome primed by radiation therapy to the breast

A prospective study of the changes in immune status following radiotherapy for Hodgkin's Disease

Chest CT has shown high sensitivity in diagnosis of Covid-19 pneumonia 2. CT findings display a variety of pictures not specific of Covid-19 pneumonia 3. Atypical radiation pneumonitis occurring after thoracic radiotherapy as Hypersensivity pneumonitis and RT-BOOP mimic images pictures of several Covid-19 pneumonia scenarios