ABSTRACT Introduction: Lung injury and STAT1 deficit can induce EGFR overexpression in SARS-CoV2 infected cells. Methods: Considering the role of EGFR in inflammation and fibrosis, a Phase I/II trial was done to evaluate the safety and preliminary effect of nimotuzumab, a humanized anti-EGFR antibody, in severe and high-risk moderate patients with COVID-19. Patients were able to receive other drugs included in the national protocol. Treatment consisted on nimotuzumab intravenous infusions, administered every 72 hours. Before launching the study, EGFR expression was confirmed by immunohistochemistry in 20 lung samples from COVID-19 deceased subjects. Results: They were included forty-one patients (31 severe/10 moderate) in the trial. The median age was 62 years and the main comorbidities were hypertension, diabetes, cardiovascular disease and obesity. Seven patients received one dose of nimotuzumab, 29 received 2 infusions while 5 subjects required 3 doses. The antibody was very safe. There were only 4 related adverse events in 2 subjects. Eight patients required invasive mechanical ventilation. The 14 day recovery rate was 82,9%. 90% in moderate patients and 80,64 % in severe patients. Inflammatory markers decreased overtime and interleukin-6 concentration diminished from 46,5 pg/ml to 14,51 pg/ml at day 7. None of the evaluated patients showed signs of fibrosis in the follow-up evaluation. After the use of nimotuzumab in 1,536 patients in the real-world scenario, a high recovery rate was achieved in severe and moderate patients (89,4% and 79.4%, respectively), which compares very favorably with the phase I/II trial data. Conclusions: our results suggest that nimotuzumab is a safe antibody that can reduce inflammation and avoid fibrosis in severe and moderate COVID-19 patients at high risk of aggravation.

RESUMEN Introducción: La lesión pulmonar y el déficit del transductor de señal y el activador de la transcripción 1 (STAT1) inducen la sobreexpresión de receptor del factor de crecimiento epidérmico (EGFR) en células infectadas con SARS-CoV-2. Métodos: Teniendo en cuenta el papel del EGFR en la inflamación y la fibrosis, se realizó un ensayo de fase I/II para evaluar la seguridad y el efecto del nimotuzumab, un anticuerpo anti-EGFR humanizado, en pacientes con COVID-19 graves y moderados. Los pacientes recibieron otros medicamentos incluidos en el protocolo nacional. El tratamiento consistió en infusiones intravenosas de nimotuzumab, administradas cada 72 h. Antes de iniciar el estudio, la expresión de EGFR se confirmó mediante inmunohistoquímica en 20 muestras de pulmón de sujetos fallecidos por COVID-19. Resultados: En el ensayo se incluyeron 41 pacientes (31 graves/10 moderados). La media de edad fue de 62 años y las principales comorbilidades fueron hipertensión, diabetes, enfermedad cardiovascular y obesidad. Recibieron una dosis de nimotuzumab 7 pacientes, 29 recibieron 2 infusiones mientras que 5 sujetos requirieron 3 dosis. El anticuerpo fue seguro. Solo se detectaron 4 eventos adversos en 2 sujetos. Requirieron ventilación mecánica invasiva 8 pacientes. La tasa de recuperación a los 14 días fue del 82,9 %: pacientes moderados 90 % y 80,64 % en pacientes graves. Los marcadores inflamatorios disminuyeron en el tiempo y la concentración de interleucina-6 disminuyó de 46,5 pg/ml a 14,51 pg/ml el día 7. Ninguno de los pacientes evaluados mostró signos de fibrosis en el seguimiento. Tras el uso del nimotuzumab en 1536 pacientes en las condiciones del mundo real, se logró una alta tasa de recuperación en los pacientes graves y moderados (89,4 y 79,4 %, respectivamente), lo cual se compara muy favorablemente con los datos del ensayo fase I/II. Conclusiones: estos resultados sugieren que el nimotuzumab es un anticuerpo seguro que puede reducir la inflamación y evitar la fibrosis en pacientes con COVID-19 graves y moderados.

Abstract INTRODUCTIONSARS-CoV-2 infection can produce endothelial injury and microvascular damage, one cause of the multiorgan failure associated with COVID-19. Cerebrovascular endothelial damage increases the risk of stroke in COVID-19 patients, which makes prompt diagnosis important. Endothelial dysfunction can be evaluated by using transcranial Doppler ultrasound to study cerebral hemodynamic reserve, but there are few of these studies in patients with COVID-19, and the technique is not included in COVID-19 action and follow-up guidelines nationally or internationally. OBJECTIVEEstimate baseline cerebral hemodynamic patterns, cerebral hemodynamic reserve, and breath-holding index in recovered COVID-19 patients. METHODWe conducted an exploratory study in 51 people; 27 men and 24 women 20–78 years of age, divided into two groups. One group comprised 25 recovered COVID-19 patients, following clinical and epidemiological discharge, who suffered differing degrees of disease severity, and who had no neurological symptoms or disease at the time they were incorporated into the study. The second group comprised 26 people who had not been diagnosed with COVID-19 and who tested negative by RT-PCR at the time of study enrollment. Recovered patients were further divided into two groups: those who had been asymptomatic or had mild disease, and those who had severe or critical disease. We performed transcranial Doppler ultrasounds to obtain baseline and post-apnea tests of cerebral hemodynamic patterns to evaluate cerebral hemodynamic reserve and breath-holding indices. We characterized the recovered patient group and the control group through simple descriptive statistics (means and standard deviations). RESULTSThere were no measurable differences in baseline cerebral hemodynamics between the groups. However, cerebral hemodynamic reserve and breath-holding index were lower in those who had COVID-19 than among control participants (19.9% vs. 36.8% and 0.7 vs. 1.2 respectively). These variables were similar for patients who had asymptomatic or mild disease (19.9% vs.19.8%) and for those who had severe or critical disease (0.7 vs. 0.7). CONCLUSIONSPatients recovered from SARS-CoV-2 infection showed decreased cerebral hemodynamic reserve and breath-holding index regardless of the disease’s clinical severity or presence of neurological symptoms. These abnormalities may be associated with endothelial damage caused by COVID-19. It would be useful to include transcranial Doppler ultrasound in evaluation and follow-up protocols for patients with COVID-19.