Pulmonary fat embolism: a potentially new fatal complication of SARS-CoV-2 infection. A case report

Microthrombus embolism caused by SARS-CoV-2 has been a major threat of death. Ackermann et al. [3]. reported that the incidence of alveolar capillary microthrombi was 9 times higher in patients with COVID-19 than in patients with influenza. Autopsy results have shown that 80-100% of COVID-19 patients have microthrombi [4]. D-dimer is an important indicator indicating of thrombus formation. Fox et al. [5]. reported 10 autopsy cases of COVID-19 patients. Interestingly, six of these patients had significantly elevated D-dimers before death, and four were not tested. Their data suggested a correlation between elevated D-dimer levels and the outcome of fatal pulmonary embolism in COVID-19 patients. In this case, the patient is confirmed to be infected with SARS-CoV-2 by immunohistochemistry of the spike protein and nucleocapsids protein. The D-dimer level was much higher than the normal value, suggesting that the deceased was in a hypercoagulable state and most likely had thromboembolism. The results of HE and PTAH staining proved that she had microthrombus embolism. The current treatment guidelines related to COVID-19 worldwide mention the plan of anticoagulant therapy, which is the main reason why only 4% of the patients had pulmonary embolism cases occurred in the multicenter study of von Stillfried et al. [2].

Fat embolism is a pathological diagnosis of microvascular or capillary occlusion by lipid droplets in the lung or peripheral circulation. Since Zenker first described the presence of fat droplets in the lung of a railway worker who died of severe crush injury in the chest and abdomen in 1861, many scholars have explored the formation mechanism of fat embolism. The mechanical theory proposed by Guass [6] and the biochemical theory proposed by Lehman and Moore [7] have been accepted and applied by a large number of scholars.

On the basis of Lehman and Moore, Hulman et al. [8]. further confirmed the biochemical theory by conducting in vitro creaming tests on the serum of intensive care patients. Fat emboli are made up of chylomicron and very low density lipoprotein in the case of elevated plasma CRP and calcium dependency agglutination, forming a giant ball of fat with a diameter of 2–35 μm microns. CRP, an acute phase protein first described by Tillet and Francis, is a widely used biomarker of inflammation [9, 10]. Since early in the SARS-CoV-2 pandemic, high serum CRP concentrations, a good predictor of adverse outcome, have been associated with the severity and complications of COVID-19 patients [11]. To the best of our knowledge, there have been no reports of fatal PFE due to elevated CRP in patients with COVID-19. In this case, the CRP was as high as 26.55 mg/L before death, and the PCT was within the normal range, which could exclude the possibility of bacterial, fungal and parasitic infections. In the absence of other histopathological abnormalities, combined with the positive immunohistochemical results, it is reasonable to believe that the elevated CRP in this patient was caused by infection with SARS-CoV-2. According to the grading method of pulmonary fat embolism proposed by Falzi [12] and Sevitt [13], we evaluated the patient for grade III fatal PFE. Combined with the biochemical theory proposed by Lehman and Moore, we further believe that the patient was infected with SARS-CoV-2, which resulted in the formation of fatal PFE.

In addition to the widely accepted mechanical and biochemical theories, Cinti et al. [14]. proposed in 2020 that visceral fat necrosis and free fat droplet transfer into the vascular lumen in obese patients may be the key factors of SARS-CoV-2-induced pulmonary fat embolism. In 2022, Colleluori and Cinti et al. [15]. proved the authenticity of the conjecture by means of transmission electron microscopy and ORO staining. However, in this case, we did not find evidence of SARS-CoV-2 infection in the adipose tissue surrounding the right ventricle, adrenal gland and thymus (Supplementary Fig. 1a-f), so we cannot support this theory for the time being.

The clinical manifestations associated with fat embolism are known as fat embolism syndrome(FES). At present, the diagnostic criteria for FES mainly include Gurd’s criteria [16], Schonfeld’s criteria [17] and Lindeque’s criteria [18], but there is a lack of prospective studies with big data. In terms of laboratory diagnosis, in addition to the secondary criteria proposed by Gurd, IL-6 [19] and > 30% of macrophages in alveolar lavage fluid containing lipid droplets [20] are also considered as early diagnostic markers of FES. Imaging, as an auxiliary method, is characterized by interlobular septal thickening, ground glass opacity, diffuse nodules, and pulmonary consolidation [21]. However, these changes are still nonspecific. Yohsuke et al. [22]. detected fat in the right ventricle and pulmonary artery branches by computed tomography and magnetic resonance imaging of cadavers, providing an alternative method for the diagnosis of FE. In conclusion, a characteristic diagnosis of FES is still lacking and further studies are needed.

The treatment of FES is still at a supportive stage. Since the 1950s, people have tried a variety of drug treatments, including heparin, corticosteroids, albumin, aprotinin, hypertonic glucose, etc., but little effect has been achieved. The treatment of FES is still controversial and needs further research and exploration [23].