Elevated vascular transformation blood biomarkers in Long-COVID indicate angiogenesis as a key pathophysiological mechanism.

BACKGROUND: Long-COVID is characterized by prolonged, diffuse symptoms months after acute COVID-19. Accurate diagnosis and targeted therapies for Long-COVID are lacking. We investigated vascular transformation biomarkers in Long-COVID patients. METHODS: A case-control study utilizing Long-COVID patients, one to six months (median 98.5 days) post-infection, with multiplex immunoassay measurement of sixteen blood biomarkers of vascular transformation, including ANG-1, P-SEL, MMP-1, VE-Cad, Syn-1, Endoglin, PECAM-1, VEGF-A, ICAM-1, VLA-4, E-SEL, thrombomodulin, VEGF-R2, VEGF-R3, VCAM-1 and VEGF-D. RESULTS: Fourteen vasculature transformation blood biomarkers were significantly elevated in Long-COVID outpatients, versus acutely ill COVID-19 inpatients and healthy controls subjects (P < 0.05). A unique two biomarker profile consisting of ANG-1/P-SEL was developed with machine learning, providing a classification accuracy for Long-COVID status of 96%. Individually, ANG-1 and P-SEL had excellent sensitivity and specificity for Long-COVID status (AUC = 1.00, P < 0.0001; validated in a secondary cohort). Specific to Long-COVID, ANG-1 levels were associated with female sex and a lack of disease interventions at follow-up (P < 0.05). CONCLUSIONS: Long-COVID patients suffer prolonged, diffuse symptoms and poorer health. Vascular transformation blood biomarkers were significantly elevated in Long-COVID, with angiogenesis markers (ANG-1/P-SEL) providing classification accuracy of 96%. Vascular transformation blood biomarkers hold potential for diagnostics, and modulators of angiogenesis may have therapeutic efficacy.

A 34-Year-Old Woman from Brazil with Pulmonary Lymphangioleiomyomatosis Diagnosed by Raised Serum Vascular Endothelial Growth Factor-D (VEGF-D) Levels and Lung Cysts on Computed Tomography Imaging Presenting with COVID-19 Pneumonia.

BACKGROUND There is growing concern about the clinical course of certain diseases in patients who are simultaneously infected by SARS-CoV-2. This report is of a 34-year-old woman from Brazil with a recent diagnosis of pulmonary lymphangioleiomyomatosis (LAM) diagnosed by raised serum VEGF-D levels and the finding of lung cysts on computed tomography (CT) imaging, who presented with COVID-19 pneumonia. CASE REPORT Five months after the diagnosis of pulmonary LAM, which was based on the presence of diffuse and bilateral cystic lesions on CT scan associated with high serum VEGF-D levels, the patient presented with worsening dyspnea, drop in peripheral oxygen oxygenation, fever, and diffuse myalgia. She was using Sirolimus because it inhibits the development of LAM cells. A worsening of lung abnormalities was demonstrated in a chest CT examination, with the appearance of areas of consolidation and ground-glass abnormalities. A nasal swab sample tested positive for SARS-CoV-2 infection using reverse-transcription polymerase chain reaction. Thus, Sirolimus was suspended because of concern about its immunosuppressive action. She received hospital support following the institutional protocol in force at the time, without the need for invasive mechanical ventilation. After 2 weeks, she was discharged from the hospital, with supplemental oxygen at home and return of Sirolimus. CONCLUSIONS This report has described the presentation of COVID-19 pneumonia due to SARS-CoV-2 infection in a 34-year-old woman with a recent diagnosis of LAM involving the lungs.

Asymptomatic COVID-19: disease tolerance with efficient anti-viral immunity against SARS-CoV-2.

The immune responses and mechanisms limiting symptom progression in asymptomatic cases of SARS-CoV-2 infection remain unclear. We comprehensively characterized transcriptomic profiles, cytokine responses, neutralization capacity of antibodies, and cellular immune phenotypes of asymptomatic patients with acute SARS-CoV-2 infection to identify potential protective mechanisms. Compared to symptomatic patients, asymptomatic patients had higher counts of mature neutrophils and lower proportion of CD169+ expressing monocytes in the peripheral blood. Systemic levels of pro-inflammatory cytokines were also lower in asymptomatic patients, accompanied by milder pro-inflammatory gene signatures. Mechanistically, a more robust systemic Th2 cell signature with a higher level of virus-specific Th17 cells and a weaker yet sufficient neutralizing antibody profile against SARS-CoV-2 was observed in asymptomatic patients. In addition, asymptomatic COVID-19 patients had higher systemic levels of growth factors that are associated with cellular repair. Together, the data suggest that asymptomatic patients mount less pro-inflammatory and more protective immune responses against SARS-CoV-2 indicative of disease tolerance. Insights from this study highlight key immune pathways that could serve as therapeutic targets to prevent disease progression in COVID-19.