Single-Cell Sequencing Illuminates Thymic Development: An Updated Framework for Understanding Thymic Epithelial Tumors.

Thymic epithelial tumors (TETs) are rare tumors for which treatment options are limited. The ongoing need for improved systemic therapies reflects a limited understanding of tumor biology as well as the normal thymus. The essential role of the thymus in adaptive immunity is largely effected by its epithelial compartment, which directs thymocyte (T-cell) differentiation and immunologic self-tolerance. With aging, the thymus undergoes involution whereby epithelial tissue is replaced by adipose and other connective tissue, decreasing immature T-cell production. Against this natural drive toward involution, a fraction of thymuses will instead undergo oncologic transformation, leading to the formation of TETs, including thymoma and thymic carcinoma. The rarity of these tumors restricts investigation of the mechanisms of tumorigenesis and development of rational treatment options. To this end, the development of technologies which allow deep molecular profiling of individual tumor cells permits a new window through which to view normal thymic development and contrast the malignant changes that result in oncogenic transformation. In this review, we describe the findings of recent illuminating studies on the diversity of cell types within the epithelial compartment through thymic differentiation and aging. We contextualize these findings around important unanswered questions regarding the spectrum of known somatic tumor alterations, cell of origin, and tumor heterogeneity. The perspectives informed by single-cell molecular profiling offer new approaches to clinical and basic investigation of thymic epithelial tumors, with the potential to accelerate development of improved therapeutic strategies to address ongoing unmet needs in these rare tumors.

Anastomosing haemangioma of the mediastinum: Clinicopathological series with radiological and genetic characterisation.

AIMS: Anastomosing haemangiomas are benign tumours with anastomosing vascular channels that may mimic angiosarcoma. While anastomosing haemangiomas have been described in diverse locations, particularly the abdominal/paraspinal region, data on anastomosing haemangiomas in the mediastinum remain limited. We report the clinicopathological, radiological and molecular characteristics of the largest single-institutional series of mediastinal anastomosing haemangiomas. METHODS AND RESULTS: In our pathology archives in 2011-23, we reviewed all vascular lesions involving the mediastinum and identified seven anastomosing haemangiomas. Clinical information was abstracted from medical charts; available radiological imaging was reviewed. Targeted DNA-based next-generation sequencing (447 genes, including GNAQ and GNA11) was performed on five cases. The seven patients included five women and two men, with an age range of 55-77 (median = 72) years. Of the six tumours with available radiology, two each were in the prevascular, visceral and paravertebral mediastinum, with lobulated peripheral enhancement in all tumours examined with contrast enhancement. Six patients underwent tumour resection; one patient received proton radiotherapy. Microscopically, each tumour was solitary and characterised by anastomosing capillary-sized vessels lined by hobnail endothelial cells. Fibrin microthrombi, hyaline globules and extramedullary haematopoiesis were common. In the five tumours analysed by next-generation sequencing, GNAQ p.Q209P was identified in one tumour; no additional reportable alterations were identified in the remaining cases. No recurrence was noted in the four patients with available follow-up of 3-58 (median = 9.5) months after resection. CONCLUSION: While mediastinal anastomosing haemangiomas can microscopically mimic angiosarcoma, awareness of this entity and radiological correlation may help to circumvent this diagnostic pitfall.

Longitudinal CT and MRI Characteristics of Unilocular Thymic Cysts.

Background Isoattenuating and hyperattenuating thymic cysts at CT are often misinterpreted as lymphadenopathy or thymic epithelial neoplasms. Purpose To evaluate the longitudinal change in thymic cyst appearance at CT and MRI. Materials and Methods All chest MRI studies showing thymic cysts between July 2008 and December 2019, identified from a retrospective search of a quality assurance database, were included in this study if initial CT depicted a thymic lesion, the patient was referred for follow-up MRI for characterization, and the baseline (ie, index) MRI indicated a cystic lesion. Follow-up CT scans and/or MRI scans were identified through July 2020. Thymic cyst characteristics, such as size, location, and morphologic features, as well as CT and MRI characteristics, were recorded. Change in size, attenuation, and T1-weighted MRI signal was assessed longitudinally. Descriptive statistics of longitudinal change were tabulated. Results A total of 244 chest MRI studies in 140 patients with 142 unique cysts and 392 CT examinations (636 total examinations and 645 thymic cysts-nine examinations with two cysts each) were evaluated. The median follow-up duration was 2.2 years. Thirty-three patients with 34 unique cysts (34 of 142 cysts [24%]) underwent imaging follow-up for more than 5 years. Thymic cysts followed up for more than 5 years were most commonly saccular (189 of 274 cysts [69% axially]) and retrosternal (14 of 34 cysts [41%]). Craniocaudal dimension was larger than transverse and anteroposterior dimensions in 223 of 274 cysts (81%). Mean thymic cyst attenuation was 25 HU (range, 15-100 HU). Five of 31 cysts (16%) exhibited wall calcification. The median cyst wall thickness was 2.0 mm (range, 0.9-3.0 mm). Most thymic cysts changed in volume (31 of 34 cysts [91%]), CT attenuation (15 of 35 cysts [43%]), and T1-weighted MRI signal (12 of 18 cysts [67%]) over time. None developed mural irregularity, nodularity, or septations. Conclusion Unilocular thymic cysts, defined at index MRI, never developed irregular wall thickening, mural nodularity, or septations that would raise concern for malignant transformation. However, these cysts showed mural calcification and change in size, CT attenuation, and MRI signal over more than 5 years of follow-up. © RSNA, 2021 Online supplemental material is available for this article.

Inhaled high dose nitric oxide is a safe and effective respiratory treatment in spontaneous breathing hospitalized patients with COVID-19 pneumonia.

BACKGROUND: Inhaled nitric oxide (NO) is a selective pulmonary vasodilator. In-vitro studies report that NO donors can inhibit replication of SARS-CoV-2. This multicenter study evaluated the feasibility and effects of high-dose inhaled NO in non-intubated spontaneously breathing patients with Coronavirus disease-2019 (COVID-19). METHODS: This is an interventional study to determine whether NO at 160 parts-per-million (ppm) inhaled for 30 min twice daily might be beneficial and safe in non-intubated COVID-19 patients. RESULTS: Twenty-nine COVID-19 patients received a total of 217 intermittent inhaled NO treatments for 30 min at 160 ppm between March and June 2020. Breathing NO acutely decreased the respiratory rate of tachypneic patients and improved oxygenation in hypoxemic patients. The maximum level of nitrogen dioxide delivered was 1.5 ppm. The maximum level of methemoglobin (MetHb) during the treatments was 4.7%. MetHb decreased in all patients 5 min after discontinuing NO administration. No adverse events during treatment, such as hypoxemia, hypotension, or acute kidney injury during hospitalization occurred. In our NO treated patients, one patient of 29 underwent intubation and mechanical ventilation, and none died. The median hospital length of stay was 6 days [interquartile range 4-8]. No discharged patients required hospital readmission nor developed COVID-19 related long-term sequelae within 28 days of follow-up. CONCLUSIONS: In spontaneous breathing patients with COVID-19, the administration of inhaled NO at 160 ppm for 30 min twice daily promptly improved the respiratory rate of tachypneic patients and systemic oxygenation of hypoxemic patients. No adverse events were observed. None of the subjects was readmitted or had long-term COVID-19 sequelae.

Significance of Acquisition Parameters for Adipose Tissue Segmentation on CT Images.

OBJECTIVE. CT-based body composition analysis quantifies skeletal muscle and adipose tissue. However, acquisition parameters and quality can vary between CT images obtained for clinical care, which may lead to unreliable measurements and systematic error. The purpose of this study was to estimate the influence of IV contrast medium, tube current-exposure time product, tube potential, and slice thickness on cross-sectional area (CSA) and mean attenuation of subcutaneous (SAT), visceral (VAT), and inter-muscular adipose tissue (IMAT). MATERIALS AND METHODS. We retrospectively analyzed 244 images from 105 patients. We applied semiautomated threshold-based segmentation to CTA, dual-energy CT, and CT images acquired as part of PET examinations. An axial image at the level of the third lumbar vertebral body was extracted from each examination to generate 139 image pairs. Images from each pair were obtained with the same scanner, from the same patient, and during the same examination. Each image pair varied in only one acquisition parameter, which allowed us to estimate the effect of the parameter using one-sample t or median tests and Bland-Altman plots. RESULTS. IV contrast medium application reduced CSA in each adipose tissue compartment, with percentage change ranging from -0.4% (p = .03) to -9.3% (p < .001). Higher tube potential reduced SAT CSA (median percentage change, -4.2%; p < .001) and VAT CSA (median percentage change, -2.8%; p = .001) and increased IMAT CSA (median percentage change, -5.4%; p = .001). Thinner slices increased CSA in the VAT (mean percentage change, 3.0%; p = .005) and IMAT (median percentage change, 17.3%; p < .001) compartments. Lower tube current-exposure time product had a variable effect on CSA (median percentage change, -3.2% for SAT [p < .001], -12.6% for VAT [p = .001], and 58.8% for IMAT [p < .001]). IV contrast medium and higher tube potential increased mean attenuation, with percentage change ranging from 0.8% to 1.7% (p < .05) and from 6.2% to 20.8% (p < .001), respectively. Conversely, thinner slice and lower tube current-exposure time product reduced mean attenuation, with percentage change ranging from -5.4% to -1.0% (p < .001) and from -8.7% to -1.8% (p < .001), respectively. CONCLUSION. Acquisition parameters significantly affect CSA and mean attenuation of adipose tissue. Details of acquisition parameters used for CT-based body composition analysis need to be scrutinized and reported to facilitate interpretation of research studies.

Building blocks for thoracic MRI: Challenges, sequences, and protocol design.

Thoracic MRI presents important and unique challenges. Decreased proton density in the lung in combination with respiratory and cardiac motion can degrade image quality and render poorly executed sequences uninterpretable. Despite these challenges, thoracic MRI has an important clinical role, both as a problem-solving tool and in an increasing array of clinical indications. Advances in scanner and sequence design have also helped to drive this development, presenting the radiologist with improved techniques for thoracic MRI. Given this evolving landscape, radiologists must be familiar with what thoracic MR has to offer. The first step in developing an effective thoracic MRI practice requires the creation of efficient and malleable protocols that can answer clinical questions. To do this, radiologists must have a working knowledge of the MR sequences that are used in the thorax, many of which have been adapted from use elsewhere in the body. These sequences can be broadly divided into three categories: traditional/anatomic, functional, and cine based. Traditional/anatomic sequences allow for the depiction of anatomy and pathologic processes with the ability for characterization of signal intensity and contrast enhancement. Functional sequences, including diffusion-weighted imaging, and high temporal resolution dynamic contrast enhancement, allow for the noninvasive measurement of tissue-specific parameters. Cine-based sequences can depict the motion of structures in the thorax, either with retrospective ECG gating or in real time. The purpose of this article is to review these categories, the building block sequences that comprise them, and identify basic questions that should be considered in thoracic MRI protocol design. Level of Evidence: 5 Technical Efficacy Stage: 3 J. Magn. Reson. Imaging 2019;50:682-701.

Impact of Nonvascular Thoracic MR Imaging on the Clinical Decision Making of Thoracic Surgeons: A 2-year Prospective Study.

Purpose To determine the impact of nonvascular thoracic magnetic resonance (MR) imaging on the clinical decision making and diagnostic certainty of thoracic surgeons. Materials and Methods Seven thoracic surgeons at Massachusetts General Hospital, an academic quaternary referral hospital, participated in this 2-year, prospective, institution review board-approved, HIPAA-compliant pre- and post-MR imaging survey study after completing a one-time demographic survey. Between July 16, 2013, and July 13, 2015, each time a thoracic surgeon ordered a nonvascular thoracic MR imaging study via radiology order entry, he or she was sent a link to the pre-test survey that ascertained the clinical rationale for MR imaging, the clinical management plan if MR imaging was not an option, and pre-test diagnostic certainty. Upon completion of the MR imaging report, the surgeon was sent a link to the post-test survey assessing if/how MR imaging changed clinical management, the surgeon's comfort with the clinical management plan, and post-test diagnostic certainty. Data were analyzed with Student t, Wilcoxon, and McNemar tests. Results A total of 99 pre- and post-test surveys were completed. Most MR imaging studies (64 of 99 [65%]) were requested because of indeterminate computed tomographic findings. The use of MR imaging significantly reduced the number of planned surgical interventions (P < .001), modified the surgical approach in 54% (14 of 26) of surgical cases, and increased surgeon comfort with the patient management plan in 95% (94 of 99) of cases. Increased diagnostic certainty as a result of MR imaging was highly significant (P < .0001). In 21% (21 of 99) of cases, definitive MR imaging results warranted no further follow-up or clinical care. Conclusion In appropriate cases, assessment with nonvascular thoracic MR imaging substantially affects the clinical decision making and diagnostic certainty of thoracic surgeons. (©) RSNA, 2016 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on May 2, 2016.

Tracheal tube obstruction in mechanically ventilated patients assessed by high-resolution computed tomography.

BACKGROUND: Tracheal intubation compromises mucus clearance and secretions accumulate inside the tracheal tube (TT). The aim of this study was to evaluate with a novel methodology TT luminal obstruction in critically ill patients. METHODS: This was a three-phase study: (1) the authors collected 20 TTs at extubation. High-resolution computed tomography (CT) was performed to determine cross-sectional area (CSA) and mucus distribution within the TT; (2) five TTs partially filled with silicone were used to correlate high-resolution CT results and increased airflow resistance; and (3) 20 chest CT scans of intubated patients were reviewed for detection of secretions in ventilated patients' TT. RESULTS: Postextubation TTs showed a maximum CSA reduction of (mean±SD) 24.9±3.9% (range 3.3 to 71.2%) after a median intubation of 4.5 (interquartile range 2.5 to 6.5) days. CSA progressively decreased from oral to lung end of used TTs. The luminal volume of air was different between used and new TTs for all internal diameters (P<0.01 for new vs. used TTs for all studied internal diameters). The relationship between pressure drop and increasing airflow rates was nonlinear and depended on minimum CSA available to ventilation. Weak correlation was found between TT occlusion and days of intubation (R²=0.352, P=0.006). With standard clinical chest CT scans, 6 of 20 TTs showed measurable secretions with a CSA reduction of 24.0±3.9%. CONCLUSIONS: TT luminal narrowing is a common finding and correlates with increased airflow resistance. The authors propose high-resolution CT as a novel technique to visualize and quantify secretions collected within the TT lumen.

Submillisievert chest CT with filtered back projection and iterative reconstruction techniques.

OBJECTIVE: The purpose of this study was to compare submillisievert chest CT images reconstructed with filtered back projection (FBP), SafeCT, adaptive statistical iterative reconstruction (ASIR), and model-based iterative reconstruction (MBIR) with standard of care FBP images. SUBJECTS AND METHODS: Fifty patients (33 men and 17 women; mean age [± SD], 62 ± 10 years) undergoing routine chest CT gave written informed consent for acquisition of an additional submillisievert chest CT series with reduced tube current but identical scanning length as standard of care chest CT. Sinogram data of the submillisievert series were reconstructed with FBP, SafeCT, ASIR, and MBIR and compared with FBP images at standard-dose chest CT (n = 8 × 50 = 400 series). Two thoracic radiologists performed independent comparison for visualization of lesion margin, visibility of small structures, and diagnostic acceptability. Objective noise measurements and noise spectral density were obtained. RESULTS: Of 287 detected lesions, 162 were less than 1-cm noncalcified nodules. Lesion margins were well seen on all submillisievert reconstruction images except MBIR, on which they were poorly visualized. Likewise, only submillisievert MBIR images were suboptimal for visibility of normal structures, such as pulmonary vessels in the outer 2 cm of the lung, interlobular fissures, and subsegmental bronchial walls. MBIR had the lowest image noise compared with other techniques. CONCLUSION: FBP, SafeCT, ASIR, and MBIR can enable optimal lesion evaluation on chest CT acquired at a volume CT dose index of 2 mGy. However, all submillisievert reconstruction techniques were suboptimal for visualization of mediastinal structures. Submillisievert MBIR images were suboptimal for visibility of normal lung structures despite showing lower image noise.

Sex difference in normal thymic appearance in adults 20-30 years of age.

PURPOSE: To determine whether there is a sex difference in the appearance of the normal thymus in 20-30-year-old men and women. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board and was compliant with HIPAA. The requirement for informed consent was waived. Images and medical records of 238 consecutive subjects without known thymic disease (175 men, 63 women) who underwent chest computed tomography with intravenous contrast material in 2008 were reviewed. Average thymic region of interest (ROI), subjective assessment of thymic attenuation by using a scale of grades 0-3, thymic anteroposterior measurement, and mean maximal thymic lobe thickness were recorded by two independent thoracic radiologists, blinded to subject age and sex. Thymic morphologic characteristics were assessed in consensus. The two-sided Wilcoxon rank-sum test, Student t test, test for linear regression, analysis of covariance, two-way factorial analysis of variance, and continuity-adjusted χ(2) test were used for statistical analysis. RESULTS: There was a significant sex difference in thymic attenuation as measured objectively by using mean thymic ROI measurement (P < .0001) and subjectively by using a scale of grades 0-3 (P < .0001), which held true when corrected for age (P < .0001). A sex difference was also found in regard to the rate of decrease in mean thymic attenuation with age, with men's thymuses exhibiting a significant decrease in attenuation during the decade, unlike women (P = .0479). There was no significant sex difference in mean maximal thymic lobe thickness (P = .8697). A quadrilateral, as opposed to triangular, configuration of the thymus was more common in women than men (P = .0034). CONCLUSION: There is a significant sex difference in normal thymic appearance in 20-30-year-old men and women. The thymus of 20-30-year-old women typically exhibits higher attenuation and more commonly exhibits a quadrilateral configuration.

MR Angiography of Pulmonary Vasculature.

Pulmonary MR angiography (MRA) is a useful alternative to computed tomographic angiography (CTA) for the study of the pulmonary vasculature. For pulmonary hypertension and partial anomalous pulmonary venous return, a cardiac MR imaging and the pulmonary MRA are useful for flow quantification and planning treatment. For the diagnosis of pulmonary embolism (PE), MRA-PE has been shown to have non-inferior outcomes at 6 months when compared with CTA-PE. Over the last 15 years, pulmonary MRA has become a routine and reliable examination for the workup of pulmonary hypertension and the primary diagnosis of PE at the University of Wisconsin.

Intralesional microbleeding in resected thymic cysts indeterminate on imaging.

Background: The propensity of thymic cysts to mimic solid thymic epithelial tumors (TETs) on computed tomography (CT), on account of attenuation values greater than water and thickened or calcified walls, can lead to non-therapeutic thymectomy. These lesions can fluctuate in volume, CT attenuation, and magnetic resonance imaging (MRI) signal over time. We hypothesized that spontaneous hemorrhage and resorption may contribute to their variable appearance over time. Methods: Completely excised thymic cysts were identified retrospectively over a 20-year period by their pathologic diagnosis. Cysts were excluded if they did not have available presurgical imaging, were not prevascular, were located within or contained an enhancing mass by imaging, or were of non-thymic origin upon microscopic review. Histopathological analysis of all available resected thymic cyst material and radiologic analysis of the cysts on pre-operative imaging were performed. Results: Upon application of exclusion criteria, we identified 18 thymic cysts from the initial 85 mediastinal cystic specimens. Most cysts were unilocular (11/15, 73%), showed turbid-to-semisolid, hemorrhagic fluid (10/12, 83%) and showed histopathological findings suggestive of intralesional microbleeding (14/18, 78%), remodeling (8/18, 44%), pathological wound healing/scarring of the capsule (16/18, 89%), and fat necrosis in the surrounding thymic tissue (12/18, 67%). On CT, 6/17 (35%) cysts demonstrated wall calcification. Sixty-five percent (11/17) had attenuation values ≥20 Hounsfield units (HU). Two of the 4 cysts imaged by MRI were T1-isointense, one was mixed hyper- and isointense, and one T1-hypointense to muscle, with iso- and hyperintensity indicating hemorrhagic or proteinaceous content. Twenty-five percent (1/4) of cyst walls imaged by MRI were T1/T2-hypointense, indicating presence of calcification, hemosiderin, and/or fibrosis. Conclusions: Resected thymic cysts in this cohort often showed features suggestive of intralesional microbleeding, inflammation, and fibrosis, which may explain their appearance and behavior over time on CT and MRI.

Accurate auto-labeling of chest X-ray images based on quantitative similarity to an explainable AI model.

The inability to accurately, efficiently label large, open-access medical imaging datasets limits the widespread implementation of artificial intelligence models in healthcare. There have been few attempts, however, to automate the annotation of such public databases; one approach, for example, focused on labor-intensive, manual labeling of subsets of these datasets to be used to train new models. In this study, we describe a method for standardized, automated labeling based on similarity to a previously validated, explainable AI (xAI) model-derived-atlas, for which the user can specify a quantitative threshold for a desired level of accuracy (the probability-of-similarity, pSim metric). We show that our xAI model, by calculating the pSim values for each clinical output label based on comparison to its training-set derived reference atlas, can automatically label the external datasets to a user-selected, high level of accuracy, equaling or exceeding that of human experts. We additionally show that, by fine-tuning the original model using the automatically labelled exams for retraining, performance can be preserved or improved, resulting in a highly accurate, more generalized model.

Prediction of oxygen requirement in patients with COVID-19 using a pre-trained chest radiograph xAI model: efficient development of auditable risk prediction models via a fine-tuning approach.

Risk prediction requires comprehensive integration of clinical information and concurrent radiological findings. We present an upgraded chest radiograph (CXR) explainable artificial intelligence (xAI) model, which was trained on 241,723 well-annotated CXRs obtained prior to the onset of the COVID-19 pandemic. Mean area under the receiver operating characteristic curve (AUROC) for detection of 20 radiographic features was 0.955 (95% CI 0.938-0.955) on PA view and 0.909 (95% CI 0.890-0.925) on AP view. Coexistent and correlated radiographic findings are displayed in an interpretation table, and calibrated classifier confidence is displayed on an AI scoreboard. Retrieval of similar feature patches and comparable CXRs from a Model-Derived Atlas provides justification for model predictions. To demonstrate the feasibility of a fine-tuning approach for efficient and scalable development of xAI risk prediction models, we applied our CXR xAI model, in combination with clinical information, to predict oxygen requirement in COVID-19 patients. Prediction accuracy for high flow oxygen (HFO) and mechanical ventilation (MV) was 0.953 and 0.934 at 24 h and 0.932 and 0.836 at 72 h from the time of emergency department (ED) admission, respectively. Our CXR xAI model is auditable and captures key pathophysiological manifestations of cardiorespiratory diseases and cardiothoracic comorbidities. This model can be efficiently and broadly applied via a fine-tuning approach to provide fully automated risk and outcome predictions in various clinical scenarios in real-world practice.

The diagnostic value of magnetic resonance imaging compared to computed tomography in the evaluation of fat-containing thoracic lesions.

Intrathoracic fat-containing lesions may arise in the mediastinum, lungs, pleura, or chest wall. While CT can be helpful in the detection and diagnosis of these lesions, it can only do so if the lesions contain macroscopic fat. Furthermore, because CT cannot demonstrate microscopic or intravoxel fat, it can fail to identify and diagnose microscopic fat-containing lesions. MRI, employing spectral and chemical shift fat suppression techniques, can identify both macroscopic and microscopic fat, with resultant enhanced capability to diagnose these intrathoracic lesions non-invasively and without ionizing radiation. This paper aims to review the CT and MRI findings of fat-containing lesions of the chest and describes the fat-suppression techniques utilized in their assessment.

High-Dose Inhaled Nitric Oxide for the Treatment of Spontaneously Breathing Pregnant Patients With Severe Coronavirus Disease 2019 (COVID-19) Pneumonia.

OBJECTIVE: To evaluate whether the use of inhaled nitric oxide (iNO)200 improves respiratory function. METHODS: This retrospective cohort study used data from pregnant patients hospitalized with severe bilateral coronavirus disease 2019 (COVID-19) pneumonia at four teaching hospitals between March 2020 and December 2021. Two cohorts were identified: 1) those receiving standard of care alone (SoC cohort) and 2) those receiving iNO200 for 30 minutes twice daily in addition to standard of care alone (iNO200 cohort). Inhaled nitric oxide, as a novel therapy, was offered only at one hospital. The prespecified primary outcome was days free from any oxygen supplementation at 28 days postadmission. Secondary outcomes were hospital length of stay, rate of intubation, and intensive care unit (ICU) length of stay. The multivariable-adjusted regression analyses accounted for age, body mass index, gestational age, use of steroids, remdesivir, and the study center. RESULTS: Seventy-one pregnant patients were hospitalized for severe bilateral COVID-19 pneumonia: 51 in the SoC cohort and 20 in the iNO200 cohort. Patients receiving iNO200 had more oxygen supplementation-free days (iNO200: median [interquartile range], 24 [23-26] days vs standard of care alone: 22 [14-24] days, P=.01) compared with patients in the SoC cohort. In the multivariable-adjusted analyses, iNO200 was associated with 63.2% (95% CI 36.2-95.4%; P<.001) more days free from oxygen supplementation, 59.7% (95% CI 56.0-63.2%; P<.001) shorter ICU length of stay, and 63.6% (95% CI 55.1-70.8%; P<.001) shorter hospital length of stay. No iNO200-related adverse events were reported. CONCLUSION: In pregnant patients with severe bilateral COVID-19 pneumonia, iNO200 was associated with a reduced need for oxygen supplementation and shorter hospital stay.