Radiologic evaluation of discharge quality in patients with COVID-19

Background Worldwide spread of the novel coronavirus disease 2019 (COVID-19) has made hundreds of thousands people sick and fortunately many of them have been treated and discharged. However, it remains unclear how well the discharged patients were recovering. Chest CT scan, with demonstrated high sensitivity to COVID-19, was used here to examine clinical manifestations in patients at discharge. Methods This study registered retrospectively single-center case series of 180 discharged patients, all conrmed with COVID-19 at Wuhan Red Cross Hospital in Wuhan, China. Epidemiological, demographic, clinical, laboratory and treatment data were collected. CT imaging features of absorption vs progressive stage were compared and analyzed. Results Five pulmonary lobes were affected in 54 (30%) of the 180 patients at the absorption stage, comparing to 66% of them at the progressive stage (P=1.45×10 -11 ). Forty ve (25%) patients had pleural effusion on admission and 13 of them still carried hydrothorax when discharged as per standard discharge criteria (P=4.48×10 -6 ). Besides, compared with those at progressive stage, 97 (54%) discharged patients had interlobular thickening (P=6.95×10 -3 ) and 43% of them still presented adjacent pleura thickening (P=5.58×10 -5 ). The median total CT score of discharged patients at absorption stage was lower than progressive stage (3 vs 12.5 ). The median total CT score recovery rate was 67% (range, 0-100%) and 139 (77%) patients showed less than 90% improvement at discharge. Conclusions A majority (77%) of the discharged patients had not recovered completely. The current discharge criteria may need to include 90% or higher CT score-based recovery rate. Authors Jingwen Li, Xi Long, Fang Fang, and Xuefei Lv contributed equally to this work. Authors Zhicheng Lin and Nian Xiong


Introduction
Since the outbreak of novel coronavirus disease 2019  in December 2019 Wuhan of China hundreds of thousands people have been diagnosed with this highly contagious pneumonia around the world [1]. Infection by its underlying severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, previously known as 2019-nCoV) becomes a threat to global health [2]. With a period of symptomatic and supportive treatment, more than seventy eight thousand people in China had been reportedly cured of COVID-19 and discharged by April 15 th , 2020 [3].
All the hospital discharges met four criteria: (1) normal temperature lasting for longer than three days, (2) resolved respiratory symptoms, (3) substantially improved acute exudative lesions on chest computed tomography (CT) images, and (4) two consecutively negative RT-PCR test results separated by at least one day; which was a standard protocol of the Seven Revised Edition novel coronavirus pneumonia treatment guideline from the National Health Commission of China. However a recent study has indicated that positive RT-PCR test results can be found in recovered COVID-19 patients [4]. Moreover, another study has just indicated that RT-PCR results for pharyngeal swabs samples support only 32% of COVID-19 subjects [5], suggesting that many discharged patients may still carry this virus given the 68% false negative rate. Together, different discharged patients may carry various densities of the viral RNA, implying an elusive consequence. Therefore, whether or not a discharged patient has truly recovered becomes a bona de concern at all levels.
At Wuhan Red Cross hospital (WRCH), Wuhan, Hubei, a general hospital which was turned into a healthcare system specialized for treating severe COVID-19 patients in January of 2020 and till March 15 th , more than 1,100 COVID-19 patients had been discharged. We have found that among these patients, some had lung CT results back to normal whereas others had improved lungs but with obvious abnormality at discharge. Here we present for the rst time clinical and radiological ndings as a result of the analysis of 180 recovered and discharged patients with COVID-19, by comparing the imaging features of absorption stage with progressive stage.

Study Design and Participants
One hundred eighty discharged patients were registered at WRCH. WRCH, one mile away from Huanan Seafood Wholesale Market to which SARS-CoV-2 was tracked back, is a trusteeship hospital of Union Hospital and one of the rst hospitals admitting COVID-19 patients only. All patients were diagnosed with COVID-19 according to the guideline of SARS-CoV-2 (Trial Version 5 to 7 of the Chinese Government). The data of included cases have been submitted to the Chinese Center for Disease Control and Prevention.
We analyzed epidemiological, demographic, clinical and radiological features, and laboratory data.
Outcomes including length of stay, discharges and fatality were followed up and recorded until March 6 th , 2020. The study was approved by WRCH Ethics Committee and written informed consent obtained from each subject before enrolment, followed by retrospective data collection.

Data and Specimen Collection
Individuals con rmed to have COVID-19 by SARS-CoV-2 real-time reverse transcriptase-polymerase chain reaction (RT-PCR) were eligible for inclusion in this study. Data were collected at Wuhan Red Cross Hospital that provided care for these patients. Data from electronic health records were summarized using a standardized data collection form. Two researchers independently reviewed the data collection forms for accuracy. Specimens (nasopharyngeal swabs) were collected at multiple time points in the rst 2 weeks following study enrollment and tested by RT-PCR for the presence of SARS-CoV-2. After collection, the throat swabs were placed into a collection tube with 200 μL of virus preservation solution, and total RNA was extracted within 2 hours using the respiratory sample RNA isolation kit ( Union hospital, Tongji Medical University, Huazhong university of Science and Technology and ADICON clinical laboratory). After standing at room temperature for 30 minutes, the collection tube was centrifugated at 8000 rpm/min for a few seconds. The suspension was used for RT-PCR assay of SARS-CoV-2. RT-PCR assay was performed under the following conditions: incubation at 50 °C for 15 minutes and 95 °C for 15 minutes, 45 cycles of denaturation at 94 °C for 15 seconds, and extending and collecting uorescence signal at 55 °C for 45 seconds. RT-PCR cycle threshold values were collected. A cycle threshold value (Ct-value) less than 40 was de ned as a positive test result. The cycle threshold value correlates with the number of copies of the virus in a biological sample, in an inversely proportional and exponential manner. Sequencing of PCR products of the RNA-dependent RNA polymerase (RdRp) gene were used to construct phylogenetic trees.

Clinical Management
Epidemiological information, clinical manifestations, laboratory results, radiological characteristics, treatments and outcomes were recorded during the hospital stays and then collected from the medical records. All data were checked by two trained physicians (J.L. and N.X.). Patients were asked about basic information, medical history, exposure history, symptoms and comorbidities. Acute respiratory distress syndrome (ARDS) was de ned according to the Berlin de nition [6]. As part of standard of care, complete blood cell count, tests of kidney and liver function, and measurement of C-reactive protein and lactate dehydrogenase levels were performed. Respiratory samples were tested for in uenza and other respiratory viruses with a multiplex PCR assay. Treatment measures included symptomatic therapy, antiviral therapy, corticosteroid therapy and respiratory support. All patients received supportive therapy, including supplemental oxygen when saturations as measured by pulse oximeter dropped below 92%. Patients clinically suspected of having community-acquired pneumonia were administered empirically.
Informed consent for collection of clinical data from infected individuals was granted by the Wuhan Red Cross Hospital Committee. Written informed consent was obtained from study participants for collection of biological samples after review and approval of the study protocol by the institutional ethics committee.

Imaging analysis
All COVID-19 patients were from WRCH and were imaged with1-mmslice thickness CT on a Siemens SOMATOM go.Top 64 scanner (Siemens Healthineers, Suzhou, China). Scanning eld of view (FOV) 413×413mm, tube voltage 130kV, tube current 138mA, pitch 0.6, reconstruction layer thickness 1.5mm. Lung window reconstruction was performed using high-resolution algorithm. After inhaling, the patient held his breath to acquire images, and the scanning range was from the lung tip to the lung bottom. All CT images were reviewed by two fellowship-trained cardiothoracic radiologists with approximately ve years of experience each (X.L, F.F, XF.L, D.Z, Y.S, S.H) using a viewing console. Imaging was reviewed independently and nal decisions reached by consensus are reported. No negative control cases were examined. For each patient, the chest CT scan was evaluated for the following characteristics: (1) presence of ground-glass opacities, (2) presence of consolidation, (3) laterality of ground-glass opacities and consolidation, (4) number of lobes affected where either ground-glass or consolidative opacities were present, (5) degree of involvement of each lung lobe in addition to overall extent of lung involvement measured by means of a "total severity score" as detailed below, (6) presence of nodules, (7) presence of a pleural effusion, (8) presence of thoracic lymphadenopathy (de ned as lymph node size of ≥10 mm in short-axis dimension), (9) airways abnormalities (including airway wall thickening, bronchiectasis, and endoluminal secretions), (10) axial distribution of disease (categorized as no axial distribution of disease, central "peribronchovascular" predominant disease, or peripheral predominant disease), and (11) presence of underlying lung disease such as emphysema or brosis. Other abnormalities, including linear opacities, opacities with a rounded morphology, opacities with a "reverse halo" sign, opacities with a "crazy-paving" pattern, and opacities with intralesional cavitation, were noted. Ground-glass opaci cation was de ned as hazy increased lung attenuation with preservation of bronchial and vascular margins, whereas consolidation was de ned as opaci cation with obscuration of margins of vessels and airway walls. Each of the ve lung lobes was assessed for degree of involvement and classi ed as none (0%), minimal (1 -25%), mild (26 -50%), moderate (51 -75%), or severe (76 -100%). No involvement corresponded to a lobe score of 0, minimal to a lobe score of 1, mild to a lobe score of 2, moderate to a lobe score of 3, and severe to a lobe score of 4. An overall lung "total severity score" was reached by summing the ve lobe scores (range of possible scores, 0 -20) [7]. The amount of time between the initial appearance of patient symptoms and the date of admission as well as the date of the initial chest CT examination was noted for each patient.

Statistical Analysis
Categorical variables were described as frequency rates and percentages, and continuous variables were described using median, minimum and maximum grades. SPSS (Statistical Package for the Social Sciences, version 25) was used for all analyses. P < 0.05 was considered as statistically signi cant. Continuous variables were expressed as median (range) and compared between independent groups by Student's t tests; categorical variables were expressed as number (%) and compared by χ² tests or Fisher's exact tests.

Basic characteristics, Clinical symptoms, Complications and Treatment, Laboratory examinations
The study population had a group of 180 discharged patients all con rmed with COVID-19 and registered from January 21 st to February 20 th , 2020. The median age was 50 years (range, 21-87 years).  Table 1).
The most results of laboratory examinations of these patients at admission were basically normal, except 37% with leucopenia (white blood cell count less than 4 × 10 /L), 13% with abnormal indexes such as high creatine kinase (CK) and lactate dehydrogenase (LDH) levels and 18% with increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. As noticed, the infection-related biomarker C-reactive protein (CRP) level did not drop to a normal range ( Table 2).

CT image presentations
Multiple patchy ground glass opacities in bilateral multiple lobular with periphery distribution are chest tomographic features typical of the COVID-19 pneumonia [7]. We compared these features in discharged patients at absorption stage with those at progressive stage, as required by discharge criteria. Comparision of CT images between patients at progressive and absorption stages were showed in Figure  1.

Discussion
This report, to our knowledge, is the rst CT evaluation of a large cohort of discharged patients with COVID-19. It presents the latest recovering status, at discharge, as revealed by chest CT imaging, the most consistently sensitive method for detecting COVID-19 progression. To our surprise, three quarters (77%) of the discharged patients carried unrecovered lungs, with common abnormalities including ground-glass opacities, pleural uid and thickened adjacent pleura.
Still, these patients can be discharged according to the imaging criteria that most of the original in ammatory lesions are absorbed and no new lesions in the lung are found according to the Seventh Revised Edition Chinese guideline. A critical question here is whether any of the discharged patients are still carrying the virus. Consistently, some COVID-19 patients had reportedly showed re-fever and positive nucleic acid test results after discharged [4]. This might be due to the biological characteristics of SARS-CoV-2, the basic disease, clinical status, glucocorticoid using, sampling, processing, detecting, or related to viral re-infection [10]. Of course, another possibility is that the virus is still surviving in the partially recovered, although discharged, patients.
Because of that possibility, discharged patients with partially recovered lungs may become new source of infection. This possibility has not been veri ed in China yet because China's current polices require all discharged patients to be under quarantine at a designated rehabilitation site for two weeks. Nevertheless, considering SARS-CoV-2's high contagiosity, we strongly suggest that more attention should be paid to CT results-based discharge of the patients, which may provide greater precaution about consequences of discharge. Repeated CT scanning is helpful for monitoring disease progression and implementing timely treatment. As an alternative detection method for assessing COVID-19, we suggest that viral serological (IgM, IgG) tests be performed when necessary [11], which have been added into the latest discharge criteria of the novel coronavirus pneumonia treatment guideline and may have a higher sensitivity compared with RT-PCR tests. Together, different measures may provide a better understanding of each discharge. Future studies are warranted to elucidate correlations between CT ndings and clinical manifestations or viral viability, including individual variation and the underlying pathogenesis.
We are aware of limitations in this study. Our CT imaging had short-term follow-up only. Long-term follow-up CT data to observe prognosis of the disease should be collected. And CT data need to be correlated with clinical ndings as well in order to further appreciate its clinical value.

Conclusion
A majority of patients (77%) did not recover completely at discharge. To better control the rapid spread of SARS-CoV-2 and consolidate clinical therapeutic e cacy of COVID-19 patients, current discharge criteria should consider total CT score recovery rate higher than 90%. Con ict of interests: The authors declare they have no con ict of interests.

Declarations
Declaration of Helsinki: The research protocol have been submitted for consideration, comment, guidance and approval to the concerned research ethics committee before the study begins. The Wuhan Red Cross Hospital Ethics committee is transparent in its functioning, independent of the researcher, the sponsor and any other undue in uence and is duly quali ed. It has been taken into consideration the laws and FKEregulations of the country or countries in which the research is to be performed as well as applicable international norms and standards Ethical approval: This study was approved by the Ethics Committee of the Wuhan Red Cross Hospital.
Informed consent: Obtained from all individual participants included in the study.

Supplementary Files
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