key: cord-0819801-cj5f592m
authors: Zhou, Qian; Rao, Qiuchen; Li, Haidong; Zhang, Ming; Zhao, Xiuchao; Shi, Lei; Ye, Chaohui; Zhou, Xin
title: Evaluation of Injuries Caused by Coronavirus Disease 2019 Using Multi-Nuclei Magnetic Resonance Imaging
date: 2021-08-08
journal: Magnetic Resonance Letters
DOI: 10.1016/j.mrl.2021.100009
sha: 032bc32bc71f486e706df1e91932fac15cc86502
doc_id: 819801
cord_uid: cj5f592m

The ongoing pandemic of coronavirus disease 2019 (COVID-19) has been a great burden for the healthcare system in many countries because of its high transmissibility, severity, and fatality. Chest radiography and computed tomography (CT) play a vital role in the diagnosis, detection of complications, and prognostication of COVID-19. Additionally, magnetic resonance imaging (MRI), especially multi-nuclei MRI, is another important imaging technique for disease diagnosis because of its good soft tissue contrast and the ability to conduct structural and functional imaging, which has also been used to evaluate COVID-19-related organ injuries in previous studies. Herein, we briefly reviewed the recent research on multi-nuclei MRI for evaluating injuries caused by COVID-19 and the clinical 1H MRI techniques and their applications for assessing injuries in lungs, brain, and heart. Moreover, the emerging hyperpolarized 129Xe gas MRI and its applications in the evaluation of pulmonary structures and functional abnormalities caused by COVID-19 were also reviewed.

COVID-19 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1] . Since the first known case was reported in December 2019 in Wuhan, China, the disease has rapidly spread worldwide. On March 11, 2020 , the World Health Organization (WHO) declared the COVID-19 outbreak as a pandemic. To date, more than 182 million confirmed cases and 3.95 million deaths have been reported worldwide [2] .

The ongoing pandemic of COVID-19 has been a great burden for the national healthcare system in many countries because of its high transmissibility, severity, and fatality.

COVID-19 is mainly transmitted via respiratory droplets [3] and close contact, and other transmissions [4] include contacting with contaminated objects and aerosol transmission in relatively closed environments. Patients with COVID-19, including asymptomatic patients, are the main source of infection. Some immunity can be obtained after infection or vaccination; however, the duration of immunity remains unknown.

The severity of COVID-19 could be classified as asymptomatic, mild, moderate, or severe according to the clinical symptoms. Most symptomatic patients with COVID-19 have mild to moderate symptoms [5] . The most common symptoms are fever, dry cough, and fatigue. While other symptoms, including sore throat, nasal congestion, muscle or joint pain, headache, loss of smell and taste, and diarrhoea [6, 7] , are less common but would also affect some patients. The clinical symptoms of COVID-19 are summarized in Table 1 . Multiple organs, including lungs, brain, kidneys, and heart, can be affected by COVID-19, and pneumonia is one of the most common clinical manifestations [8] . Some critically ill patients would eventually develop acute respiratory distress syndrome (ARDS), multiple organ failure, or septic shock [13] . Moreover, a severe disease onset may lead to death due to massive alveolar damage and progressive respiratory failure [9] . Fortunately, most patients recover from the acute phase of COVID-19. However, some discharged patients may have some sequelae. Dry cough 59%-82% [10] J o u r n a l P r e -p r o o f Fatigue 44%-70% [10] Shortness of breath 31%-40% [10] Muscle pain 11%-35% [10] Sore throat 13.9% [11] Headache 13.6% [11] The clinical symptoms of COVID-19 are the first and most accessible information [12] for diagnosis and are used for severity classification but cannot be used for definite diagnosis, because common symptoms, such as fever and dry cough, are also typical symptoms of the Chest imaging is a crucial element for patient management and plays a vital role in the diagnosis, detection of complications, and prognostication of COVID-19 [12, 14] . Among chest imaging modalities, CT is the most widely used modality for COVID-19 owing to its high resolution and scanning speed, and typical features, such as ground-glass opacities (GGOs), consolidation, and crazy-paving [15] , could be found among patients with COVID- 19 . Chest CT has shown a high sensitivity for COVID-19 pneumonia diagnosis [16] , and some patients have early typical lung consolidation on CT when RT-PCR yields negative findings [17] . Significant destruction of the lung parenchyma, including interstitial inflammation and extensive consolidation [18] , is the typical radiographic manifestation of COVID-19 pneumonia. Extensive GGOs and pulmonary consolidation may suggest ARDS and massive lung infections with alveolar damage [19] . Chest CT could also be used to evaluate the lesion absorption of residual GGOs and subpleural parenchymal bands ( Fig. 1 ) [14, 15] . In addition, it has also been used to evaluate the short-term and long-term health consequences among discharged patients with COVID-19. According to a retrospective study, chest imaging abnormalities were found in more than half of the discharged patients in the J o u r n a l P r e -p r o o f early convalescence phase [20] . Moreover, significant radiological and physiological abnormalities were still observed in a considerable proportion of COVID-19 survivors without critical illness at 3 months after discharge [21] . Meanwhile, more abnormal chest imaging manifestations were found in COVID-19 survivors with more severe illness during hospitalization at 6 months after discharge from the hospital [22] .

patients. Reproduced with permission [14] .

In addition to CT, magnetic resonance imaging (MRI) is another important clinical imaging technique for disease diagnosis because of its good soft tissue contrast and the ability to conduct structural and functional imaging. It is more suitable for long-term evaluation of diseases because it is free of ionizing radiation. Although many nuclei, including 1 H, 13 C, 23 Na, 31 P, 35 Cl, 17 OE-MRI was first proposed by Edelman in 1996. It has the ability to assess pulmonary regional oxygen delivery and uptake [26] . OE-MRI is mainly based on the relaxation effect of protons caused by oxygen, which is a paramagnetic substance that can reduce the In addition to OE-MRI, high-performance low-field MRI can also be used to detect pneumonia. To resolve the low MR image quality owing to the low water density and airtissue interfaces causing local magnetic susceptibility gradients [27] , researchers have developed a high-performance low-field MRI system integrating modern technology at 0.55 T [28] . The system has a lower and more uniform field to reduce magnetic susceptibility gradients caused by air-tissue interface and reduce image distortion caused by field inhomogeneity. To overcome the motion artifacts and short T 2 * of the lung parenchyma, researchers have also developed PROPELLER based on fast spin echo (FSE) and UTE radial MRI, which could correct the artifacts without additional acquisitions by taking advantage of oversampling at the center of the k-space used as inherent navigator information. Because this technique is based on FSE, the obtained images have fewer artifacts resulting from B 0 inhomogeneity and are not affected by image warping owing to eddy currents [29] .With the J o u r n a l P r e -p r o o f aid of high-performance low-field MRI with PROPELLER, a precise visualization of persistent pulmonary changes was achieved, including GGOs caused by COVID-19 [25] .

With this method, patchy GGOs could be easily measured, and the measured GGOs agree well with those obtained by CT. In a previous longitudinal study, follow-up MRI was performed 2 weeks later, and the imaging results were almost unchanged, which demonstrated its potential for repetitive monitoring of morphological changes in patients with COVID-19.

The results indicated that high-performance low-field MRI with PROPELLER could detect lung impairments in patients with COVID-19 and is suitable for long-term longitudinal evaluation.

COVID-19 is essentially a multisystem disease, and brain injuries caused by this disease have also been observed by doctors and researchers [30] . Physicians around the world have also conducted numerous investigations to evaluate neurological performance in patients with COVID-19. Among the techniques for brain examination, 1 H MRI has been widely used for clinical diagnosis because it is free of ionizing radiation and radioactivity and has high soft tissue contrast.

Generally, the common neurological manifestations caused by COVID-19 include altered consciousness, pathological wakefulness upon cessation of sedation, confusion, agitation [30] , and skeletal muscle damage [31] . With the aid of clinical MRI techniques, intracranial hemorrhagic lesions, acute thrombosis [30] , encephalitis, cytotoxic edema, abnormal blood perfusion, and multifocal white matter lesions can be observed in some patients with COVID-19. The identified cerebral diseases among affected patients mainly include acute ischemic stroke, acute necrotizing encephalopathy (ANE), acute disseminated encephalomyelitis, parkinsonism, edema-associated brain infection, and COVID-19-related disseminated leukoencephalopathy (CRDL).

Acute stroke is a cerebrovascular disease that is generally caused by sudden rupture or obstruction of the cerebrovascular system, resulting in damage to the brain tissue. Helms and colleagues found acute and subacute ischemic strokes in patients with COVID-19 using diffusion-weighted imaging (DWI). Moreover, enhancement in leptomeningeal spaces and J o u r n a l P r e -p r o o f bilateral hypoperfusion in the frontotemporal lobes could be found in some patients using brain MRI [32] .

COVID-19 is considered likely to represent an immune-mediated phenomenon and is associated with acute severe encephalopathy, such as ANE. ANE is a complication of influenza and other viral infections associated with intracranial cytokine storms, which can cause blood-brain barrier breakdown with no symptoms of direct viral invasion or parainfectious demyelination [33] . In a previous study by Dixon et al., increased brainstem swelling was observed on T 1 /T 2 -weighted images (T1WIs/T2WIs), diffusion-weighted images, and susceptibility-weighted images in a patient on day 6, and hemorrhagic lesions in the brainstem, amygdala, putamina, and thalamic nuclei were also observed ( Fig. ) [34] . 

HP 129 Xe gas MRI is an emerging technique for pulmonary function and microstructure evaluation and has developed rapidly in recent years. The technique utilizes HP 129 Xe as an inhalation gas contrast agent, whose MR signal could be enhanced by more than 50,000 times than that in thermal equilibrium via the technique of rubidium-vapor SEOP [41] . With the HP 129 Xe gas MRI technique, high-resolution lung gas images could be obtained [42] . Owing to its good solubility and chemical shift sensitivity to the surrounding environment, HP 129 Xe gas MRI has unique advantages for probing the gas exchange function of the lung globally and regionally. It has been widely used for evaluating lung injuries caused by diseases, such as chronic obstructive pulmonary disease [43] , asthma [44] , cystic fibrosis [45] , idiopathic pulmonary fibrosis [46] , and other lung diseases [47] , including COVID-19 [48] . Moreover, discharged patients with COVID-19 and healthy volunteers, and a higher ventilation defect percent (VDP) was found in the former (5.5%) than in the latter (3.7%). Moreover, morphological parameters derived from 129 Xe aired pulmonary gas exchange function, that is, longer gas exchange time constant, was found in the patients with COVID-19. These findings suggested that regional ventilation and alveolar airspace dimensions were relatively normal after the patients were discharged, while the gas exchange function diminished (Error! Reference source not found. Reproduced with permission [48] .

As previously reported, fatigue and breathlessness still existed in some patients after long-term infection, although they have no significant abnormality in pulmonary function tests (PFTs), imaging, or clinical tests [51] . Recently, HP 129 Xe gas MRI has also been used to identify the possible causes of breathlessness in patients with COVID-19 at 3 months after J o u r n a l P r e -p r o o f discharge [52] . Ventilation and dissolved-phase 129 Xe gas MRI were performed in patients and healthy volunteers, and abnormalities of gas transfer were found in patients with post-COVID-19 pneumonia. These results might explain the possible etiology of the breathlessness symptom lasting for months after discharge and indicate that HP 129 Xe gas MRI might be a useful technique for the diagnosis of dyspneic patients with COVID-19.

COVID-19 is a multisystem disease, and some patients could experience long-term COVID as reported. Clinical imaging techniques play an important role in COVID-19 diagnosis as well as in the assessment of injuries caused by the disease. Apart from chest CT, multi-nuclei MRI also has potential in COVID-19 diagnosis and long-term COVID evaluation because it is free of ionizing radiation and has good soft tissue contrast. With the use of multinuclei MRI techniques, especially the emerging HP 129 Xe gas MRI technique, the pulmonary structural and functional changes caused by COVID-19 could be quantified. Moreover, combined with the accelerated acquisition techniques and emerging reconstruction method based on artificial intelligence, MRI with 13 C, 23 Na, 17 O and 31 P, could also be used for evaluating brain, heart, liver, and other organ injuries caused by COVID-19, especially the functional injuries. Previous studies have demonstrated the feasibility and potential of multinuclei MRI techniques in the evaluation of injuries caused by COVID-19. The preliminary results indicate that it is a promising imaging modality for long-term COVID evaluation and management, which might make it a helpful tool for the evaluation in the post-COVID-19

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CAS) in 2004. He is currently a professor at Innovation Academy for Precision Measurement Science and Technology

Suzhou in 2016. Currently, she is pursuing her Ph.D. degree in Magnetic Resonance Imaging (MRI) with the Innovation Academy of Precision Measurement Science and Technology (APM)

Wuhan in 2016. He is currently pursuing his Ph.D. degree with the Wuhan National Laboratory for Optoelectronics, HUST. His research interests include hyperpolarized 129 Xe MRI method and applications for human lung imaging

This work is supported by National Natural Science Foundation of China (grant no.