Bevacizumab in Severe or Critical Patients With COVID-19 Pneumonia
Bevacizumab in Severe or Critical Patients With COVID-19 Pneumonia
The novel identified coronavirus (SARS-CoV-2) in 2019 causes an nationwide outbreak as well
 as public health crisis in China, and expands globally. Pulmonary edema is one of the most
 detrimental symptoms and usually presents in severe and critical coronavirus disease
 (COVID-19), resulting in dyspnea, acute lung injury (ALI) ,acute respiratory distress
 syndrome (ARDS), and even death. Recent evidence revealed higher levels of blood Vascular
 Endothelial Growth Factor (VEGF) in COVID-19 patients compared with healthy controls. VEGF is
 considered as the most potent vascular permeability inducers. Numerous studies have revealed
 that VEGF was a key factor and a potential therapeutic target in ALI and ARDS. Bevacizumab,
 an anti-VEGF drug, approved by the FDA on February 26, 2004 and widely used in clinical
 oncotherapy, is a promising drug for ALI/ARDS in COVID-19 through suppression of pulmonary
 edema.
In December 2019, a new identified coronavirus (SARS-CoV-2) outbreak in Wuhan, causes public
 health crisis in China and spreads worldwide. On February 11,2020, the World Health
 Organization officially named the disease caused by the new coronavirus "COVID-19". The
 Chinese Government takes stronger and harsher measures to control the progression of its
 outbreak. Meanwhile, five editions of "Diagnosis and Treatment for Novel Coronavirus-Infected
 Pneumonia" has been timely and continuously issued, which play extremely important roles in
 guiding the clinical management of COVID-19 nationwide in China.

 The symptoms of human infection with SARS-CoV-2 are generally fever, fatigue, dry cough and
 dyspnea. Noteworthy, a considerable percentage of COVID-19 cases have rapidly progressed to
 severe and critical type, among which acute lung injury (ALI) and acute respiratory distress
 syndrome (ARDS) are the most common complications, resulting in a large number of pneumonia
 hospitalized patients requiring supplemental oxygen, mechanical ventilation, or even
 ECMO.Pulmonary edema is a detrimental feature as well as a key causal factor of ALI/ARDS.

 Vascular Endothelial Growth Factor (VEGF) is considered as the most potent vascular
 permeability inducers. Recent evidence has revealed higher VEGF levels in COVID-19 patients
 compared with healthy controls. The rise of VEGF levels may be caused by hypoxia, severe
 inflammation, and upregulation of the infected respiratory tract epithelium itself. Numerous
 studies have confirmed a key role of VEGF as potential therapeutic target in acute lung
 injury (ALI) and acute respiratory distress syndrome (ARDS) due do increase vascular
 permeability and induce pulmonary edema.

 Thus, Bevacizumab, an anti-VEGF medication, may offer a unique approach to treat ALI/ARDS
 caused by COVID-19. Bevacizumab is a humanized monoclonal antibody with long half-life. It
 has been approved by the FDA on February 26, 2004 and widely used in clinical oncotherapy,
 with the pharmacokinetics and pharmacodynamics having been widely understood. Therefore,
 Bevacizumab is a promising drug for the treatment of ALI/ARDS as well as reduction of
 mortality in severe and critical COVID-19 patients through suppression of pulmonary edema.
Inclusion Criteria:

 1. Age 18 to 80.

 2. Confirmed COVID-19 diagnosis(including the clinically confirmed cases in Hubei).

 3. Accord with any of the following: respiratory distress, RR ≥ 30 breaths/min; or SpO2 ≤
 93% at rest; or partial arterial oxygen pressure (PaO2) / fraction of inspiration O2
 (FiO2) >100mmHg and ≤ 300mmHg (1mmHg = 0.133kPa).

 4. Chest imaging confirms lung involvement and has inflammatory exudation or pleural
 effusion.

 Exclusion Criteria:

 1. Cannot obtain informed consent.

 2. Severe hepatic dysfunction (Child Pugh score ≥ C, or AST> 5 times the upper limit);
 Severe renal dysfunction (estimated glomerular filtration rate ≤ 30mL / min / 1.73 m2)
 or receive continuous renal replacement therapy, hemodialysis, or peritoneal dialysis.

 3. Unsatisfactory controlled hypertension (seated systolic blood pressure> 160mmHg, or
 diastolic blood pressure> 100mmHg); previous history of hypertension crisis or
 hypertensive encephalopathy.

 4. Poorly controlled heart diseases, such as NYHA class II and above cardiac
 insufficiency, unstable angina pectoris, myocardial infarction within 1 year before
 enrollment, supraventricular or ventricular arrhythmia need treatment or intervention.

 5. Hereditary bleeding tendency or coagulopathy; received full-dose anticoagulant or
 thrombolytic therapy within10 days before enrollment, or have taken non-steroidal
 anti-inflammatory drugs with platelet suppression within 10 days before enrollment
 (Except those who use small doses of aspirin ≤325mg / day for preventive use).

 6. Thrombosis within 6 months before enrollment. And from those patients, screen who had
 arterial / venous thromboembolic events, such as, ischemic stroke, transient ischemic
 attack, deep venous thrombosis, pulmonary embolism, etc. within 1 year ahead of
 enrollment. Severe vascular disease (including aneurysms or arterial thrombosis
 requiring surgery) within 6 months before enrollment.

 7. Unhealed wounds, active gastric ulcers or fractures. Gastrointestinal perforation,
 gastrointestinal fistula, abdominal abscess, visceral fistula formation within 6
 months before enrollment. Major surgery (including preoperative Chest biopsy) or major
 trauma (such as a fracture) within 28 days before enrollment. May have surgery during
 the trial.

 8. Severe, active bleeding such as hemoptysis, gastrointestinal bleeding, central nervous
 system bleeding, and nosebleeds within 1 month before enrollment.

 9. Malignant tumors within 5 years before enrollment.

 10. Allergic to bevacizumab or its components.

 11. Untreated active hepatitis or HIV-positive patients.

 12. Pregnant and lactating women and those planning to get pregnant.

 13. Participated in other clinical trials, not considered suitable for this study by the
 researchers.