In SARS-CoV-2 patients, a radiological imaging examination is a decisive tool for diagnosis, assessing disease severity and monitoring the clinical course, helping to reduce morbidity and mortality through early diagnosis, suitable treatment, and prevention of disease spread [16].
The RSNA Expert consensus document on reporting chest CT findings related to SARS-CoV-2 endorsed by the STR (Society of Thoracic Radiology) and ACR on 24 March 2020 [12] is shown in Fig. 8.
The level of suspicion for SARS-CoV-2according to the CT findings ranges from very low or CO-RADS 1 to very high or CO-RADS 5, and clinical severity is determined based on comorbidity and differential diagnosis data [17]. CO-RADS 1 has a high negative predictive value in patients with symptoms for four or more days, and CO-RADS 5 has a very high positive predictive value. However, interobserver variation for CO-RADS 2-4 is high and has a negative and poor predictive value. Therefore, interpretation of CT findings should be combined with clinical symptoms and duration, as CT can be negative during the first days of mild infection (Fig. 9).
Mesenchymal stem cells (MSCs) have immunomodulatory effects that can neutralize the intensified immune response and repair damaged and injured cells and tissues in the context of acute respiratory distress syndrome (ARDS). MSCs secrete multiple factors involved in the regeneration and modulation of tissue damage, such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and insulin-like growth factor, and lung injury in vivo [7].
MSCs have been used to treat SARS-CoV-2 to reverse the cytokine storm [18,19,20]. These cells act in various processes of innate and adaptive immunity, which likely cause changes in the activation of the immune system in patients with inflammatory diseases and by stimulating secretion of anti-apoptotic and regenerative factors.
The number of MSC-based clinical trials in these SARS-CoV-2 subjects is increasing. To date, there are nearly 60 clinical, multi-phase trials evaluating MSC therapy in SARS-CoV-2 subjects listed on clinicaltrials.gov [21]. Most of these trials have not been published, as they are ongoing. According to 1 clinical study of 10 subjects with SARS-CoV-2 pneumonia, 7 were administered MSCs, while the remaining 3 were used as controls [21, 22]. MSC transplantation was safe, with no reports of infusion-related effects or delayed hypersensitivity, and led to reduced serum CRP, the normalization of white blood cell counts, and symptomatic relief of pneumonia.
In this study, we identified a high incidence of GGOs and consolidations without differences between the two groups; corresponding to a meta-analysis, these findings were reported in 94.5% (52/55) of studies [11]. Our results suggest a significant improvement in radiological images in group A after treatment secondary to the stem cell effect on reducing inflammation and stimulating the pulmonological healing process. This method is already being used as a treatment option for lung inflammation via nebulization, with an increase in the number of lungs’ endothelial cells, accelerating airway healing and favorably altering the pathophysiological changes [23].
Few stem cell therapy trials have been reported, most of which were performed by intravenous injection techniques and not by nebulization. Two studies described outcomes of SARS-CoV-2 patients who received umbilical cord-derived MSCs in different regimens. Zhang et al. infused a single dose of 1 million cells/kg in a critically ill SARS-CoV-2 patient who significantly benefited from therapy and was discharged 7 days after the procedure [20]. Liang et al. treated a critically ill SARS-CoV-2 patient unresponsive to prior glucocorticoids, antivirals, and antibiotics with a dose of three 50 million MSCs. No adverse effects were observed, and the patient presented clinical and biomarker improvement after the second cellular infusion [24].
Leng et al. conducted a pilot trial designed in parallel in seven critical patients with SARS-CoV-2 pneumonia treated with intravenous administration of human MSCs and a control group with three patients. Reportedly, treated patients showed relief of all symptoms 2 to 4 days after receiving MSC infusion with no apparent adverse effects. These findings were supported by decreased pneumonia infiltration indicated on chest CT scan and negative results of the SARS-CoV-2 nucleic acid test 2 weeks after infusion [19].
Previously, within the framework of this clinical trial, we examined the frequency of acute kidney injury (ARI) in patients with SARS-CoV-2 and its relationship with clinical outcomes, finding it in approximately one-third of critically ill patients [7]. In addition, those who received the treatment showed a tendency to improve in terms of hospital stay and the evolution of biomarkers (amelioration of lymphopenia [8, 18, 25], neutrophil-lymphocyte ratio [26,27,28,29], and C-reactive protein (CRP)) compared to those in the control group. Likewise, we identified stem cells as a protective factor against secondary infection in SARS-CoV-2 cases in terms of sepsis and UTI, also finding an indiscriminate and massive use of antimicrobial agents, which is why rational use of these agents is needed.
The fact that the range in hospital stay after the intervention was much shorter in group A than in group B, given the homogeneity of the treated group thanks to the therapy, and the statistical dispersion of the control group data, although the median was not significant between the groups, may explain why there were fewer radiological controls in the treated group since shorter hospital stay is a protective factor against additional complications and nosocomial infections [7, 30, 31].
Following international recommendations, public hospitals in Abu Dhabi performed most of the radiographic control with CXR [30] due to infection control issues related to transporting patients to CT rooms for SARS-CoV-2 cases. It was also suggested that portable chest radiography should be considered to minimize the risk of cross-infection and in settings with limited access to the reliable real-time reverse transcription-polymerase chain reaction (RT-PCR) test [12]. Additionally, a positive CXR may avoid the need for a CT scan, minimizing radiation exposure.