Diagnosis challenge of suspected COVID-19 pneumonia in cancer patients with radiation-induced pneumonitis

Background During the outbreak period of COVID-19 pneumonia, cancer patients have been neglected and in greater danger. Furthermore, the differential diagnosis between COVID-19 pneumonia and radiation pneumonitis in caner patients remains a challenge. The study aimed to determine their clinical presentations and radiological features to familiarize radiologists and clinical teams with them in order to early diagnosis and prompt early patient isolation. Methods From January 21, 2019 to February 18, 2020, the patients selected consecutively met the following criteria: (i) presumed COVID-19 pneumonia; (ii) patients with a history of malignancy and lung exposure to ionizing radiation. A retrospective analysis including all patients’ presenting was performed. Results 4 patients from 112 suspected individals were selected, including 2 males and 2 females with a median age of 54 years (39–64 years). After repeated pharyngeal swab nucleic acid tests, 1 case was con�rmed and 3 cases were excluded from COVID-19 pneumonia. Conclusions


Background
As we were writing this manuscript,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) has spread across the world at an alarming rate and become a pandemic 1 .More recent attention has focused on the diagnosis and treatment strategies of coronavirus disease 2019 (COVID-19) 2 .Ever-growing infected and suspected individuals were bound to be isolated and a large number of medical personnel from other departments such as surgery, oncology, and medicines have been transferred to the frontline departments for coping with the disease 3 .Thus, treatment implementation for patients with malignant tumor has to delay due to the scarcity of sickbeds and shortage of medical staff in oncology.Unlike ordinary patients, cancer patients are susceptible to infection because of their systemic immunosuppressive state caused by cancer and related treatments, such as chemotherapy and/or radiation therapy (RT).A recent study by JX He examined 18 cancer patients in SARS-COV-2 infection and argued cancer patients might have a higher risk of COVID-19 and poorer outcomes than individuals without cancer 4 .They also propose more intensive surveillance or treatment should be considered when patients with cancer are infected with SARS-CoV-2.
In our fever clinics, of particular concern is the differential diagnosis between radiation-induced lung injury (RILI) and radiological suspicion of COVID-19 pneumonia in patients with malignancy and a history of lung exposure to ionizing radiation.So far, however, there has been little discussion about the similarity and the difference between COVID-19 pneumonia and RILI.
Therefore, our current study was performed to retrospectively summarize and distinguish their clinical presentations and CT manifestations with the goal of familiarizing radiologists and clinical teams with them in order to early diagnosis, speed up treatment and prompt early patient isolation.

Methods
From January 21, 2019 to February 18, 2020, records for patients diagnosed with suspected COVID-19 pneumonia were reviewed retrospectively in our hospital, which is the major tertiary teaching hospital in Zhuhai (Guangdong Province) and responsible for the treatments for COVID-19 designated by local healthcare authorities.The patients selected consecutively met the following criteria: (i) presumed COVID-19 pneumonia according to the diagnostic criteria (version 5) by the National Health Commission of the People's Republic of China.(ii) patients with a history of malignancy and lung exposure to ionizing radiation.No exclusion criteria were applied.The study was approved by the hospital review board and the Medical Ethics Committee.We were granted a waiver of written informed consent because it was a retrospective study involved no potential risk to patients.To avoid any potential breach of con dentiality, no link between the researchers and the patients was made available.All patients were evaluated by the following examinations within 2 days after admission: complete patient history, clinical symptoms, physical examination, hematology inspecting such as routine blood test, blood biochemistry, arterial blood gas analysis, and detection of T lymphocyte subsets, chest CT, pathogenic examination including nose and pharyngeal swab nucleic acid test for COVID-19, in uenza A and B test, if necessary, blood cultures, Sputum cultures, and high throughput screening were also performed.All patients received follow-up chest CT after treatment.The management of these patients included isolation, diagnosis, treatment according to the guideline of COVID-19 (Version 5).

Chest CT protocol
The detailed protocol has been described in our previous study 5 .To put it simple, chest CT scans were performed using 1-mm slice thickness on a UCT 760 scanner (United Imaging; Shanghai, China).To minimize motion artifacts, patients in the supine position were instructed on breath-holding; CT images were then acquired during end-inspiration without intravenous contrast.

Image interpretation
All CT images were reviewed by thoracic radiologists and oncologists [QZ, CT and HS] (with over 5 years of experience) independently and resolved discrepancies by consensus.No negative control cases were examined and no blinding occurred.The axial CT and multiplanar reconstruction images were assessed independently and freely on both lung (width, 1400 HU; level, − 500 HU) and mediastinal (width, 350 HU; level, 40 HU) settings, using terms including ground-glass opacities, consolidation, number of lobes affected by ground-glass or consolidative opacities, degree of lobe involvement, nodules, a pleural effusion, thoracic lymphadenopathy (de ned as lymph node size of ≥ 10 mm in short-axis dimension), underlying lung disease such as emphysema, brosis, cavitation, interlobular septal thickening, reticulation, bronchiectasis, or calci cation.The detailed de nitions of the above CT demonstrations were as described in the peer-reviewed literature on COVID-19 pneumonia 5,6 .The distribution of lung lesions was documented as predominantly diffuse (continuous involvement without respect to lung segments), subpleural (involving mainly the peripheral one-third of the lung), and cross-segment (con ned to radiation elds and nonconformity to anatomic boundaries) 7 .

Follow-up chest CT
Previous and follow-up chest CT scans were also reviewed by two radiologists (CTand SL) to evaluate the evolution of lung lesions rated as either no signi cant change, improvement, or progression.Decisions were reached by consensus.
In total, 5 individuals have a history of malignancy, but only 4 cases received radiation therapy were included in this present study (Fig. 1), with a median age of 54 years (39-64 years).In them with 2 males and 2 females, 1 case was con rmed and 3 cases were excluded from COVID-19.Two patients with nasopharyngeal carcinoma had completed their concurrent chemoradiotherapy without any signs of tumor recurrence, whereas another 2 patients with advanced thoracic tumors present unsatisfactory outcomes to anti-tumor systematic therapies including palliative chemotherapy, radiotherapy, or target therapy et al.
The detailed description of 4 patients with suspected COVID-19 at admission was presented below (Table  A 53-year-old male was admitted to the hospital with sputum production and cough of more than ten days duration and a little bit hemoptysis of two days duration on January 28, 2020.He also felt fatigued, chest distress, vomiting after eating, but no fever, neither from the infected area nor contact with infected peoples.The physical examination revealed coarse breath sounds during auscultation, and laboratory studies showed normal leukocyte, but lymphopenia and serious thrombocytopenia.Marked elevated concentrations of D-dimer, Procalcitonin (PCT), C-reactive protein (CRP), and N-terminal-pro hormone brain-type natriuretic peptide (NT-BNP) were observed at admission.In September 2016, Patient was diagnosed with middle and lower esophageal squamous cell carcinoma with multiple bone metastases staged with T4aN2M1 and began to receive palliative concurrent chemoradiotherapy on September 29, 2016.The radiotherapy dose using intensity-modulated radiation therapy (IMRT) for GTV (esophageal tumor lesions) was 49.4 Gy / 26Fr, and the paclitaxel/Carboplatin regimen concurrently was administered intravenously every three weeks for two cycles, then patients received palliative chemotherapy with paclitaxel monotherapy for only one cycle because of intolerance of side effects.On December 12, 2018, patients began to receive a second palliative concurrent chemoradiotherapy for recurrence lesions (GTV 44 Gy/22Fr plus nedaplatin), after that, regular reviews were performed.
Serial CT scans showed pericardial effusion, multiple enlarged lymph nodes in the mediastinum, scattered, multiple, similar round thin wall/no wall transparent areas (Fig. 2:A2, B2, C3), smooth or nodular interlobular septal thickening (Fig. 2:A1, B1), and multiple nodules in the dorsal segment of the lower lobe of both lungs with spotted calci cations and adjacent pleural thickening (Fig. 2:A2, A3).These above lung lesions were approximately the same as before.Compared with the previous CT scan 1 year before, chest CT images performed at the 10th day after symptom onset showed the following lung lesions obvious progressively, including patchy areas of consolidation co-existed with ground-glass opacities (Fig. 2:A3), or linear scarring with discrete consolidation (Fig. 2:A2), air bronchograms (Fig. 2:A1), and irregular intralobular or interlobular septal thickening (Fig. 2:A1, A2, A3) predominately in the lower lobes of both lungs adjacent to the mediastinum conforming completely to the irradiated area.
These lesions suggest the possibility of RILI, interstitial pneumonia or viral pneumonia.After 3 days of anti-infective therapy with tazocin, moxi oxacin, and arbidol, combined with aggressive supportive care, follow-up CT demonstrated partial improvement (Fig. 2: B1) but primarily increment in the extent and density of lung lesions (Fig. 2: B2, B3), continued segmental consolidations and atelectasis were observed in the lower lobe of both lungs (Fig. 2: B3).Repeated three times of swab nucleic acid test for the COVID-19 were negative.Afterward, the patient was transferred to the department of oncology to continue treatment to reduce the burden of the frontier department.

Patient 2
A 55-year-old female was admitted to the hospital with dyspnea for 1 week and exacerbation for 1 day after more than 1-year targeted therapy for lung adenocarcinoma on January 23, 2020.Fatigue, chest distress, and sputum production with cough were also present.He had no fever, neither from the infected area, nor contact with infected peoples.The physical examination revealed disappeared breath sounds of the left lung during auscultation, and laboratory studies showed slightly elevated white blood cell and neutrophil, but lymphopenia.Elevated concentrations of D-dimer, CRP and NT-BNP were displayed at admission.Sputum culture examination revealed normal ora growth, neither Hemophilus in uenza nor fungal growth.In April 2018, the patient was diagnosed with left lung adenocarcinoma with intrapulmonary metastases and multiple bone metastases staged with T4N3M1 and received palliative comprehensive treatment based on target therapy of EGFR inhibitor.On November 14, 2018, the patient began to receive palliative radiotherapy for C6-T2 vertebral metastasis (GTV 30 Gy/10Fr) and left supraclavicular metastatic lymph nodes(45 Gy/15Fr).
Compared with the previous CT scan ten months before, chest CT images performed on the 6th day after symptom onset showed enlarged mass with calci cation in the left upper lobe and lung hilum with the maximum section of about 79mm*48 mm, and multiple mediastinal lymph node metastases.The boundary between them is obscure with atelectasis.Magni ed irregular nodules scattered in both lungs.
Metastatic tumors of the left pleura increased in the extent and quantity, so did the left pleural effusion and pericardial effusion (Fig. 3: A1, B1, C1), All these lung lesions indicated a progressive left central lung cancer after systematic therapy.There were bilateral diffused ground-glass opacities with partial consolidation (Fig. 3: B2), and a reticular pattern associated with bronchiectasis and intralobular or interlobular septal thickening (Fig. 3: B2), which indicated the possibility of viral pneumonia.After 9 days of anti-infective therapy with tazocin, combined with aggressive supportive care and glucocorticoid therapy(methylprednisolone), follow-up CT demonstrated continuous development in the scope and extent (Fig. 3:C1, C2).Repeated two times of swab nucleic acid test for the COVID-19 were negative, and blood high throughput screening for pathogenic microorganisms or viruses was also negative.The patient's disease continued to progress and died on February 6, 2020 in the department of oncology.
Patient 3 A 64-year-old woman who worked in Beijing presented to the hospital with a 1-day history of fever and cough on February 17, 2020.The maximum body temperature was 39.5 °C (103.1°F).She also had a little cough and headache.The patient traveled to Zhuhai and lived in her community where several patients were con rmed COVID-19.At admission, both lungs were clear on auscultation.Laboratory studies showed normal white blood cell and higher neutrophil, but serious lymphopenia.The concentrations of PCT and CRP increased signi cantly, and so did those of D-dimer and NT-BNP.The T lymphocyte subsets test showed a sharp drop in CD4 + and CD8 + T cell counts.Screening for in uenza A and B were negative.In July 2019, the patient was diagnosed with nasopharyngeal carcinoma(T3N2M0) treated with de nitive concurrent chemoradiotherapy followed by adjuvant chemotherapy.By September12, 2019, the patient received IMRT for nasopharyngeal tumor (GTVnx 70 Gy/33Fr), neck metastatic lymph nodes (GTVnd 66 Gy/33Fr) and lymphatic drainage of the neck (CTV 54 Gy/33Fr).
Chest CT images obtained on the second day after symptom onset showed there were minimal groundglass opacities with partially rounded consolidation (Fig. 4: A1) in the apexes of both lungs, conforming completely to the irradiated area of low exposure.Multiple ill-de ned patchy ground-glass opacities (Fig. 4: A2) were observed in the middle lobe of the right lung, considering the possibility of COVID-19 pneumonia.After 3 days of antiviral therapy with arbidol, antibiotic treatment with sulperazone, and supportive treatment with albumin injection et al, Follow-up CT demonstrated no obvious changes of lung lesions (Fig. 4: B1, B2).But the patient's symptoms improved signi cantly.Repeated four times of swab nucleic acid test for the COVID-19 were negative.Finally, blood culture suggested an Escherichia coli infection.Then the patient was transferred to the department of oncology.

Patient 4
A 39-year-old male was admitted to the hospital with a positive result of the swab nucleic acid test for COVID-19 a half of the day on February 14, 2020.The patient had transient diarrhea ten days ago and no other symptoms afterward.The patient traveled to Zhuhai from the infected area (Wuhan) and had close contact with the con rmed COVID-19 patient, his aunt.At admission, both lungs were clear on auscultation.Laboratory studies showed normal blood routine results.Screening for in uenza A and B were negative.The T lymphocyte subsets test showed a slight drop in CD4 + and CD8 + T cell counts.In June 2013, the patient was diagnosed with nasopharyngeal carcinoma(T2N2M0) treated with radical concurrent chemoradiotherapy.By August 18, 2013, the patient received IMRT for GTVnx 70 Gy/33Fr, GTVnd 66 Gy/33Fr and CTV 54 Gy/33Fr.
Chest CT images obtained on the 10th day after symptom onset showed there were multiple groundglass opacities of the lower lobes of both lungs peripherally and subpleurally (Fig.

Discussion
This subject was conceived during my time working for the department of infectious disease.As a radiation oncologist, I was committed to the frontline to deal with COVID-19 due to the shortfall of medical staff from January 23, 2019 to March 5, 2020.During the pandemic period, it is utterly imperative to discern and distinguish COVID-19 pneumonia from other lung pathologies for further isolation and appropriate treatment as early as possible.Particularly, the differential diagnosis remains as a challenge between RILI and radiological suspicion of COVID-19 pneumonia in patients with malignancy and a history of lung exposure to ionizing radiation.
Radiation therapy is one of the most common treatments for cancer, especially lung cancer, esophageal carcinoma, and nasopharyngeal carcinoma 8-10 .The advances in radiation delivery techniques make a global decrease in normal tissue exposure, however the lung is one of the most sensitive tissues to radiation, RILI is one of the most clinically challenging toxicities secondary to lung radiotherapy or head and neck radiotherapy with an extended eld including upper lobes of the lungs 11 .The incidence of RILI is estimated to be 15-40% 12 .Based on the time interval after the completion of radiotherapy, RILI is typically divided into radiation pneumonitis (RP), occurring within 6 months following radiotherapy (most often within 12 weeks), and pulmonary brosis, occurring over 1 year after radiotherapy 11,12 .Although pulmonary brosis ensues from RP, they cannot be split up due to the presence of other underlying patient and treatment-related factors 7,13 .
The severity of RILI varies from CT imaging abnormalities with no obvious symptoms to life-threatening diseases.Ordinarily, the classic symptoms of RILI include low-grade fevers, non-productive cough, dyspnea on exertion, and hypoxemia 14 .Likewise, prior studies have shown that mild to severe symptoms from COVID-2019 patients included fever, fatigue, dry cough and shortness of breath, and some patients may have dyspnea, productive cough, hemoptysis, myalgia, headache, sore throat, and rhinorrhea 2,15,16 .This distinction proves particularly di cult because clinical presentations can be very similar.In our study, three patients with RILI presented with fever, cough, sputum production, dyspnea, or hemoptysis respectively.By contrast, one patient with con rmed COVID-2019 presented with only transient diarrhea.
In a word, no speci c symptoms can de nitively identify COVID-19.
Laboratory ndings in the early stage of COVID-2019 included normal or higher white blood cells, slight or marked lymphopenia and normal infection-related biomarkers (PCT, CRP), then elevated PCT and CRP may appear in the acute stage 15 .As the disease progressed, the levels of D-dimer, creatine, creatinine kinase and blood urea progressively increased before death 16 .Likewise, because of the impact of the tumor itself and treatment-related factors, laboratory tests of patients with RIDI may show signs of in ammation, such as an increased white blood cell, marked lymphopenia, CRP and PCT 12 .The results in our study seem to be coherent with those of previous researches.In addition, it is noteworthy that time course is important for laboratory tests, such as elevated PCT, CRP and D-dimer level always appears in malignancies, RP or bacteria infective pneumonia, whereas no obvious changes in the early stage of COVID-2019 17 .
Further laboratory studies are warranted to evaluate for alternate etiologies, including screening for in uenza A and B, blood cultures, and the swab nucleic acid tests.Nevertheless, blood cultures and swab tests are a litter bit slow and cumbersome, and the previous study showed the sensitivity of chest CT for COVID-19 was higher compared to swab test sensitivity (98% VS. 71%, p < .001)for insu cient cellular material and improper extraction of nucleic acid from clinical materials 18,19 .
As mentioned above, chest CT scans keep a vital component in the diagnostic algorithm for patients with presumed COVID-19 pneumonia.The previous researches 5,17,20 have established that typical chest CT imaging abnormalities of COVID-19 pneumonia showed unilateral, multifocal, predominantly groundglass opacities in the incubation period, with lesions mainly located peripherally and subpleurally, followed by the rapid development of bilateral, diffuse disease in the acute stage (Fig. 5), with GGO progressed to or co-existed with consolidations.Subsequently, consolidation continued to increase with GGO further declined, and nally, crazy paving pattern, air bronchograms and irregular intralobular or interlobular septal thickening appeared progressively.These interstitial changes indicated the development of brosis.Other ndings included pleural effusion, lymphadenopathy, and round cystic changes 17 .However, none of the imaging characteristics of COVID-19 pneumonia seem speci c and diagnostic, which bear some resemblance to those of other viral infections and non-infectious conditions.
In the current study, the appearance of RILI on chest CT imaging often correlates with the stage of lung injury, evolving from GGO in the initial phase(Fig.4), subsequently patchy areas of consolidation roughly within the areas of the high-dose radiation treatment elds and likewise does not conform to normal lobar anatomy(Fig.2, 3) 12 .As the disease progresses to pulmonary brosis, the chest CT imaging may show scarring (Fig. 5) with consolidation and a de ned area of volume loss 11 .There are a number of similarities of CT ndings between COVID-19 pneumonia and RILI, but serial chest CT imaging of patients could help to continuously monitor the progression or improvement of lung lesions during treatment, sensitively re ecting the differences.
To the best of our current knowledge, this is the rst study that regarding differential diagnosis between COVID-19 pneumonia and RILI.Our ndings will facilitate the correct diagnosis of COVID-19 pneumonia early.However, there were several limitations to our study.Firstly, this was a retrospective analysis and lack of enough patients due to the scarcity of patients with suspicious COVID-19 pneumonia and a history of radiotherapy.Secondly, follow-up CT scans were available only two times and long-term radiological follow-up is warranted to con rm our results.Finally, bacterial pneumonia may be present in some patients in spite of the sputum cultures.

Conclusion
In conclusion, there are many similarities of clinical symptoms, laboratory ndings and CT imaging features between COVID-19 pneumonia and RILI, in particular radiation pneumonitis, consequently, it remains as a challenge to differentiate COVID-19 pneumonia from radiation pneumonitis in the absence of pharyngeal swab nucleic acid test.Nevertheless, due to relatively low sensitivity, repeated swab tests for con rmation are needed, which delays the process of accurately diagnose COVID-19 pneumonia.
Undoubtedly, elucidating key differences between COVID-19 pneumonia and radiation pneumonitis through a comprehensive evaluation of imaging characteristics combined with clinical and laboratory ndings could facilitate early diagnosis and appropriate management.As a nal note, several differences are summarized below based on previous research and our study:

Epidemiological history and past medical history
Patients COVID-19 tend to have the epidemiological links, such as travel history to endemic areas or contact with potential con rmed cases.Likewise, patients with radiation pneumonitis had a history of thoracic radiotherapy.

laboratory ndings
In the early stage, patients tend to present higher PCT, CRP and D-dimer levels due to radiation pneumonitis and/or recurrence cancer itself, whereas no obvious changes in patients with COVID-2019 pneumonia.Magni ed irregular nodules scattered in both lungs.metastatic tumors of the left pleura increased in the extent and quantity, so did left pleural effusion and pericardial effusion (  Transverse unenhanced thin-section serial CT scans from a 64-year-old female with suspected COVID-19 pneumonia, ultimately who be excluded by repeated nucleic acid tests.She was in the fth month after the completion of IMRT due to nasopharyngeal carcinoma, with upper lobes of lungs exposure to ionizing radiation.Chest CT images obtained on the second day after symptom onset showed there were minimal ground-glass opacities with partially rounded consolidation (Figure4: A1) in the apexes of both lungs, conforming completely to the irradiated area of low exposure.Multiple ill-de ned patchy ground-glass opacities (Figure4: A2) were observed in the middle lobe of right lung.Follow-up CT on the fth day demonstrated no obvious change of lung lesions (Figure4: B1, B2).

Thoracic CT imaging tests
Transverse unenhanced thin-section serial CT scans from a 39-year-old male with COVID-19 pneumonia.
He was in the 6th year after the completion of IMRT due to nasopharyngeal carcinoma, with upper lobes of lungs exposure to ionizing radiation due to adjacent to the treatment eld.Chest CT images obtained on the 10th day after symptom onset showed there were multiple ground-glass opacities of the lower lobes of both lungs peripherally (Figure5: A2); A few linear opacities presented in upper lobe lower lingual segment of the left lung ( : white blood cell; INR: International Normalized Ratio; PT: Prothrombin time; APTT: Activated partial thromboplastin time; CK: Creatine kinase; LDH: Lactate dehydrogenase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BUN: Blood urea nitrogen; CTNI : Troponin I; NT-BNP: N-terminal-pro hormone brain-type natriuretic peptide; PCT: Procalcitonin; CRP: C-reactive Protein; NR: no report.*The numbers in the brackets represent the number times of swab tests.Patient 1

5 :
A2); A few linear opacities presented in upper lobe lower lingual segment of the left lung (Fig.5: A3) within the ionizing radiation area, indicative of radiation brosis.After 8 days of antiviral therapy with resochin and supportive treatment, Follow-up CT scans demonstrated signi cant improvement in the extent and density of the ground-glass opacities (Fig.5: B2), but a new focal ground-glass opacity of the upper lobe of right lung appeared (Fig.5: A1, B1).Treatment continued until the result of the swab test became negative.

Figure 3 :
A1, B1, C1), All these lung lesions indicated a progressive left central lung cancer after systematic therapy.There were bilateral diffused ground-glass opacities with partial consolidation (Figure 3: B2), and a reticular pattern associated with bronchiectasis and intralobular or interlobular septal thickening (Figure 3: B2), which indicated the possibility of viral pneumonia.Follow-up CT on the 15th day demonstrated continuous development in the scope and extent (Figure 3:C1, C2), in spite of aggressive therapy.

Figure 5 :
A3) within the ionizing radiation area, indicative of radiation brosis.Follow-up CT at the 18th day demonstrated signi cant improvement in the extent and density of the ground-glass opacities (Figure 5: B2), but the new focal ground-glass opacities of the upper lobe of right lung appeared (Figure 5: B1).
Radiation pneumonitis tends to present on serial lung CT scans as GGO with partial consolidation within 6 months after the completion of irradiation, evolved into brosis in the late stage, including linear scarring with discrete consolidation, air bronchograms and irregular intralobular or interlobular septal thickening.Lung lesions are usually considered to develop slowly and con nement to radiation elds and nonconformity to anatomic boundaries,whereas typical chest CT imaging abnormalities of COVID-19 pneumonia showed unilateral, multifocal, predominantly ground-glass opacities in the early stage, with lesions mainly located peripherally and subpleurally, followed by the rapid development of the bilateral, diffuse disease, with GGO progressed to or co-existed with consolidations within 1-3weeks after initial symptoms, and nally, crazy paving pattern, air bronchograms and irregular intralobular or interlobular septal thickening appeared progressively.Overall, in spite of the comparable morphologic characteristics of lung CT imaging, the location, extent, and distribution of lung lesions between COVID-19 pneumonia and radiation pneumonitis differ signi cantly.and HS conceived and designed the study.QZ and JL contributed to the literature search.QZ, CT and LD contributed to data collection.QZ, CT, and SL contributed to CT analysis.SW and HS contributed to data interpretation.QZ and LD contributed to the gures.QZ and SW contributed to writing of the report.All authors have read and approved the manuscript. QZ