Devices and methods for treating viral infections and symptoms thereof

Abstract

By using the device and method of the present invention, COVID-19-mediated nanoparticles and / or exosomes associated with COVID-19 or a similar disease can be captured and removed from the circulatory system of a patient in need of removal of COVID-19-mediated nanoparticles and / or exosomes associated with COVID-19 or a similar disease (including patients with post-COVID-19 syndrome or patients showing symptoms of similar sequelae after the disease of COVID-19 or a similar disease).The present invention provides an extracorporeal circulation method using a lectin, which is characterized in that the virus load in blood infected with SARS-CoV-2 is reduced by binding SARS-CoV-2 virions or fragments thereof (e.g., glycoproteins derived from SARS-CoV-2) to the lectin and physically removing the SARS-CoV-2 virions or fragments thereof from the circulatory system. Furthermore, the present invention provides a lectin-based extracorporeal circulation method, which comprises binding non-viral COVID-19-mediated nanoparticles (e.g., exosomes and / or other biomolecules containing glycoproteins derived from SARS-CoV-2) to the lectin and physically removing the non-viral COVID-19-mediated nanoparticles from the circulatory system, thereby reducing the severity of the disease.

Description

[Technical Field]

[0001] Sequence Listing Reference This application has been filed with an electronic Sequence Listing, which is provided as a 687-byte file named SeqListingAETH037PR2.TXT, created on March 21, 2022. The information set forth in this electronic Sequence Listing is expressly incorporated herein by reference in its entirety.

[0002] The present invention relates to therapeutic methods and devices for treating or inhibiting viral infections, including coronavirus infections, betacoronavirus infections, or COVID-19 infections (including infections caused by COVID-19 variants) and the sequelae associated with these infections. Additionally, the present invention relates to the treatment of Epstein-Barr virus infections and / or their reactivation. Reactivation of Epstein-Barr virus infections can result from bacterial or viral (e.g., coronavirus) superinfections or other conditions. [Background technology]

[0003] The ongoing coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 virus is primarily spread through close contact with others or through droplets produced by an infected patient's cough, sneeze, or conversation. It can also be transmitted by touching a contaminated surface and then touching one's face. Furthermore, coronaviruses can survive on surfaces for up to 72 hours. While coronaviruses are most contagious during the first three days after the onset of symptoms, spread can occur before symptoms appear or in later stages of the disease. Common symptoms include fever, cough, and shortness of breath. Complications include pneumonia, acute respiratory distress syndrome, cardiac complications, neurological complications, septic shock, and death. Vaccines have only recently been approved. The emergence of various SARS-CoV-2 variants has raised concerns about the effectiveness of current vaccines.

[0004] The COVID-19 pandemic has caused significant losses in people's lives. Approximately 15–20% of patients develop severe respiratory distress syndrome or severe septic shock. Treating patients in such critical conditions is particularly challenging, requiring sedation, supplemental oxygen, and mechanical ventilation as life support. Furthermore, some patients continue to experience symptoms even after clearance of the coronavirus. Patients who develop post-acute sequelae (PASC) of COVID-19 have been reported to develop debilitating sequelae affecting the respiratory, cardiac, and neurological systems. The elderly and those with comorbidities have the highest rates of COVID-19 morbidity and COVID-19-related mortality.

[0005] Therefore, there is an urgent need for therapeutic intervention, especially for critically ill patients with advanced COVID-19 disease or those at high risk of developing advanced COVID-19 disease. Summary of the Invention [Means for solving the problem]

[0006] Aspects of the invention described herein include devices and methods for capturing and removing coronavirus, betacoronavirus, or COVID-19 viral particles (e.g., COVID-19 variant viral particles), or their associated subcellular nanoparticles (e.g., exosomes), or both such viral particles and their associated subcellular nanoparticles, from the circulatory system of a subject. The subject may be infected with such a coronavirus, have previously been infected with such a coronavirus, or exhibit sequelae from such an infection even after circulating virus levels have decreased compared to the initial or pre-infection period, or have previously been infected with such a virus and exhibit such sequelae. The subcellular nanoparticles may include viral particles or components thereof, or other molecules, such as cytokines, chemokines, miRNAs, and the like, that cause or are associated with coronavirus infection or its symptoms or sequelae (e.g., coagulopathy, hypoxia, etc.). Some embodiments described herein may directly benefit COVID-19 patients with active or cleared infection by providing a lectin-based extracorporeal circulation method. This method can treat or suppress COVID-19 infection or its symptoms or sequelae by binding subcellular nanoparticles (e.g., exosomes) or viral particles, or both, in a patient's blood to a lectin and physically removing the nanoparticles from the patient's blood. Some embodiments described herein provide a lectin-based extracorporeal circulation method that reduces exosome-mediated COVID-19 infection or its sequelae by binding non-viral COVID-19-mediated nanoparticles (e.g., exosomes) in the circulatory system to a lectin and physically removing the nanoparticles from the circulatory system, thereby improving total lymphocyte count levels or total lymphocyte counts or reducing the severity or onset of lymphopenia.Use of the devices and methods described herein in patients who are critically ill with severe COVID-19 disease due to SARS-CoV infection or who are at high risk for severe COVID-19 disease due to SARS-CoV infection can reduce the time on a ventilator, the likelihood of cardiac complications or blood clots, the likelihood of multiple organ failure, and the likelihood of acute kidney disease, sepsis, and / or other complications. More generally, further embodiments relate to the use of one or more lectin-based extracorporeal circulation methods to treat, inhibit, reduce, or ameliorate coagulopathy or hypoxia in a patient. The method involves binding subcellular nanoparticles (e.g., exosomes) and / or viral particles in the patient's blood to the lectin and physically removing them from the patient's blood, preferably, but not necessarily, a patient infected with or previously infected with a virus (e.g., COVID-19). Coagulopathy is a condition in which the coagulation system is activated and fibrin is formed in blood vessels. Coagulation disorders can impair blood flow and reduce oxygen delivery to tissues.

[0007] Embodiments of the methods described herein can be used to inhibit the development of coagulation disorders, such as COVID-19-associated coagulation disorders, or to inhibit the amount or levels of markers such as D-dimer, C-reactive protein, and / or troponin T. For example, in severe COVID-19 patients with compounds that contribute to coagulation disorders and / or systemic inflammation, the devices and methods described herein can be used to inhibit or reduce the production or abundance of circulating chemokines and / or circulating cytokines, such as IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, troponin T, or any combination thereof. The level or amount of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNF-α, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, may be measured in a patient's plasma or blood sample before the lectin-based extracorporeal circulation method is performed or after the lectin-based extracorporeal circulation method is completed (e.g., after 4 days or more of treatment).

[0008] Furthermore, the present invention relates to a method for removing coronaviruses or related subcellular nanoparticles, or both, from coronavirus-infected blood or plasma by using a lectin (e.g., snowdrop agglutinin (GNA), daffodil agglutinin (NPA), or cyanovirin from Nostoc ellipsosporum (referred to herein as cyanovirin)) in an extracorporeal circulation device, wherein the lectin binds to coronavirus, betacoronavirus, or COVID-19 viral particles (including viral particles of COVID-19 variants) or related subcellular nanoparticles (e.g., exosomes), or both these viral particles and related subcellular nanoparticles (in particular, SARS-CoV-2 virions or fragments thereof) and these coronavirus-related subcellular non-viral nanoparticles (e.g., exosomes). Accordingly, some embodiments provide a method of treating or inhibiting a coronavirus infection or a symptom or sequelae thereof in an individual, comprising: obtaining blood or plasma from an individual; Passing the blood or plasma through a filtration membrane (preferably a porous hollow fiber membrane) having a lectin molecule (e.g., snowdrop agglutinin (GNA), daffodil agglutinin (NPA), or Nostoc ellipsosporum-derived cyanovirin) immobilized on its outer portion (preferably a porous portion), and recovering the blood or plasma, or both, that have passed through the filtration membrane; and reinfusing the blood and / or plasma that has passed through the membrane into the individual. The present invention provides a method comprising:

[0009] For example, by passing blood through lectin-immobilized hollow fibers, SARS-CoV-2 virions and their fragments, as well as subcellular non-viral nanoparticles (e.g., exosomes) containing glycoproteins, can be bound to the lectin, thereby reducing the amount of virus and subcellular non-viral nanoparticles (e.g., exosomes) in the effluent. In some embodiments, lectins that bind to viral envelope proteins (e.g., spike proteins) of various coronavirus subtypes, variants, or mutants are used in the devices described herein. The methods described herein effectively reduce the number of SARS-CoV-2 virions and their fragments and subcellular non-viral nanoparticles (e.g., exosomes) in the blood, thereby enabling rapid recovery of patients from SARS-CoV-2 infection or its symptoms or sequelae.

[0010] Therefore, the present invention aims to provide a method for reducing the COVID-19 viral load in the blood of an individual infected with COVID-19. In one embodiment, COVID-19 virions or protein fragments thereof, or a combination thereof, are removed from the blood of an individual infected with the COVID-19 virus. The amount of exposure to the virus or the circulating viral load (e.g., the amount of virus detected in blood or plasma) in an individual may be measured, for example, by detecting the level of SARS CoV-2 RNA in plasma samples and nasopharyngeal samples (e.g., nasopharyngeal samples isolated from nasal swabs) obtained from the patient before each lectin-based extracorporeal circulation procedure, every two hours during treatment with the extracorporeal circulation procedure, and / or after completion of the treatment.

[0011] The present invention also provides a method for reducing the COVID-19 viral load or the amount of subcellular nanoparticles (e.g., exosomes), or both, in the blood or plasma of a patient infected with or who has previously been infected with COVID-19. The method comprises extracorporeally circulating the patient's blood through a cartridge containing hollow fibers onto which is immobilized a lectin (e.g., snowdrop agglutinin (GNA), daffodil agglutinin (NPA), or Nostoc ellipsosporum-derived cyanovirin) that has affinity for COVID-19 viral glycoproteins or other subcellular nanoparticles (e.g., exosomes). The patient is preferably identified, diagnosed, or selected as having or having previously been infected with COVID-19 before performing the method. Before or after performing the method, the COVID-19 viral load or a marker for COVID-19 infection may be measured in the patient in a biological sample, such as blood, nasal secretion, or saliva, or both. In some embodiments, the method is performed on a patient selected for having reduced, reduced, or absent amounts of COVID-19 viral particles circulating in their blood or plasma compared to the time of initial infection, but who still has sequelae attributable to COVID-19 infection, such as a patient with "long-term COVID syndrome," or a patient who has sequelae attributable to COVID-19 infection but no or negligible amounts of COVID-19 viral particles in their plasma or blood.

[0012] The present invention also provides a method for reducing the amount or level of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in the blood or plasma of a patient infected with or previously infected with a virus (e.g., COVID-19), comprising extracorporeally circulating the patient's blood through a cartridge containing hollow fibers onto which is immobilized a lectin (e.g., snowdrop agglutinin (GNA), daffodil agglutinin (NPA), or Nostoc ellipsosporum-derived cyanovirin) having affinity for COVID-19 viral glycoproteins or other subcellular nanoparticles (e.g., exosomes). Preferably, the patient has been identified, diagnosed, or selected as having or having previously been infected with COVID-19 prior to the method. Before or after performing the method, or both, a COVID-19 viral load or a marker of COVID-19 infection, or the level or amount of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, may be measured in a biological sample, such as the patient's blood, nasal secretions (e.g., nasal secretions isolated from a nasal swab), or saliva, for example.In some embodiments, the patient on whom the method is performed is a patient selected as having a reduced, reduced, or absent amount of COVID-19 viral particles circulating in their blood or plasma compared to the time of initial infection, but who is exhibiting sequelae attributable to COVID-19 infection, for example, a patient with "long-term COVID-19 sequelae," or a patient with sequelae attributable to COVID-19 infection, but who has no or negligible amounts of COVID-19 viral particles in their plasma or blood.

[0013] The present invention also provides a method for reducing the biomarker D-dimer in the blood or plasma of a patient, preferably (but not necessarily) infected with a virus (e.g., COVID-19) or a patient who has previously been infected with COVID-19, comprising extracorporeally circulating the patient's blood through a cartridge containing hollow fibers onto which is immobilized a lectin (e.g., snowdrop agglutinin (GNA), daffodil agglutinin (NPA), or Nostoc ellipsosporum-derived cyanovirin) that has affinity for COVID-19 viral glycoproteins or other subcellular nanoparticles (e.g., exosomes). The patient is preferably a patient who, prior to performing the method, has COVID-19 infection, a patient who has previously been infected with COVID-19 infection, or a patient identified, diagnosed, or selected as a patient in need of treatment and with elevated D-dimer levels (e.g., a patient with or at risk for a coagulation disorder). Before or after performing the method, or both, a COVID-19 viral load or a marker of COVID-19 infection, or the level of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), or troponin T, or any combination thereof, may be measured in a biological sample, such as the patient's blood, nasal secretions (e.g., isolated from a nasal swab), or saliva. In some embodiments, the patient on whom the method is performed is a patient selected as having a reduced, reduced, or absent amount of COVID-19 viral particles circulating in the blood compared to the initial infection, but exhibiting sequelae attributable to COVID-19 infection, for example, a patient with "long-term COVID syndrome," or a patient with sequelae attributable to COVID-19 infection but with no or negligible amounts of COVID-19 viral particles in their plasma or blood.

[0014] The present invention also provides a method for reducing the biomarker troponin T in the plasma or blood of a patient, preferably (but not necessarily) infected with a virus (e.g., COVID-19) or a patient who has previously been infected with COVID-19, comprising extracorporeally circulating the patient's blood through a cartridge containing hollow fibers onto which is immobilized a lectin (e.g., snowdrop agglutinin (GNA), daffodil agglutinin (NPA), or Nostoc ellipsosporum-derived cyanovirin) that has affinity for COVID-19 viral glycoproteins or other subcellular nanoparticles (e.g., exosomes). The patient is preferably identified, diagnosed, or selected as having or having previously been infected with COVID-19 prior to carrying out the method. Before or after performing the method, or both, a COVID-19 viral load or a marker of COVID-19 infection, or the level or amount of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), or D-dimer, or any combination thereof, may be measured in a biological sample, such as the patient's blood, nasal secretions (e.g., nasal secretions isolated from a nasal swab), or saliva. In some embodiments, the patient on whom the method is performed is a patient selected as having a reduced, reduced, or absent amount of COVID-19 viral particles circulating in their blood or plasma compared to the time of initial infection, but exhibiting sequelae attributable to COVID-19 infection, for example, a patient with "long-term COVID syndrome," or a patient with sequelae attributable to COVID-19 infection but with no or negligible amounts of COVID-19 viral particles in their plasma or blood.

[0015] The present invention also provides a method for reducing subcellular nanoparticles (e.g., exosomes) containing miR-424-5p (miR-424) or miR-16-2-3p (miR-16), or both, in the plasma or blood of a patient, preferably a patient infected with a virus (e.g., COVID-19) or a patient who has previously been infected with a virus (e.g., COVID-19), the method comprising extracorporeally circulating the patient's blood through a cartridge containing hollow fibers onto which is immobilized a lectin (e.g., snowdrop agglutinin (GNA), daffodil agglutinin (NPA), or Nostoc ellipsosporum-derived cyanovirin) having affinity for subcellular nanoparticles (e.g., exosomes, particularly exosomes containing miR-424 or miR-16, or both). Preferably, the patient has been identified, diagnosed, or selected, prior to carrying out the method, as a patient suffering from or having previously been infected with COVID-19. Before or after performing the method, or both, one may measure a COVID-19 viral load or a marker of COVID-19 infection, or the level or amount of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, or the amount of exosomes containing miR-424, miR-16, or both, in a biological sample, such as the patient's blood, nasal secretions (e.g., nasal secretions isolated from a nasal swab), or saliva. In some embodiments, the patient on whom the method is performed is a patient selected as having a reduced, reduced, or absent amount of COVID-19 viral particles circulating in the blood compared to the initial infection, but exhibiting sequelae attributable to COVID-19 infection, for example, a patient with "long-term COVID-19" syndrome, or a patient with sequelae attributable to COVID-19 infection but with no or negligible amounts of COVID-19 viral particles in their plasma or blood.

[0016] The present invention further provides a device for use in removing COVID-19 and / or non-viral glycoproteins or other subcellular nanoparticles, comprising hollow fibers, wherein a lectin (e.g., snowdrop agglutinin (GNA), daffodil agglutinin (NPA), or Nostoc ellipsosporum cyanovirin) is immobilized adjacent to the outer surface of the hollow fibers.

[0017] Preferred aspects of the present invention relate to the following numbered embodiments:

[0018] 1. A method for reducing SARS-CoV-2 virions or portions thereof in a COVID-19 patient in need thereof, comprising: a) introducing blood or plasma from a COVID-19 infected patient into an extracorporeal circulation device containing a lectin that binds to the SARS-CoV-2 virion or a portion thereof; b) contacting the patient's blood or plasma with the lectin in the extracorporeal circulation device for a time sufficient for SARS-CoV-2 virions or portions thereof in the blood or plasma to bind to the lectin; and c) returning to said patient the blood or plasma that has been subjected to step (b) and therefore has a reduced amount of SARS-CoV-2 virions or a portion thereof compared to said patient's blood or plasma before step (b) was performed. Including, d) detecting or identifying SARS-CoV-2 virions or portions thereof in a sample (e.g., a nasal sample (e.g., a nasal sample isolated from a nasal swab), a blood sample, a plasma sample, etc.) obtained from the patient before step (a) or after step (b), or both; and / or Selecting or identifying patients with COVID-19 for treatment that reduces the SARS-CoV-2 virion or a fragment thereof. The method may include:

[0019] 2. A method for reducing COVID-19 mediated nanoparticles in a COVID-19 patient in need thereof, comprising: a) introducing blood or plasma from a COVID-19 infected patient into an extracorporeal circulation device containing a lectin that binds to COVID-19-mediated nanoparticles; b) contacting the patient's blood or plasma with the lectin in the extracorporeal circulation device for a time sufficient for the COVID-19-mediated nanoparticles to bind to the lectin; and c) returning to the patient the blood or plasma that has been subjected to step (b) and therefore has a reduced amount of COVID-19-mediated nanoparticles compared to the patient's blood or plasma before step (b) was performed. Including, d) detecting or identifying SARS-CoV-2 virions or parts thereof or COVID-19-mediated nanoparticles in a sample (e.g., a nasal sample (e.g., a nasal sample isolated from a nasal swab), a blood sample, a plasma sample, etc.) obtained from the patient before step (a) or after step (b), or both; and / or Selecting or identifying patients with COVID-19 for treatment that reduces COVID-19-mediated nanoparticles. The method may include:

[0020] 3. A method for reducing COVID-19 antigen-containing exosomes in a COVID-19 patient, comprising: a) introducing blood or plasma from a COVID-19 infected patient into an extracorporeal circulation device containing a lectin that binds to COVID-19 antigen-containing exosomes; b) contacting the patient's blood or plasma with the lectin in the extracorporeal circulation device for a period of time sufficient for the COVID-19 antigen-containing exosomes to bind to the lectin; and c) returning to the patient the blood or plasma in which the amount of COVID-19 antigen-containing exosomes has been reduced as a result of step (b) compared to the patient's blood or plasma before step (b) has been performed. Including, d) detecting or identifying SARS-CoV-2 virions or portions thereof or COVID-19 antigen-containing exosomes in a sample (e.g., a nasal sample (e.g., a nasal sample isolated from a nasal swab), a blood sample, a plasma sample, etc.) obtained from the patient before step (a) or after step (b), or both; and / or Selecting or identifying patients with COVID-19 for treatment that reduces COVID-19 antigen-containing exosomes. The method may include:

[0021] 4. A method for reducing interleukin 6 (IL-6) in a COVID-19 patient, comprising: a) introducing blood or plasma from a COVID-19 infected patient into an extracorporeal circulation device containing a lectin that binds to SARS-CoV-2 virions or fragments thereof or COVID-19 antigen-containing exosomes; b) contacting the patient's blood or plasma with the lectin in the extracorporeal circulation device for a time sufficient for SARS-CoV-2 virions or fragments thereof or COVID-19 antigen-containing exosomes to bind to the lectin; and c) returning to the patient the blood or plasma in which the amount of SARS-CoV-2 virions or fragments thereof or COVID-19 antigen-containing exosomes has been reduced as a result of step (b) compared to the patient's blood or plasma before step (b). Including, d) measuring the level or amount of IL-6 in a sample (e.g., a blood sample, a plasma sample, etc.) obtained from the patient before step (a) or after step (b), or both; and Selecting or identifying patients with COVID-19 for treatment that reduces the level of IL-6. The method may include:

[0022] 5. A method for reducing the amount of circulating D-dimer in a COVID-19 patient, comprising: a) introducing blood or plasma from a COVID-19 infected patient into an extracorporeal circulation device containing a lectin that binds to SARS-CoV-2 virions or fragments thereof or COVID-19 antigen-containing exosomes; b) contacting the patient's blood or plasma with the lectin in the extracorporeal circulation device for a time sufficient for SARS-CoV-2 virions or fragments thereof or COVID-19 antigen-containing exosomes to bind to the lectin; and c) returning to the patient the blood or plasma in which the amount of SARS-CoV-2 virions or fragments thereof or COVID-19 antigen-containing exosomes has been reduced as a result of step (b) compared to the patient's blood or plasma before step (b). Including, d) measuring the level or amount of D-dimer in a sample (e.g., a blood sample, a plasma sample, etc.) obtained from the patient before step (a) or after step (b), or both; and Selecting or identifying patients with COVID-19 for D-dimer-reducing therapy. The method may include:

[0023] 6. A method for reducing the amount of troponin T in a COVID-19 patient, comprising: a) introducing blood or plasma from a COVID-19 infected patient into an extracorporeal circulation device containing a lectin that binds to SARS-CoV-2 virions or fragments thereof or COVID-19 antigen-containing exosomes; b) contacting the patient's blood or plasma with the lectin in the extracorporeal circulation device for a time sufficient for SARS-CoV-2 virions or fragments thereof or COVID-19 antigen-containing exosomes to bind to the lectin; and c) returning to the patient the blood or plasma in which the amount of SARS-CoV-2 virions or fragments thereof or COVID-19 antigen-containing exosomes has been reduced as a result of step (b) compared to the patient's blood or plasma before step (b). Including, d) measuring the level or amount of Troponin T in a sample (e.g., a blood sample, a plasma sample, etc.) obtained from the patient before step (a) or after step (b), or both; and Selecting or identifying patients with COVID-19 for treatment with a troponin T-reducing therapy. The method may include:

[0024] 7. A method for treating or suppressing coronavirus infection, or a symptom or sequelae thereof, in a patient in need thereof, comprising: a) introducing blood or plasma containing the coronavirus or a portion thereof, which has been taken from a patient suffering from coronavirus infection or symptoms or sequelae thereof, into an extracorporeal circulation device containing a lectin that binds to the coronavirus or a portion thereof; b) contacting the patient's blood or plasma with the lectin in the extracorporeal circulation device for a time sufficient for the coronavirus or a portion thereof in the blood or plasma to bind to the lectin; and c) returning to the patient the blood or plasma in which the amount of coronavirus or a part thereof has been reduced as a result of step (b) compared to the blood or plasma of the patient before step (b) was performed. Including, d) detecting or identifying a coronavirus or a portion thereof in a sample (e.g., a nasal sample (e.g., a nasal sample isolated from a nasal swab), a blood sample, a plasma sample, etc.) obtained from the patient before step (a) or after step (b), or both; and / or Selecting or identifying patients with coronavirus infection or its symptoms or sequelae for treatment to reduce the risk of the coronavirus or a portion thereof. The method may include:

[0025] 8. A method for treating or suppressing coronavirus infection or its symptoms or sequelae in a patient in need thereof, comprising: a) introducing blood or plasma containing exosomes associated with coronavirus infection or its symptoms or sequelae, which has been removed from a patient with coronavirus infection or its symptoms or sequelae, into an extracorporeal circulation device containing a lectin that binds to exosomes associated with coronavirus infection or its symptoms or sequelae; b) contacting the patient's blood or plasma with the lectin in the extracorporeal circulation device for a period of time sufficient to allow the exosomes in the blood or plasma to bind to the lectin; and c) returning to the patient the blood or plasma in which the amount of exosomes has been reduced compared to the blood or plasma of the patient before step (b) has been performed. Including, d) detecting or identifying the exosomes in a sample (e.g., a nasal sample, a blood sample, a plasma sample, etc.) obtained from the patient before step (a) or after step (b), or both; and / or Selecting or identifying a patient with coronavirus infection or its symptoms or sequelae for treatment that reduces exosomes. The method may include:

[0026] 9. A method of treating or inhibiting a coronavirus infection or a symptom or sequelae thereof in a patient in need thereof, wherein the symptom or sequelae comprises COVID-19 associated coagulation disorder (CAC), the method comprising: a) introducing blood or plasma containing CAC-associated exosomes, taken from a patient with CAC, into an extracorporeal circulation device containing a lectin that binds to CAC-associated exosomes; b) contacting the patient's blood or plasma with the lectin in the extracorporeal circulation device for a period of time sufficient to allow the exosomes in the blood or plasma to bind to the lectin; and c) returning to the patient the blood or plasma in which the amount of exosomes has been reduced compared to the blood or plasma of the patient before step (b) has been performed. Including, d) detecting or identifying the exosomes in a sample (e.g., a nasal sample, a blood sample, a plasma sample, etc.) obtained from the patient before step (a) or after step (b), or both; and / or Selecting or identifying a patient with CAC for treatment with the exosome-reducing therapy. The method may include:

[0027] 10. The method of any one of embodiments 7 to 9, wherein the symptoms or sequelae include reactivation of Epstein-Barr virus (EBV) in the patient.

[0028] 11. A method for treating Epstein-Barr virus (EBV) reactivation in a patient with a coronavirus infection, comprising: a) introducing blood or plasma containing coronavirus or a part thereof and EBV or a part thereof, which has been taken from a patient with coronavirus infection, into an extracorporeal circulation device containing lectins that bind to coronavirus or a part thereof and EBV or a part thereof; b) contacting the patient's blood or plasma with the lectin in the extracorporeal circulation device for a time sufficient for the coronavirus or portion thereof and EBV or portion thereof in the blood or plasma to bind to the lectin; and c) returning to the patient the blood or plasma in which the amount of coronavirus or a part thereof and EBV or a part thereof has been reduced as a result of step (b) compared to the blood or plasma of the patient before step (b) was performed. Including, d) detecting or identifying a coronavirus or a portion thereof and / or EBV or a portion thereof in a sample (e.g., a nasal sample (e.g., a nasal sample isolated from a nasal swab), a blood sample, a plasma sample, etc.) obtained from the patient before step (a) or after step (b), or both; and / or Selecting or identifying patients with coronavirus infection and / or EBV infection for treatment to reduce coronavirus or a portion thereof and / or EBV or a portion thereof. The method may include:

[0029] 12. The method of any one of embodiments 1 to 11, wherein the patient does not have a coronavirus infection before step (a), but is exhibiting symptoms or sequelae of a coronavirus infection.

[0030] 13. The method of any one of embodiments 1 to 12, wherein the patient has recovered from a coronavirus infection prior to step (a), but still exhibits symptoms or sequelae of a coronavirus infection.

[0031] 14. The method of any one of embodiments 1 to 13, wherein the patient's blood or plasma is coronavirus-free before step (a) is performed, but the patient still exhibits symptoms or sequelae of coronavirus infection.

[0032] 15. The method of any one of embodiments 1-14, further comprising the step of determining, before step (a) or after step (b), or both, whether the patient has early acute lung injury (ALI), early acute respiratory distress syndrome (ARDS), dyspnea, respiratory frequency of 30 breaths / minute or more, blood oxygen saturation of 93% or less, arterial oxygen tension to fractional inspired oxygen ratio of less than 300, pulmonary infiltrates of more than 50%, respiratory failure within 24 to 48 hours, elevated ferritin level, elevated lactate level, elevated lactate dehydrogenase (LDH) level, decreased absolute lymphocyte count (ALC), decreased platelet count, prolonged prothrombin time international normalized ratio (PT / INR), septic shock, or multiple organ dysfunction or failure, or any combination thereof.

[0033] 16. The method of any one of embodiments 1 to 15, further comprising determining whether the patient has an elevated level or amount of IL-6 before step (a) or after step (b), or both.

[0034] 17. The method of embodiment 16, wherein the elevated serum IL-6 level is 2 pg / mL or greater.

[0035] 18. The method of any one of embodiments 1-17, further comprising determining whether the patient has an elevated level or amount of D-dimer before step (a) or after step (b), or both.

[0036] 19. The method of embodiment 18, wherein the elevated serum DD-dimer level is 500 ng / mL or greater.

[0037] 20. The method of any one of embodiments 1-19, further comprising determining whether the patient has an elevated level or amount of Troponin T before step (a) or after step (b), or both.

[0038] 21. The method of embodiment 20, wherein the elevated serum troponin T level is 15 ng / L or greater.

[0039] 22. The method of any one of embodiments 1 to 21, wherein the lectin is snowdrop agglutinin (GNA).

[0040] 23. The method of any one of embodiments 1 to 22, wherein the extracorporeal circulation device comprises a hollow fiber cartridge containing the lectin, and the blood or plasma flows through hollow fibers of the hollow fiber cartridge.

[0041] 24. The method of embodiment 23, wherein the hollow fibers of the hollow fiber cartridge have a pore size that does not allow cellular components in the blood or plasma to pass through, so that the lectin does not come into contact with cellular components in the blood or plasma.

[0042] 25. The method of embodiment 24, wherein the pore size is 200 nm or about 200 nm.

[0043] 26. The method of any one of embodiments 20 to 25, wherein the lectin is immobilized or adsorbed on a solid support, and the hollow fiber cartridge comprises the lectin immobilized or adsorbed on the solid support.

[0044] 27. The method of embodiment 26, wherein the solid carrier comprises diatomaceous earth.

[0045] 28. The method according to any one of embodiments 1 to 27, further comprising the step of isolating coronavirus virions or parts thereof bound to the lectin contained in the extracorporeal circulation device.

[0046] 29. The method according to any one of embodiments 1 to 28, further comprising the step of isolating exosomes associated with a coronavirus infection or a symptom or sequelae thereof, bound to a lectin contained in the extracorporeal circulation device.

[0047] 30. The method of embodiment 29, further comprising examining the contents of the isolated exosomes.

[0048] 31. The method of embodiment 29 or 30, wherein the exosomes associated with a coronavirus infection or a symptom or sequelae thereof comprise miR-424-5p or miR-16-2-3p or both.

[0049] 32. The method of any one of embodiments 1 to 31, further comprising observing or measuring a decrease in the number of coronavirus virions or portions thereof, or a decrease in the number of exosomes associated with coronavirus infection or its symptoms or sequelae, in the patient's blood sample obtained after step (b) compared to the patient's blood sample obtained before step (b); or measuring the relative level or amount of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in the patient's blood sample obtained after step (b) compared to the patient's blood sample obtained before step (b).

[0050] 33. The method of any one of embodiments 1 to 32, further comprising observing an improvement in the coronavirus infection or symptoms or sequelae thereof in the patient who has undergone step (b) or step (c), or both.

[0051] 34. The method of embodiment 33, wherein observing the improvement of coronavirus infection or its symptoms or sequelae comprises determining in the patient an improvement in early acute lung injury (ALI), early acute respiratory distress syndrome (ARDS), respiratory frequency, blood oxygen saturation, arterial oxygen tension to fractional inspired oxygen ratio, pulmonary infiltrates, respiratory failure, ferritin, lactate, LDH, absolute lymphocyte count (ALC), platelet count, PT / INR ratio, septic shock, or multiple organ dysfunction or failure, or any combination thereof.

[0052] 35. The method of embodiment 33 or 34, wherein the step of observing an improvement in the coronavirus infection or its symptoms or sequelae comprises observing a decrease in the number of coronavirus virions or portions thereof, or a decrease in the number of exosomes associated with the coronavirus infection or its symptoms or sequelae in the patient compared to before treatment; or measuring the relative level or amount of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in the patient compared to before treatment.

[0053] 36. The method of any one of embodiments 7 to 35, wherein the coronavirus infection is caused by a coronavirus selected from SARS-CoV-2, SARS-CoV-1, MERS-CoV, HCoV-229E, HCoV-OC43, HCoV NL63, and HCoV-HKU1.

[0054] 37. The method of embodiment 36, wherein the SARS-CoV-2 is a SARS-CoV-2 mutant strain.

[0055] 38. The SARS-CoV-2 variant strain is 20I / 501Y.V1 (alpha strain, B.1.1.7), 20H / 501Y.V2 (beta strain, B.1.351), 20J / 501Y.V3 (gamma strain, P.1), B.1.617.2 (delta strain), AY.1, AY.2, C.37 (lambda strain), B.1.621 (mu strain), B.1.1.207, VUI-202102 / 03 (B.1.525), VUI-202101 / 01 (P2), VUI-202102 / 01 (A.23.1), VUI 202102 / 04 (B.1.1.318), VUI 202103 / 01 (B.1.324.1), B.1.427, CAL.20C (B.1.429), R.1, B.1.466.2, B.1.1.519, C.36.3, B.1.214.2, B.1.1.523, B.1.619, B.1.620, C.1.2, B.1.617.1, B.1.1.529 (Omicron strain), and B.1.526.

[0056] 39. The method according to any one of embodiments 1 to 38, wherein, before carrying out step (a), blood clotting is prevented by priming the extracorporeal circulation device with an anticoagulant, preferably heparin.

[0057] 40. The method according to any one of embodiments 1 to 39, wherein the flow rate of the blood flowing through the extracorporeal circulation device is about 50 to about 600 mL / min, preferably about 200 to about 400 mL / min, and preferably about 200 to about 240 mL / min.

[0058] 41. The method of any one of embodiments 1-40, wherein returning the blood to the patient comprises flushing the extracorporeal circulation device with saline.

[0059] 42. The method of any one of embodiments 1 to 41, wherein the contact time of the blood or plasma with the extracorporeal circulation device is 0.1 hours, 0.2 hours, 0.3 hours, 0.4 hours, 0.5 hours, 0.6 hours, 0.7 hours, 0.8 hours, 0.9 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours, or a range of any two of these times.

[0060] 43. The method of any one of embodiments 1-42, wherein steps (a), (b) and (c) and optional step (d) are repeated daily for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days or 15 days.

[0061] 44. An extracorporeal circulation device containing a lectin for use in treating a coronavirus infection or its symptoms or sequelae in a patient in need of such treatment; or for use in reducing the levels or amounts of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in a patient in need of such reduction.

[0062] 45. An extracorporeal circulation device comprising a lectin for use in treating COVID-19 associated coagulation disorders in a patient in need thereof.

[0063] 46. ​​An extracorporeal circulation device containing a lectin for use in a method for treating a coronavirus infection or a symptom or sequelae thereof in a patient in need thereof, said method comprising the steps of: flowing blood removed from the patient through said extracorporeal circulation device to contact the blood with the lectin to obtain treated blood; and returning said treated blood to the patient.

[0064] 47. The extracorporeal circulation device of embodiment 44 or 45, wherein the symptoms or sequelae include reactivation of EBV in the patient.

[0065] 48. An extracorporeal circulation device containing lectin for use in treating EBV reactivation in patients with coronavirus infection.

[0066] 49. The extracorporeal circulation device according to any one of embodiments 44 to 48, wherein the lectin is snowdrop agglutinin.

[0067] 50. An extracorporeal circulation device according to any one of embodiments 44 to 49, wherein the extracorporeal circulation device comprises a hollow fiber cartridge containing the lectin, and the patient's blood flows through the hollow fibers of the hollow fiber cartridge.

[0068] 51. The extracorporeal circulation device according to embodiment 50, wherein the lectin is immobilized or adsorbed on a solid support, and the hollow fiber cartridge comprises the lectin immobilized or adsorbed on the solid support.

[0069] 52. The extracorporeal circulation device of embodiment 51, wherein the solid carrier comprises diatomaceous earth.

[0070] 53. An extracorporeal circulation device according to any one of embodiments 44 to 52, wherein the lectin selectively binds to a coronavirus virion or a part thereof, an exosome associated with a coronavirus infection or its symptoms or sequelae, or any combination thereof.

[0071] 54. An extracorporeal circulation device according to any one of embodiments 44 to 53, wherein the coronavirus infection is caused by a coronavirus selected from SARS-CoV-2, SARS-CoV-1, MERS-CoV, HCoV-229E, HCoV-OC43, HCoV NL63 and HCoV-HKU1.

[0072] 55. An extracorporeal circulation device as described in embodiment 54, wherein the SARS-CoV-2 is a SARS-CoV-2 mutant strain.

[0073] 56. The SARS-CoV-2 variant strain is 20I / 501Y.V1 (alpha strain, B.1.1.7), 20H / 501Y.V2 (beta strain, B.1.351), 20J / 501Y.V3 (gamma strain, P.1), B.1.617.2 (delta strain), AY.1, AY.2, C.37 (lambda strain), B.1.621 (mu strain), B.1.1.207, VUI-202102 / 03 (B.1.525), VUI-202101 / 01 (P2), VUI-202102 / 01 (A.23.1), VUI 202102 / 04 (B.1.1.318), VUI 56. The extracorporeal circulation device of embodiment 55, wherein the circulatory system is selected from 202103 / 01 (B.1.324.1), B.1.427, CAL.20C (B.1.429), R.1, B.1.466.2, B.1.1.519, C.36.3, B.1.214.2, B.1.1.523, B.1.619, B.1.620, C.1.2, B.1.617.1, B.1.1.529 (Omicron strain) and B.1.526.

[0074] 57. An extracorporeal circulation device described in any one of embodiments 44 to 56, wherein the extracorporeal circulation device is used for 0.1 hours, 0.2 hours, 0.3 hours, 0.4 hours, 0.5 hours, 0.6 hours, 0.7 hours, 0.8 hours, 0.9 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours or 10 hours per session, or for a period within a range defined by any two of these periods.

[0075] 58. An extracorporeal circulation device according to any one of embodiments 44 to 57, wherein the extracorporeal circulation device is used daily for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days or 15 days.

[0076] 59. A method for reducing exosomes containing miR-424-5p or miR-16-2-3p, or both, in a patient, preferably a patient suffering from or having a coronavirus infection (e.g., COVID-19), comprising: a) introducing blood or plasma taken from a patient into an extracorporeal circulation device containing a lectin (e.g., GNA, NPA, or cyanovirin) that binds to the exosomes; b) contacting the patient's blood or plasma with the lectin in the extracorporeal circulation device for a period of time sufficient for the exosomes to bind to the lectin; and c) returning to the patient the blood or plasma in which the amount of exosomes has been reduced compared to the blood or plasma of the patient before step (b) has been performed. Including, d) detecting or identifying exosomes containing miR-424-5p or miR-16-2-3p, or both, in a sample (e.g., a nasal sample (e.g., a nasal sample isolated from a nasal swab), a blood sample, a plasma sample, etc.) obtained from the patient before step (a) or after step (b), or both; and / or Selecting or identifying patients with COVID-19 for treatment that reduces exosomes containing miR-424-5p or miR-16-2-3p, or both. The method may include:

[0077] 60. The method of embodiment 59, wherein the patient does not have a coronavirus infection (e.g., COVID-19) before step (a), but is exhibiting symptoms or after-effects of a coronavirus infection.

[0078] 61. The method of embodiment 59 or 60, wherein the patient has recovered from a coronavirus infection (e.g., COVID-19) prior to step (a) but still exhibits symptoms or after-effects of a coronavirus infection.

[0079] 62. The method of any one of embodiments 59-61, wherein the patient's blood or plasma is free of coronavirus (e.g., COVID-19) before step (a) is performed, but the patient still exhibits symptoms or sequelae of coronavirus infection.

[0080] 63. The method of any one of embodiments 59-62, further comprising, before step (a) or after step (b), or both, determining whether the patient has early acute lung injury (ALI), early acute respiratory distress syndrome (ARDS), dyspnea, respiratory frequency of 30 breaths / min or more, blood oxygen saturation of 93% or less, arterial oxygen tension to inspired oxygen ratio of less than 300, pulmonary infiltrates of more than 50%, respiratory failure within 24 to 48 hours, elevated ferritin level, elevated lactate level, elevated lactate dehydrogenase (LDH) level, decreased absolute lymphocyte count (ALC), decreased platelet count, prolonged prothrombin time international normalized ratio (PT / INR), septic shock, or multiple organ dysfunction or failure, or any combination thereof.

[0081] 64. The method of any one of embodiments 59-63, further comprising determining whether the patient has an elevated level or amount of IL-6 before step (a) or after step (b), or both.

[0082] 65. The method of embodiment 64, wherein the elevated serum IL-6 level is 2 pg / mL or greater.

[0083] 66. The method of any one of embodiments 59-65, further comprising determining whether the patient has an elevated level or amount of D-dimer before step (a) or after step (b), or both.

[0084] 67. The method of embodiment 66, wherein the elevated serum DD-dimer level is 500 ng / mL or greater.

[0085] 68. The method of any one of embodiments 59-67, further comprising determining whether the patient has an elevated level or amount of Troponin T before step (a) or after step (b), or both.

[0086] 69. The method of embodiment 68, wherein the elevated serum troponin T level is 15 ng / L or greater.

[0087] 70. The method of any one of embodiments 59 to 69, wherein the lectin is snowdrop agglutinin (GNA).

[0088] 71. The method of any one of embodiments 59-70, further comprising observing or measuring a decrease in the number of coronavirus virions or parts thereof, or a decrease in the number of exosomes associated with coronavirus infection or its symptoms or sequelae, in the patient's blood sample obtained after step (b) compared to the patient's blood sample obtained before step (b); or measuring the relative level or amount of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in the patient's blood sample obtained after step (b) compared to the patient's blood sample obtained before step (b).

[0089] 72. The method of any one of embodiments 59 to 71, wherein the coronavirus infection is caused by a coronavirus selected from SARS-CoV-2, SARS-CoV-1, MERS-CoV, HCoV-229E, HCoV-OC43, HCoV NL63, and HCoV-HKU1.

[0090] 73. The method of embodiment 72, wherein the SARS-CoV-2 is a SARS-CoV-2 mutant strain.

[0091] 74. The SARS-CoV-2 variant strain is 20I / 501Y.V1 (alpha strain, B.1.1.7), 20H / 501Y.V2 (beta strain, B.1.351), 20J / 501Y.V3 (gamma strain, P.1), B.1.617.2 (delta strain), AY.1, AY.2, C.37 (lambda strain), B.1.621 (mu strain), B.1.1.207, VUI-202102 / 03 (B.1.525), VUI-202101 / 01 (P2), VUI-202102 / 01 (A.23.1), VUI 202102 / 04 (B.1.1.318), VUI 202103 / 01 (B.1.324.1), B.1.427, CAL.20C (B.1.429), R.1, B.1.466.2, B.1.1.519, C.36.3, B.1.214.2, B.1.1.523, B.1.619, B.1.620, C.1.2, B.1.617.1, B.1.1.529 (Omicron strain), and B.1.526.

[0092] 75. A method for immobilizing the spike protein or a portion thereof of SARS-CoV-2 or a SARS-CoV-2 mutant, or a viral fragment comprising the spike protein or a portion thereof of SARS-CoV-2 or a SARS-CoV-2 mutant, comprising: A method comprising the step of contacting a spike protein or a portion thereof of SARS-CoV-2 or a SARS-CoV-2 variant, or a viral fragment comprising the spike protein or a portion thereof of SARS-CoV-2 or a SARS-CoV-2 variant, with a lectin immobilized on a carrier such as beads, resin, dish, tube, or filter, to provide an immobilized spike protein or a portion thereof of SARS-CoV-2 or a SARS-CoV-2 variant, or an immobilized viral fragment comprising the spike protein or a portion thereof of SARS-CoV-2 or a SARS-CoV-2 variant.

[0093] 76. The spike protein of the SARS-CoV-2 variant strain is 20I / 501Y.V1 (alpha strain, B.1.1.7), 20H / 501Y.V2 (beta strain, B.1.351), 20J / 501Y.V3 (gamma strain, P.1), B.1.617.2 (delta strain), AY.1, AY.2, C.37 (lambda strain), B.1.621 (mu strain), B.1.1.207, VUI-202102 / 03 (B.1.525), VUI-202101 / 01 (P2), VUI-202102 / 01 (A.23.1), VUI 202102 / 04 (B.1.1.318), VUI 76. The method of embodiment 75, wherein the spike protein is derived from a virus selected from 202103 / 01 (B.1.324.1), B.1.427, CAL.20C (B.1.429), R.1, B.1.466.2, B.1.1.519, C.36.3, B.1.214.2, B.1.1.523, B.1.619, B.1.620, C.1.2, B.1.617.1, B.1.1.529 (Omicron strain), and B.1.526.

[0094] 77. The method of embodiment 75 or 76, wherein the lectin is GNA, NPA or cyanovirin.

[0095] 78. The method of any one of embodiments 75 to 77, wherein the immobilized lectin is provided in a column or cartridge, the column or cartridge being configured for extracorporeal circulation in a patient.

[0096] 79. A method for treating or attenuating or suppressing Epstein-Barr virus (EBV) infection in a patient in need thereof, comprising: a) introducing blood or plasma containing EBV or a portion thereof, taken from a patient, into an extracorporeal circulation device containing a lectin that binds to EBV or a portion thereof; b) contacting the patient's blood or plasma with the lectin in the extracorporeal circulation device for a time sufficient for EBV or a portion thereof in the blood or plasma to bind to the lectin; and c) returning to the patient the blood or plasma in which the amount of EBV or a part thereof has been reduced as a result of step (b) compared to the blood or plasma of the patient before step (b) was performed. Including, d) detecting or identifying EBV or a portion thereof in a sample (e.g., a nasal sample (e.g., a nasal sample isolated from a nasal swab), a blood sample, a plasma sample, etc.) obtained from the patient before step (a) or after step (b), or both; and / or Selecting or identifying a patient with EBV infection for treatment to reduce EBV or a portion thereof. The method may include:

[0097] 80. The method of embodiment 79, wherein the patient has a latent EBV infection that has reactivated to develop an active EBV infection.

[0098] 81. The method of embodiment 79 or 80, wherein the patient exhibits symptoms of EBV infection before step (a).

[0099] 82. The method of any one of embodiments 79 to 81, wherein the patient's EBV infection is induced by a bacterial or viral superinfection, and may be induced by a coronavirus superinfection.

[0100] 83. The method of embodiment 82, wherein the coronavirus co-infection is caused by a coronavirus selected from SARS-CoV-2, SARS-CoV-1, MERS-CoV, HCoV-229E, HCoV-OC43, HCoV NL63, and HCoV-HKU1.

[0101] 84. The method of embodiment 83, wherein the SARS-CoV-2 is a SARS-CoV-2 mutant strain.

[0102] 85. The SARS-CoV-2 variant strain is 20I / 501Y.V1 (alpha strain, B.1.1.7), 20H / 501Y.V2 (beta strain, B.1.351), 20J / 501Y.V3 (gamma strain, P.1), B.1.617.2 (delta strain), AY.1, AY.2, C.37 (lambda strain), B.1.621 (mu strain), B.1.1.207, VUI-202102 / 03 (B.1.525), VUI-202101 / 01 (P2), VUI-202102 / 01 (A.23.1), VUI 202102 / 04 (B.1.1.318), VUI 202103 / 01 (B.1.324.1), B.1.427, CAL.20C (B.1.429), R.1, B.1.466.2, B.1.1.519, C.36.3, B.1.214.2, B.1.1.523, B.1.619, B.1.620, C.1.2, B.1.617.1, B.1.1.529 (Omicron strain), and B.1.526.

[0103] 86. The method of any one of embodiments 79-81, wherein the EBV infection is associated with multiple sclerosis, an autoimmune disease and / or malignant cancer in the patient.

[0104] 87. The method of embodiment 86, wherein the malignant cancer comprises Burkitt's lymphoma, Hodgkin's lymphoma, T / NK-cell lymphoma, gastric cancer, breast cancer, nasopharyngeal carcinoma, glioblastoma multiforme, or post-transplant lymphoproliferative disorder.

[0105] 88. The method of any one of embodiments 79 to 87, wherein the lectin is snowdrop agglutinin (GNA).

[0106] 89. The method of any one of embodiments 79 to 88, wherein the extracorporeal circulation device comprises a hollow fiber cartridge containing the lectin, and the blood or plasma flows through the hollow fibers of the hollow fiber cartridge.

[0107] 90. The method of embodiment 89, wherein the hollow fibers of the hollow fiber cartridge have a pore size that does not allow cellular components in the blood or plasma to pass through, so that the lectin does not come into contact with cellular components in the blood or plasma.

[0108] 91. The method of embodiment 90, wherein the pore size is 200 nm or about 200 nm.

[0109] 92. The method of any one of embodiments 79 to 91, wherein the lectin is immobilized or adsorbed on a solid support, and the hollow fiber cartridge comprises the lectin immobilized or adsorbed on the solid support.

[0110] 93. The method of embodiment 92, wherein the solid carrier comprises diatomaceous earth.

[0111] 94. The method according to any one of embodiments 79 to 93, further comprising the step of isolating EBV virions or parts thereof bound to the lectin contained in said extracorporeal circulation device.

[0112] 95. The method according to any one of embodiments 79 to 94, further comprising the step of isolating exosomes associated with EBV infection or symptoms or sequelae thereof, bound to a lectin contained in the extracorporeal circulation device.

[0113] 96. The method of embodiment 95, further comprising examining the contents of the isolated exosomes.

[0114] 97. The method of any one of embodiments 79-96, further comprising the step of observing an improvement in EBV infection or symptoms or sequelae thereof in patients who have undergone step (b) or step (c), or both.

[0115] 98. A method according to any one of embodiments 79 to 97, wherein, before carrying out step (a), blood clotting is prevented by priming the extracorporeal circulation device with an anticoagulant, preferably heparin.

[0116] 99. The method according to any one of embodiments 79 to 98, wherein the flow rate of the blood flowing through the extracorporeal circulation device is about 50 to about 600 mL / min, preferably about 200 to about 400 mL / min, preferably about 200 to about 240 mL / min.

[0117] 100. The method of any one of embodiments 79-99, wherein returning the blood to the patient comprises flushing the extracorporeal circulation device with saline.

[0118] 101. The method of any one of embodiments 79 to 100, wherein the contact time of the blood or plasma with the extracorporeal circulation device is 0.1 hours, 0.2 hours, 0.3 hours, 0.4 hours, 0.5 hours, 0.6 hours, 0.7 hours, 0.8 hours, 0.9 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours, or a range of any two of these times.

[0119] 102. The method of any one of embodiments 79-101, wherein steps (a), (b) and (c) and optional step (d) are repeated daily for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days or 15 days.

[0120] 103. An extracorporeal circulation device comprising a lectin for use in treating EBV infection in a patient in need thereof.

[0121] 104. The extracorporeal circulation device of embodiment 103, wherein the patient has a latent EBV infection that has reactivated to develop an active EBV infection.

[0122] 105. The extracorporeal circulation device described in embodiment 104, wherein the reactivation of EBV in the patient is induced by bacterial or viral superinfection, and may be induced by coronavirus superinfection.

[0123] 106. The extracorporeal circulation device described in embodiment 103, wherein the EBV infection is associated with multiple sclerosis, an autoimmune disease and / or malignant cancer in the patient.

[0124] 107. The method of embodiment 106, wherein the malignant cancer comprises Burkitt's lymphoma, Hodgkin's lymphoma, T / NK cell lymphoma, gastric cancer, breast cancer, nasopharyngeal carcinoma, glioblastoma multiforme, or post-transplant lymphoproliferative disorder. [Brief explanation of the drawings]

[0125] Further features and variations other than those described above will be readily apparent from the following description of the drawings and exemplary embodiments, which illustrate representative embodiments and are not intended to limit the scope of the present invention.

[0126] [Figure 1] FIG. 2 is a schematic longitudinal cross-sectional view of an affinity cartridge.

[0127] [Figure 2] 2 is a horizontal cross-sectional view taken along plane 2 in FIG. 1. FIG.

[0128] [Figure 3] 3 is a diagram illustrating the flow path shown in Figure 2. The hollow fiber membrane structure 40 includes a tubular portion with a relatively dense ultrafiltration membrane 42 and a relatively porous outer portion 44, to which an affinity molecule 46 (e.g., a lectin) may be immobilized.

[0129] [Figure 4]This graph shows the capture of SARS-CoV-2 spike 1 (S1) glycoprotein by a lectin-containing affinity cartridge. In vitro experiments were performed by continuously circulating a solution containing SARS-CoV-2 S1 glycoprotein through a porous hollow fiber membrane device. In this device, a lectin molecule consisting of snowdrop agglutinin (GNA) was immobilized on the outer porous portion of the hollow fiber membrane. Briefly, 10 mL of a 1 μg / mL solution of SARS-CoV-2 S1 in phosphate-buffered saline was injected into a porous hollow fiber membrane device filled with 0.7 g of affinity resin containing GNA and circulated at a flow rate of 50 mL / min. Fluid samples were collected at predetermined time intervals, and the capture rate of the viral S1 glycoprotein was measured as the percentage of S1 remaining in solution over time. A control was S1 glycoprotein left on the bench (i.e., S1 glycoprotein not passed through the column device). Experimental results showed that the lectin-containing affinity capture device cleared SARS-CoV-2 glycoproteins from the solution.

[0130] [Figure 5] This indicates that the patient sample contained no detectable SARS-CoV-2 RNA. Positive control PCR using a SARS-CoV-2 nucleic acid template demonstrated amplification of the SARS-CoV-2 spike (S) and nucleocapsid (N) proteins and ORF1ab sequences. When identical reactions were performed using plasma samples from the patient, none of these three SARS-CoV-2 genes were amplified. Co-amplification of an RNAse P control gene (either as part of the control template or as RNA isolated from the plasma sample) confirmed that the nucleic acids of the constituent RNAs were intact in the samples before and during the reaction. Therefore, this patient did not have circulating COVID-19 virions.

[0131] [Figure 6A]1 shows the decrease in nanoparticle concentration in untreated plasma obtained from patients treated with Hemopurifier®. "Before treatment" (t=0) indicates measurements from samples obtained before treatment, and "after treatment" (t=6) indicates measurements from samples obtained after treatment.

[0132] [Figure 6B] Particle size populations in untreated patient plasma are shown. No change in particle size populations was observed before or after treatment with Hemopurifier. "Before treatment" (t=0) indicates measurements from a sample obtained before treatment, and "after treatment" (t=6) indicates measurements from a sample obtained after treatment.

[0133] [Figure 7A] Figure 1 shows the reduction in circulating exosome concentrations in fractionated samples obtained from plasma of patients treated with Hemopurifier. "Before treatment" (t=0) shows the measurement results for samples obtained before treatment, and "after treatment" (t=6) shows the measurement results for samples obtained after treatment.

[0134] [Figure 7B] This shows the particle size of the exosome population contained in the fraction sample obtained from the patient's plasma. No change in the particle size of the exosome population was observed before and after treatment with Hemopurifier. "Before treatment" (t=0) shows the measurement results for the sample obtained before treatment, and "after treatment" (t=6) shows the measurement results for the sample obtained after treatment.

[0135] [Figure 8] The figure shows the amplification plot of qRT-PCR performed by adding cel-miR-39-3p (cel-39) derived from Caenorhabditis elegans to the exosome fraction as a spike-in control.

[0136] [Figure 9]An example of a qRT-PCR amplification plot of tested miRNAs in the exosomal fraction from a patient's plasma sample is shown. The miRNAs tested were human miR-424-5p (miR-424) and human miR-16-2-3p (miR-16).

[0137] [Figure 10] The difference in miRNA abundance in exosome fractions obtained from patient plasma samples during and after treatment with Hemopurifier compared to controls is shown.

[0138] [Figure 11] Correlation between treatment-induced exosome clearance and reduction of miRNAs (tested on days 2–4).

[0139] [Figure 12A] Relative abundance of miRNAs in day 4 whole plasma samples from COVID-19 patients versus controls is shown.

[0140] [Figure 12B] Figure 1 shows that the relative decrease in initial miRNA abundance was greater in the treated exosome fraction than in untreated plasma from COVID-19 patients.

[0141] [Figure 13A] The abundance of miRNAs (miR-424 and miR-16) and exosomes in patient samples obtained on days 1 and 4 of treatment are shown.

[0142] [Figure 13B] The abundance of miRNAs (miR-424 and miR-16) and exosomes in patient samples obtained on days 5 and 8 of treatment are shown.

[0143] [Figure 14] FIG. 1 shows a schematic diagram illustrating an example of a method for eluting substances bound to a Hemopurifier device.

[0144] [Figure 15A] Amplification of SARS-CoV-2 specific target genes from templates obtained from the eluate of a Hemopurifier device used on a COVID-19 patient.

[0145] [Figure 15B] Three different target SARS-CoV-2 genes were amplified to varying degrees from the targets contained in the Hemopurifier eluate.

[0146] [Figure 16] Clearance of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) from human serum using Hemopurifier is shown. Serum MERS-CoV was recirculated through a Hemopurifier column, and aliquots were used at the indicated time points to perform a flow cytometry-based infectivity assay (FCIA). Percentage readings of the residual viral load in serum were plotted against time. A column without GNA served as a control.

[0147] [Figure 17A] An example of a connection diagram using only a Hemopurifier is shown below.

[0148] [Figure 17B] An example of a connection diagram using a Hemopurifer connected in series with a dialyzer is shown below.

[0149] [Figure 17C] An example of a connection diagram for priming a Hemopurifer connected in series with a dialyzer is shown below.

[0150] [Figure 17D] An example of a connection diagram for a continuous renal replacement therapy (CRRT) type dialysis setup using only a hemopurifier is shown below.

[0151] [Figure 17E] An example of a connection diagram for a CRRT-type dialysis setup using a Hemopurifier connected in series with a dialyzer is shown.

[0152] [Figures 18A-C] ELISA standard curves for spike proteins of wild-type SARS-CoV-2, UK variant, or South African variant added to 1x PBS (Figure 18A) or a 50%:50% mixture of exosome-free fetal bovine serum and 1x PBS (Figure 18C). Figure 18B shows removal of spike proteins of UK variant or South African variant added to 1x PBS by GNA lectin affinity matrix from 0 to 4 hours. Figure 18D shows removal of spike proteins of UK variant, South African variant, or India variant (Delta strain) added to a 50%:50% mixture of exosome-free fetal bovine serum and 1x PBS by GNA lectin affinity matrix from 0 to 4 hours.

[0153] [Figure 19A-B] Shown are the results of qPCR amplifications detecting Epstein-Barr virus (EBV) DNA in patient plasma samples and in Hemopurifier eluates after treating patients with Hemopurifier.

[0154] [Figure 20] Graphs showing that the total amount of circulating DNA (measured by amplification of an RNAse P control) and the total amount of circulating EBV DNA in the plasma of one of the patients tested ("Patient 2") increased after treatment with Hemopurifier.

[0155] [Figure 21] A graph showing the total amount of circulating EBV DNA normalized to the total amount of RNAse P control DNA or circulating DNA is shown, demonstrating the relative reduction in EBV DNA after treatment with Hemopurifier. DETAILED DESCRIPTION OF THE INVENTION

[0156] Disclosed herein are extracorporeal circulation devices and their use for treating or suppressing coronavirus infections (e.g., betacoronavirus infections (e.g., COVID-19)) or symptoms or sequelae associated with coronavirus infections. The severe impact of the widespread COVID-19 pandemic has created an urgent need for the development of effective and safe treatments and prophylaxis against the pathogen SARS-CoV-2. While several vaccines and treatments are currently approved, the emergence of various SARS-CoV-2 mutants and variants, including those that are more virulent and / or able to evade current treatments, has raised the possibility of a prolonged pandemic. Furthermore, many patients who recover from COVID-19 infection continue to experience debilitating symptoms and sequelae, including permanent lung scarring and pulmonary fibrosis, cardiac complications and failure, stroke, seizures, and immunological disorders (e.g., Guillain-Barré syndrome). The devices disclosed herein function in an effective manner against SARS-CoV-2 variants and can treat or inhibit the underlying causes of sequelae associated with current COVID-19 infection as well as sequelae associated with previous COVID-19 infection in a subpopulation of patients who do not have circulating viral particles but who continue to experience sequelae associated with COVID-19 infection (e.g., "long COVID-19" patients).

[0157] Definition of Terms Unless otherwise specified, technical and scientific terms used herein have the meanings commonly understood by those skilled in the art. All patents, applications, published applications and other publications cited herein are expressly incorporated herein by reference in their entirety unless otherwise specified. In the event that there are multiple definitions for terms used herein, those set forth in this section shall prevail unless otherwise specified.

[0158] As used herein, the articles "a" and "an" are used to refer to one or to more than one (e.g., to at least one) of the grammatical object of the article. For example, "an element" means one component or more than one component.

[0159] As used herein, "about" or "to the extent" means that a particular quantity, level, numerical value, number, frequency, percentage, dimension, size, amount, weight, or length varies by 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% compared to a reference quantity, level, numerical value, number, frequency, percentage, dimension, size, amount, weight, or length.

[0160] Throughout this specification, unless otherwise stated, the terms "comprise" and "comprising" are meant to include the step or component or steps or components described herein, but not to exclude other steps or components or steps or components.

[0161] "Consisting of" means including only those listed before the term. Thus, the term "consisting of" indicates that the components listed before the term are necessary or essential, and that other components may not be included. "Consisting essentially of" means that the components listed before the term are necessary or essential, and also includes other components that do not interfere with or contribute to the activity or action described in connection with the disclosure of those components. Thus, the term "consisting essentially of" indicates that the components listed before the term are necessary or essential, but that other components are optional and may or may not be included depending on whether they substantially affect the activity or action of the components listed before the term.

[0162] Unless otherwise specified, all technical and scientific terms used herein have the meaning commonly understood by those skilled in the art to which this disclosure belongs. In the event that there are multiple definitions for terms used herein, those set forth in this section shall prevail unless otherwise specified. In carrying out this disclosure, unless otherwise specified, molecular biological and recombinant DNA techniques known in the art are used, most of which are described below for illustrative purposes.

[0163] As used herein, "individual," "subject," or "patient" means a human or non-human mammal, such as a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate, or bird (e.g., chicken), or other vertebrate or invertebrate.

[0164] The term "mammal" is used in the biological sense that it normally denotes, and thus specifically includes, but is not limited to, primates such as primates (chimpanzees, apes, monkeys) and humans; cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rodents, rats, mice, guinea pigs, and the like.

[0165] As used herein, the terms "function" and "functional" refer to a biological function, an enzymatic function, or a therapeutic function.

[0166] As used herein, "isolated" refers to material that has been substantially or essentially removed from components that normally accompany it in its native state. For example, an "isolated cell" as used herein includes a cell that has been purified from its native environment or organism, a cell that has been recovered from a subject or culture, e.g., a cell that is not significantly associated with in vivo or in vitro materials.

[0167] The terms "formulation," "pharmaceutical composition," and "composition," used interchangeably herein, are used interchangeably when referring to a composition of matter administered to a subject.

[0168] "Pharmaceutically acceptable" means compatible with the treatment of subjects, particularly humans.

[0169] "Drug" refers to an active agent that has biological activity and may be used therapeutically. The term "drug" is also used interchangeably with "at least one drug," "compound," or "at least one compound" and may refer to any form of drug, such as a derivative, analog, salt, or prodrug of the drug. The drug may be in various forms, may be a component of a molecular complex, or may be a pharmaceutically acceptable salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, nitrate, borate, acetate, maleate, tartrate, or salicylate). "Drug" may also refer to a pharmaceutical molecule or compound, a therapeutic molecule or compound, a matrix-forming molecule or compound, a polymer, a synthetic molecule or compound, a natural molecule or compound, or any combination thereof.

[0170] As used herein, the "purity" of a substance, compound, or material refers to the actual amount present relative to the expected amount present of that substance, compound, or material. For example, the purity of a substance, compound, or material may be at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, including any subvalues ​​therebetween. Purity may be affected by undesired impurities, including, but not limited to, by-products, isomers, enantiomers, degradation products, solvents, carriers, vehicles, or contaminants, or any combination thereof. Purity can be measured by various techniques, including, but not limited to, chromatography, liquid chromatography, gas chromatography, spectroscopy, ultraviolet-visible spectroscopy, infrared spectroscopy, mass spectroscopy, nuclear magnetic resonance, gravimetry, or titration, or any combination thereof.

[0171] Some embodiments disclosed herein relate to selecting a subject or patient in need of any one or more of the extracorporeal circulation methods described herein. In some embodiments, a patient in need of treatment or suppression of a coronavirus infection (e.g., a betacoronavirus infection (e.g., SARS-CoV-2 infection)) is selected and subjected to any one or more of the extracorporeal circulation methods described herein. In some embodiments, a patient who has previously been treated for a coronavirus infection (e.g., SARS-CoV-2 infection) is selected and subjected to any one or more of the extracorporeal circulation methods described herein. In some embodiments, a patient who has previously been treated for a coronavirus infection (e.g., a betacoronavirus infection (e.g., SARS-CoV-2 infection)) due to being at risk for coronavirus infection is selected and subjected to any one or more of the extracorporeal circulation methods described herein. In some embodiments, a patient who has experienced a recurrence of a coronavirus infection (e.g., a betacoronavirus infection (e.g., SARS-CoV-2 infection)) is selected and subjected to any one or more of the extracorporeal circulation methods described herein. In some embodiments, a patient who is resistant to treatment for a coronavirus infection (e.g., a betacoronavirus infection (e.g., SARS-CoV-2 infection)) is selected and subjected to any one or more of the extracorporeal circulation methods described herein. In some embodiments, patients exhibiting symptoms or sequelae of a coronavirus infection (e.g., a betacoronavirus infection (e.g., SARS-CoV-2 infection)) are selected and subjected to any one or more of the extracorporeal circulation methods described herein. In some embodiments, patients who have cleared a coronavirus infection (e.g., a betacoronavirus infection (e.g., SARS-CoV-2 infection)), e.g., patients who have no, reduced, or diminishing amounts of circulating viral particles in their plasma or blood but who continue to exhibit symptoms or sequelae of a coronavirus infection (e.g., a betacoronavirus infection (e.g., SARS-CoV-2 infection)), are selected and subjected to any one or more of the extracorporeal circulation methods described herein.In some embodiments, patients who have developed a coagulation disorder (e.g., a COVID-19-associated coagulation disorder) or who are at risk for developing a coagulation disorder are selected to undergo any one or more of the extracorporeal circulation methods described herein (e.g., patients with levels or amounts of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, above control or baseline levels observed in healthy patients, patients without a coagulation disorder, or patients not at risk for a coagulation disorder). Patients who have developed a coagulation disorder or who are at risk for developing a coagulation disorder may or may not have a viral infection such as COVID-19. In some embodiments, patients who have developed hypoxia (e.g., patients with reduced oxygen levels compared to healthy patients or patients without hypoxia) are selected to undergo any one or more of the extracorporeal circulation methods described herein. Patients who develop hypoxia may or may not have a viral infection, such as COVID-19. In some embodiments, patients who may have any combination of the selection criteria are selected to undergo any one or more of the extracorporeal circulation methods described herein. Such selection may be performed by clinical or diagnostic evaluation of the subject, as is routinely done in the art.

[0172] As used herein, the terms "treat," "treating," "treatment," "therapeutic," or "therapy" have their general meaning as understood in light of the present specification and do not necessarily refer to a complete cure or elimination of a disease or condition. Also, as used herein, "treat" or "treatment" refers (as is well known in the art) to an approach for achieving a beneficial or desired outcome (e.g., a clinical outcome) for a subject's condition. Beneficial or desired clinical outcomes include, but are not limited to, the alleviation or mitigation of one or more symptoms or conditions, a reduction in the extent of the disease, a stabilization of the disease state (i.e., not worsening), prevention of the spread or spread of the disease, a delay in or reduction in the rate of disease progression, alleviation or reduction in the pathology, a reduction in disease recurrence, and remission, which may be partial or total, detectable or undetectable. As used herein, "treat" and "treatment" also include prophylactic treatment. A therapeutic method involves administering a therapeutically effective amount of an active agent to a subject or using a therapeutic device. This administration may consist of a single administration or a series of multiple administrations. The compositions of the present invention are administered or applied to a subject in an amount, duration, number of times, or frequency sufficient to treat the patient. The length of the treatment period will depend on various factors, such as the severity of the condition, the age and genetic profile of the patient, etc. Furthermore, it will be appreciated that treatment or prevention may be adjusted during the implementation of a particular treatment or prevention plan. In some cases, long-term administration or application may be required. "Preventive treatment" refers to treating a subject who does not yet exhibit symptoms of a disease or condition but who is susceptible to or at risk for a particular disease or condition, and this treatment can reduce the likelihood that the patient will develop the disease or condition. "Therapeutic treatment" also refers to treating a subject who already suffers from or has already developed a disease or condition.

[0173] As used herein, "inhibition" has its general meaning as understood in the context of this specification and may refer to the reduction or prevention of a viral infection (e.g., SARS-CoV-2) or its symptoms or sequelae. The reduction may be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction, or a percentage reduction within a range of any two of these values. As used herein, "delay" has its general meaning as understood in the context of this specification and refers to slowing, postponing, or delaying an event, such as a viral infection or its symptoms or sequelae, to a later time than expected. The delay may be a 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% delay, or a percentage reduction within a range of any two of these values. "Inhibition" or "delay" does not necessarily refer to 100% inhibition or delay. Partial suppression or delay may be achieved.

[0174] As used herein, "nucleic acid" or "nucleic acid molecule" refers to a polynucleotide, including, for example, deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), oligonucleotides, fragments obtained by polymerase chain reaction (PCR), and fragments obtained by ligation, cleavage, endonuclease action, and exonuclease action. Nucleic acid molecules may be composed of natural nucleotide monomers (e.g., DNA or RNA), analogs of natural nucleotides (e.g., enantiomers of natural nucleotides), or combinations thereof. Modified nucleotides may have modifications in the sugar moiety and / or pyrimidine or purine base moieties. Modifications in the sugar moiety include, for example, replacement of one or more hydroxyl groups with halogens, alkyl groups, amines, or azide groups, and the sugar moiety may be etherified or esterified. Furthermore, the entire sugar moiety may be replaced with sterically or electronically similar structures, including, for example, azasugars and carbocyclic sugar analogs. Modified base moieties include alkylated purines, alkylated pyrimidines, acylated purines, acylated pyrimidines, and other known heterocyclic substituents. Nucleic acid monomers can be linked by phosphodiester bonds or similar bonds. Linkages similar to phosphodiester bonds include phosphorothioate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phosphoranilidate, and phosphoramidate bonds. "Nucleic acid molecule" also includes so-called "peptide nucleic acids," which contain natural or modified nucleobases attached to a polyamide backbone. Nucleic acids can be single-stranded or double-stranded. The term "oligonucleotide" can be used interchangeably with nucleic acid and can refer to double-stranded DNA or RNA, or single-stranded DNA or RNA.The nucleic acid may be contained in a nucleic acid vector or construct (e.g., a plasmid, virus, bacteriophage, cosmid, fosmid, phagemid, bacterial artificial chromosome (BAC), yeast artificial chromosome (YAC), or human artificial chromosome (HAC)) that allows for amplification and / or expression of the nucleic acid in various biological systems. Typically, the nucleic acid vector or construct also includes elements such as, but not limited to, a promoter, an enhancer, a terminator, an inducer, a ribosome binding site, a translation initiation site, a start codon, a stop codon, a polyadenylation signal, an origin of replication, a cloning site, a multiple cloning site, a restriction enzyme site, an epitope, a reporter gene, a selection marker, an antibiotic selection marker, a target sequence, a peptide purification tag, or an accessory gene, or any combination thereof.

[0175] A nucleic acid or nucleic acid molecule may contain one or more sequences encoding multiple types of peptides, polypeptides, or proteins, and these one or more sequences may be linked adjacently within a single nucleic acid or nucleic acid molecule, or may be linked via another nucleic acid in between. Examples of this other nucleic acid include a linker, a repeat sequence, or a restriction enzyme site, or a sequence that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, or 300 bases long, or a sequence with a length within a range defined by any two of these lengths. As used herein, the term "downstream" with respect to a nucleic acid refers to a sequence located on the 3'-end of a given sequence on the strand (sense strand) containing the coding sequence when the nucleic acid is double-stranded. As used herein, the term "upstream" with respect to a nucleic acid refers to a sequence located on the 5'-end of a given sequence on the strand (sense strand) containing the coding sequence when the nucleic acid is double-stranded. As used herein, the term "grouped" with respect to a nucleic acid refers to two or more adjacent sequences that are directly linked, or two or more adjacent sequences that are linked via another nucleic acid in between. Examples of this other nucleic acid include a linker, a repeat sequence, or a restriction enzyme site, or a sequence that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, or 300 bases long, or a sequence with a length within a range defined by any two of these lengths.It should be noted that the nucleic acid sequences flanking the sequences typically do not encode functional or catalytic polypeptides, proteins, or protein domains.

[0176] As used herein, "peptide," "polypeptide," and "protein" refer to macromolecules composed of amino acids linked by peptide bonds. Numerous functions of peptides, polypeptides, and proteins are known in the art, including, but not limited to, enzymatic, structural, transport, defensive, hormonal, or signal transduction functions. Peptides, polypeptides, and proteins are often produced biologically by ribosomal complexes utilizing a nucleic acid template, but this is not always the case and they can also be produced by chemical synthesis. Mutations of peptides, polypeptides, or proteins can be generated by genetically manipulating nucleic acid templates, including substitutions, deletions, truncations, additions, duplications, or fusions of two or more peptides, polypeptides, or proteins. Fusion of two or more peptides, polypeptides or proteins can be effected by linking them adjacently within a single molecule, or by linking them via another amino acid, such as a linker, a repeat sequence, an epitope or tag, or a 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 20-, 21-, 22-, 23-, 24-, 25-, 26-, 27-, 28-, 29-, 30-, 31-, 32-, 33-, 34-, 35-, 36-, 37-, 38-, 39-, 40-, 41-, 42-, 43-, 44-, 45-, 46-, 47-, 48-, 49-, 50-, 51-, 52-, 53-, 54-, 55-, 56-, 57-, 58-, 59-, 60-, 61-, 62-, 63-, 64-, 65-, 66-, 67-, 68-, 69-, 70-, 71-, 72-, 73-, 74-, 75-, 76-, 77-, 78-, 79-, 80-, 81-, 82-, 83-, 84-, 85-, 86-, 87-, 88-, 89-, 90-, 91-, 92-, 93-, 94- Examples of such sequences include sequences of 5 bases, 16 bases, 17 bases, 18 bases, 19 bases, 20 bases, 25 bases, 30 bases, 35 bases, 40 bases, 45 bases, 50 bases, 55 bases, 60 bases, 65 bases, 70 bases, 75 bases, 80 bases, 85 bases, 90 bases, 95 bases, 100 bases, 150 bases, 200 bases, or 300 bases in length, or sequences of lengths within a range of any two of these lengths. As used herein, "downstream" in a polypeptide refers to the sequence following the C-terminus of the preceding sequence. As used herein, "upstream" in a polypeptide refers to the sequence preceding the N-terminus of the following sequence.

[0177] As used herein, a "lectin" refers to a protein that selectively binds to polysaccharides and glycoproteins. While many lectins are not very useful due to insufficient specificity, certain lectins have high selectivity for enveloped viruses. Examples of lectins with such properties include those obtained from snowdrops (Galanthus nivalis) in the form of snowdrop agglutinin (GNA), those obtained from daffodils (Narcissus pseudonarcissus) in the form of daffodil agglutinin, and a lectin called "cyanovirin" obtained from the blue-green alga Nostoc ellipsosporum. Because GNA is nontoxic and sufficiently safe, it has been incorporated into genetically modified rice and genetically modified potatoes (Bell et al. Transgenic Res 10(1): 35-42, 2001; Rao et al. Plant J 15(4): 469-477, 1998). These lectins bind to high-mannose glycoproteins such as those found on the surface of HIV (Chervenak et al. Biochemistry 34(16): 5685-5695, 1995).

[0178] As used herein, "high mannose glycoprotein" refers to a glycoprotein having mannose-mannose linkages in the form of α(1→3) or α(1→6) linkages.

[0179] As used herein, "coronavirus" refers to a family of enveloped, positive-sense, single-stranded RNA viruses belonging to the Coronaviridae family that infect mammals and birds. Human coronavirus infections can cause mild, cold-like symptoms or severe respiratory illnesses, including severe acute respiratory syndrome (SARS), acute respiratory distress syndrome (ARDS), cough, congestion, sore throat, shortness of breath, pneumonia, bronchitis, and hypoxia. Other symptoms include, but are not limited to, fever, fatigue, muscle pain, and gastrointestinal symptoms (e.g., vomiting, diarrhea, and abdominal pain). To infect a host cell, an enveloped virus must fuse with the host cell's plasma membrane to deliver its genome into the host cell. The coronavirus envelope contains four transmembrane structural proteins: the spike protein ("S"), the envelope protein ("E"), the membrane protein ("M"), and the hemagglutinin esterase protein ("HE"). Coronaviruses have an average diameter of 80–120 nm, and their virion surface is densely covered with trimeric spike (S) glycoprotein protrusions decorated with N-linked glycosylation sequences. The S protein contains a receptor-binding domain (RBD), a highly immunogenic region that determines the specificity of the virus strain for host receptors. The coronavirus nucleocapsid contains multiple nucleocapsid proteins (N or NP proteins) that encase the RNA genome. During coronavirus infection, the S protein binds to the host cell receptor and initiates entry into the host cell via endocytosis or envelope membrane fusion. The RNA genome is translated by host ribosomes to produce new structural proteins and RNA-dependent RNA polymerase, which then replicates the viral genome. Virus particles are assembled in the endoplasmic reticulum of the host cell and secreted extracellularly via exocytosis via the Golgi apparatus.Further information regarding the structure and infection cycle of coronaviruses can be found in Fehr AR & Perlman S. "Coronaviruses: An Overview of Their Replication and Pathogenesis" Methods Mol. Biol. (2015); 1282:1-23, which is expressly incorporated herein by reference in its entirety.

[0180] As used herein, "SARS-CoV-2" and "2019-nCoV" refer to one or more coronavirus strains that caused the human coronavirus disease 2019 (COVID-19) pandemic. High transmissibility, long incubation periods, and the globalization of modern society have allowed coronaviruses to spread worldwide. Infected patients have developed SARS and other respiratory illnesses, placing a significant strain on healthcare infrastructure. Approval of treatments and vaccines for SARS-CoV-2 and other coronaviruses in humans is progressing, but further testing is needed. The embodiments disclosed herein may also be applicable to other coronaviruses, including HCoV-229E, HCoV-OC43, SARS-CoV-1, HCoV NL63, HCoV-HKU1, and MERS-CoV, as well as 20I / 501Y.V1 (alpha strain, B.1.1.7), 20H / 501Y.V2 (beta strain, B.1.351), 20J / 501Y.V3 (gamma strain, P.1), B.1.617.2 (delta strain), AY.1, AY.2, C.37 (lambda strain), B.1.621 (mu strain), B.1.1.207, VUI-202102 / 03 (B.1.525), VUI-202101 / 01 (P.2), and VUI-202102 / 01 These include, but are not limited to, SARS-CoV-2 variants such as (A.23.1), VUI 202102 / 04 (B.1.1.318), VUI 202103 / 01 (B.1.324.1), B.1.427, CAL.20C (B.1.429), R.1, B.1.466.2, B.1.1.519, C.36.3, B.1.214.2, B.1.1.523, B.1.619, B.1.620, C.1.2, B.1.617.1, B.1.1.529 (Omicron strain), and B.1.526. The devices and methods used are expected to be effective against coronavirus infections caused by currently identified SARS-CoV-2 variants or currently unidentified SARS-CoV-2 variants.

[0181] According to the UK National Institute for Health and Care Excellence (NICE), COVID-19 infection is classified as follows: "Acute COVID-19" refers to signs and symptoms of COVID-19 within 4 weeks of illness. "Ongoing symptomatic COVID-19" refers to signs and symptoms of COVID-19 4-12 weeks after illness. "Post-COVID-19 syndrome" refers to signs and symptoms that develop during or after an infection consistent with COVID-19 and persist beyond 12 weeks after illness that cannot be explained by an alternative diagnosis.

[0182] As used herein, "COVID-19-associated coagulation disorder (CAC)" refers to thrombotic complications associated with COVID-19 infection. Because SARS-CoV-2 can infect vascular endothelial cells using angiotensin-converting enzyme 2 (ACE2), patients with COVID-19 infection may experience significant inflammation and damage to the circulatory system during the course of the disease. Hallmarks associated with CAC include decreased platelet counts, elevated circulating D-dimers, prolonged prothrombin time (PT), and the presence of macrothrombosis and / or microthrombosis. Further information regarding CAC can be found in Iba et al. J. Clin. Med. (2021) 10:191, which is incorporated herein by reference in its entirety.

[0183] As used herein, "SARS-CoV-2-derived glycoprotein" includes glycoproteins contained in or expressed by the SARS-CoV-2 virus. For example, one of the glycoproteins derived from SARS-CoV-2 encompassed by the present invention is the SARS-CoV-2 S (spike) protein, which includes the outermost portion of the viral envelope decorated with glycoproteins or its subunits (including the S1 subunit, S2 subunit, and RBD subunit).

[0184] As used herein, the term "SARS-CoV-2 spike (S) protein" or "COVID-19 spike protein" refers to the S protein, a class I viral fusion protein consisting of a single chain of approximately 1,300 amino acid residues that folds to form a homotrimer. The S protein contains an N-terminal S1 subunit containing the receptor-binding domain and a C-terminal S2 subunit responsible for fusion with the cellular membrane. Coronavirus proteins undergo various post-translational modifications during coronavirus assembly, including extensive glycosylation, which plays a crucial role in the virus's pathogenicity. The S trimer on the coronavirus surface is extensively decorated with N-linked glycans, which are essential for coronavirus function. This N-linked glycan moiety on the coronavirus surface is crucial for virus assembly and function. Furthermore, N-linked glycans are required for stabilizing S protein production, as inhibiting N-glycosylation with tunicamycin results in the synthesis of "spikeless" virions. Furthermore, N-glycan coverage of the viral envelope masks immunogenic protein epitopes, forming a glycan shield that allows coronaviruses to evade the host immune system and host proteases. Therefore, coronavirus glycoproteins are major antigenic determinants that are prime targets for therapeutic intervention and vaccines. Therefore, these glycoproteins, which are highly conserved in SARS-CoV-2 and other coronaviruses (e.g., betacoronaviruses, e.g., COVID-19 and its variants), are ideal targets for the lectin-based affinity devices described herein. Based on these findings, the devices and methods described herein are likely to be useful for removing SARS-CoV-2 and other coronaviruses (e.g., betacoronaviruses, e.g., COVID-19 and its variants) and exosomes containing antigens derived from these viruses, even as these coronaviruses mutate over time, e.g., new variants emerge.

[0185] As used herein, "exosomes" are nanoparticles less than 200 nm in size that are part of a communication system that reprograms the function of nearby or distant target cells by transmitting signals to these cells. Exosomes can contain a variety of contents, including nucleic acids, proteins, and lipids. Exosomes can also be transported from host cells to recipient cells to alter cellular function. Exosomes function as vehicles for intercellular communication and molecular transport, facilitating the direct extracellular transport of specific proteins, lipids, miRNA, mRNA, and DNA between cells. Exosomes are present in the systemic circulatory system and are distributed throughout the body. In normal, healthy individuals, basal exosome release facilitates intercellular communication and promotes the clearance of cellular debris. Meanwhile, increased exosome abundance is thought to reflect altered physiological conditions. In pathological conditions, activated cells produce and release large amounts of exosomes, delivering the exosomal membrane structures and their cargo to distant tissues via the circulatory system. Further information regarding exosomes and the purification of their components can be found in PCT Publication WO2016 / 172598, which is expressly incorporated by reference in its entirety.

[0186] As used herein, "COVID-19-mediated nanoparticle" refers to a nanoparticle (i.e., a particle 200 nm or smaller in size) that contains or expresses glycoproteins derived from SARS-CoV-2, or to a subcellular nanoparticle that is not necessarily derived from a SARS-CoV-2 particle and is associated with COVID-19 or its symptoms or sequelae. For example, a COVID-19-mediated nanoparticle may be a SARS-CoV-2 virion or a fragment thereof (e.g., a glycoprotein derived from SARS-CoV-2), or may be a non-viral COVID-19-mediated nanoparticle or exosome.

[0187] As used herein, a "portion" refers to a smaller amount of material than the whole. A minor portion, for example, refers to an amount less than 50%, and a major portion, for example, refers to an amount greater than 50%. Thus, a coronavirus particle unit, COVID-19-mediated nanoparticle unit, or exosome unit that is less than the total amount of coronavirus particles, COVID-19-mediated nanoparticles, or exosomes removed from a subject is a portion of the removed coronavirus particles, COVID-19-mediated nanoparticles, or exosomes. In the context of this disclosure, a coronavirus particle, COVID-19-mediated nanoparticle, or exosome, or a coronavirus particle unit, COVID-19-mediated nanoparticle unit, or exosome unit, may refer to the total amount of coronavirus particles, COVID-19-mediated nanoparticles, or exosomes removed from a subject, or may refer to an amount less than the total amount of coronavirus particles, COVID-19-mediated nanoparticles, or exosomes removed from a subject. In some embodiments, the subject includes a warm-blooded animal, preferably a mammal, such as a human. In a preferred embodiment, the subject is a primate. In a more preferred embodiment, the subject is a human.

[0188] As used herein, "microRNA" or "miRNA" refers to highly conserved non-coding RNA molecules approximately 21-25 bases in length that play a crucial role in regulating post-transcriptional gene expression by targeting messenger RNA (mRNA) of protein-coding genes. Mature miRNAs exist in the cytoplasm as double-stranded RNAs, which bind to argonaute (Ago2) proteins and glycine-tryptophan repeat proteins to form the core structure of a multi-subunit complex called the miRNA-induced silencing complex (miRISC). Double-stranded miRNAs contain two strands, distinguished as "-5p" (expressed from the 5' end of the pre-miRNA) or "-3p" (expressed from the 3' end of the pre-miRNA). One of the two strands in a double-stranded miRNA is typically removed (the passenger strand), while the other, retained strand, acts as a guide for selecting the target mRNA (the guide strand). However, it has been reported that both mature miRNAs, cleaved from the 5' and 3' ends of a single pre-miRNA stem-loop, can function and target different mRNAs. When miRNAs form the miRISC complex through base-pairing interactions between complementary nucleotides, primarily in the 3' untranslated region (UTR), and 2–8 nucleotides in the miRNA, the miRNA acts as a translational repressor. Individual miRNAs bind to many specific target mRNAs but often do not bind to multiple target mRNAs in a single molecular pathway. miRNAs exist as free-flowing nucleic acids in plasma and other body fluids, as well as within exosomes. Extracellular miRNAs floating in the circulatory system without being packaged within exosomes are thought to be by-products of dead cells stably bound to Ago2 protein. Exosomes, produced in large quantities by diseased or activated cells, contain all of the parent cell's contents, including miRNAs.

[0189] Some miRNAs have been identified as being universally associated with various diseases. Certain miRNAs have been reported to be "fine tuners" of the immune response, exerting pro-inflammatory or anti-inflammatory effects by regulating Toll-like receptor signaling. Because miRNAs lack antigenicity, they can evade immune surveillance, a property that can be beneficial for viruses. In viral infections, certain miRNAs function as antiviral tools that stimulate both the innate and adaptive immune systems, while other miRNAs contribute to viral propagation. Host miRNAs can be regulated by viruses, and viruses can exploit cellular resources to produce their own miRNAs, which are involved in immune evasion and infection maintenance. The presence or absence of various viral and host miRNAs can be monitored to assess the outcome of therapeutic strategies.

[0190] Exosomes play a crucial role in the systemic transmission of pathogenic substances and host cell-derived molecules during viral infections, which is thought to contribute to viral infectivity and complications. For example, the systemic transmission of miRNAs via exosomes allows viruses to evade the immune system and maintain host cell infection. One example of such an infection is hepatitis B virus (HBV) infection of liver cells, in which exosome-derived miRNAs are released from virus-infected cells, resulting in reduced production of cytokines involved in antiviral immunity. Extracellular vesicles (EVVs) produced in response to various viruses, including coronaviruses, have been hypothesized to contribute not only to coagulation disorders but also to the maintenance of pathological conditions and the promotion of infection. In COVID-19, viral and / or host miRNAs are transported within exosomes and spread throughout the body, potentially acting as mediators of thrombosis, immune dysfunction, and multiple organ failure. MiRNAs transported between cells via exosomes and possessing pathogenic properties distinct from those of infectious virions are important for understanding the pathogenesis of COVID-19. The devices disclosed herein have an affinity for high-mannose glycoprotein moieties, and are therefore able to bind to and remove SARS-CoV2 and exosomes from the circulatory system.

[0191] When a range of values ​​is given, the upper and lower limits of the range, as well as values ​​between the upper and lower limits, are encompassed in the embodiment.

[0192] As used herein, "% w / w" or "% wt / wt" has its ordinary meaning as understood in the context of this specification and refers to the ratio of the weight of a component or agent to the total weight of a composition of the invention, multiplied by 100. As used herein, "% v / v" or "% vol / vol" has its ordinary meaning as understood in the context of this specification and refers to the ratio of the liquid volume of a compound, substance, component or agent to the total liquid volume of a composition of the invention, multiplied by 100.

[0193] Symptoms and after-effects of COVID-19 As more information about the pathogenesis of SARS-CoV-2 emerges, it is becoming clear that the virus does not exclusively target the respiratory tract, but in more severe cases can cause widespread systemic inflammation and affect other vulnerable organs, leading to respiratory failure, acute cardiac injury, acute kidney injury, neurological disease, sepsis, or other complications. There is also evidence of the development of "RNAemia" (i.e., the presence of viral RNA in the blood) in COVID-19 patients, indicating that systemic viral load can promote inflammation and tissue damage, as further described herein.

[0194] COVID-19 Disease - Cytokine Storm Recent data suggest that SARS-CoV-2-induced immunopathological events may contribute not only to acute respiratory distress syndrome (ARDS) but also to other systemic sequelae observed in COVID-19. Evidence suggests that patients with COVID-19, particularly those with severe COVID-19 disease, experience a circulating "cytokine storm." A cytokine storm is thought to be a state of uncontrolled, dysregulated inflammation that can lead to tissue damage, pulmonary edema, and disruption of normal immune function. Compared with moderate to severe cases of COVID-19, severe cases frequently present with dyspnea and hypoalbuminemia, as well as elevated levels of alanine aminotransferase, lactate dehydrogenase, C-reactive protein (CRP), ferritin, and D-dimer, and significantly elevated systemic concentrations of cytokines and their receptors (i.e., IL-2R, IL-6, IL-10, and TNF-α). Because severe inflammation is associated with poor outcomes in COVID-19 patients, inflammatory markers offer another means of assessing the outcome of therapeutic interventions in COVID-19 patients. Specifically, changes in specific cytokines, chemokines, and combinations thereof, such as IL-1β, IL-6, IL-8, IL-10, granulocyte-colony-stimulating factor (G-CSF), interferon-γ-inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory proteins (MIP-1α and MIP-1β), can be measured. Circulating cytokines, such as IL-6, have been shown to be biomarkers of the severity of COVID-19 infection (Zhang et al. J. Translational Medicine (2020) 18(1):406).

[0195] COVID-19 disease - immunosuppression In the pathogenesis of COVID-19, elevated cytokine levels during SARS-CoV-2 infection correlate with the depletion of CD4+ T cells, CD8+ T cells, and natural killer (NK) cells. Patients with COVID-19 experience a significant decrease in total CD4+ and CD8+ T cell counts, particularly in patients over 60 years of age and those requiring intensive care. Coronaviruses directly or indirectly induce lymphocyte loss and / or inflammatory processes, which are enhanced by by-products of infection and can also induce lymphocyte apoptosis. Evidence suggests that the absolute number of lymphocytes in blood and / or the proportion of lymphocytes among white blood cells can be indicators of disease progression and outcomes in COVID-19 patients. Patients with moderate to severe symptoms who are recovering show improvement in lymphocyte counts, while severely ill patients who die do not show recovery from lymphopenia. Therefore, using reference ranges for laboratory values ​​known in the art, the absolute lymphocyte count can identify the presence or absence of lymphopenia and predict the status and prognosis of COVID-19 patients. Alternatively, the number of specific lymphocytes (e.g., T cells and NK cells) and the number of specific lymphocyte subsets (CD4+ T cells and CD8+ T cells) in the peripheral blood of patients with COVID-19 can be examined to determine the status of the immune system, particularly the status of cells involved in the antiviral response.

[0196] COVID-19 Disease - RNAemia Plasma viral RNA ("RNAemia") has been identified in hospitalized patients who test positive for COVID-19. RNAemia has been observed in severely ill COVID-19 patients and correlates with elevated levels of the pro-inflammatory cytokine IL-6. This suggests that systemic SARS-CoV-2 viral load correlates with COVID-19 severity. Therefore, the methods described herein can be used to improve recovery in severely ill COVID-19 patients by reducing viral load or circulating viral RNA.

[0197] As used herein, "viral load" refers to the amount of viral particles, viral RNA, or fragments thereof in a bodily fluid (e.g., blood or plasma). "Viral load" includes all viral particles (infectious, replicated, or noninfectious) and their fragments. Thus, viral load represents the total number of viral particles and / or their fragments circulating in a bodily fluid. Therefore, viral load can be a measure of the presence of the virus, such as the number of viral copies per unit of blood or plasma, or units of viral protein or its fragments per unit of blood or plasma. The presence of SARS-CoV-2 viral RNA in the circulation correlates with poor outcomes. Changes in circulating viral load can be assessed by RT-PCR. Viral clearance can also be quantified by eluting lectin-bound viral particles, as disclosed herein.

[0198] COVID-19 Disease - Cardiac Complications Although myocardial injury is significantly associated with death from COVID-19, patients with underlying cardiovascular disease (CVD) who do not develop myocardial injury have a relatively good prognosis. Myocardial injury is associated with abnormal cardiac function and arrhythmias. Inflammation may be a potential mechanism for myocardial injury. Patients at high risk for myocardial injury may be considered for use with any one or more of the methods described herein, and the methods of the present invention can be administered multiple times (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times) during the treatment period.

[0199] As used herein, "troponin" refers to a type of protein present in cardiac muscle. Troponin and its subunits (e.g., troponin C, troponin I, troponin T) are not normally present in the blood. When cardiac muscle is damaged, troponin is released into the bloodstream. As cardiac damage increases, the amount of released troponin increases.

[0200] COVID-19 patients assessed as at risk for myocardial injury by elevated troponin T levels tend to be older and have a higher prevalence of hypertension, coronary artery disease, heart failure, and diabetes. Patients with myocardial injury also show evidence of more severe systemic inflammation, specifically elevated white blood cell counts, C-reactive protein levels, and procalcitonin levels, as well as elevated levels of other biomarkers indicative of myocardial injury and stress, such as elevated creatine kinase, myoglobin, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). These patients have a higher incidence of systemic inflammation and more frequently require assisted ventilation compared with COVID-19 patients without myocardial injury. Troponin may include and / or refer to cardiac troponin I (cTnI), cardiac troponin T (cTnT), cardiac troponin (cTN), cardiac-specific troponin I, and troponin T. Circulating troponin T has been shown to be a biomarker of the severity of COVID-19 infection (Gaze. Ann. Clin. Biochem. (2020) 57(3):202-205).

[0201] COVID-19 disease - multiple organ failure, sepsis, acute kidney disease, neurological disorders, olfactory disorders, hyperinflammation and other complications Improvement in markers of systemic inflammation and / or organ dysfunction in severely ill COVID-19 patients can be used as indicators of clinically effective therapeutic intervention. Markers that are expected to decrease in response to therapeutic intervention include C-reactive protein (CRP), ferritin, lactate dehydrogenase, alanine aminotransferase (ALT), interleukin-6 (IL-6), IL-1β, tumor necrosis factor-α (TNF-α), macrophage inflammatory protein-1α, granulocyte colony-stimulating factor, interferon-γ-inducible protein 10, and / or monocyte chemoattractant protein-1. To assess clinical outcomes associated with therapeutic interventions for COVID-19, survival rates, duration and need for assisted ventilation, multiorgan system failure, and cardiac complications may be monitored.

[0202] COVID-19 disease-coagulation system The D-dimer test examines the presence of D-dimer in the blood. D-dimer is a protein fragment generated by the degradation of cross-linked fibrin, the main component of blood clotting. During blood clotting, thrombin activates factor XIII, which then cross-links the D domain of fibrin. The activity of the serine protease plasmin degrades the cross-linked fibrin, generating circulating D-dimer. In patients with SARS-CoV-2 infection, dysregulation of blood coagulation leads to potentially fatal thrombosis, stroke, and pulmonary embolism. Circulating D-dimer has been shown to be a biomarker for the severity of COVID-19 infection (Yao et al. J. Intensive Care. (2020) 8:49). D-dimer is also known as fragment D-dimer or fibrinolysis fragment.

[0203] An example of a hemofiltration device using lectin Disclosed herein are extracorporeal circulation devices for treating viral diseases, such as coronavirus infections or associated symptoms or sequelae (e.g., long-term sequelae that may develop even after the coronavirus infection has been eliminated, such as those observed in patients recovering from COVID-19), and methods for using the devices to treat such viral diseases. The extracorporeal circulation devices of the present invention contain lectins that bind to various biological components (e.g., exosomes) containing glycoproteins. When used for hemofiltration, the lectin-containing extracorporeal circulation devices of the present invention can filter, for example, glycoprotein-bearing viral particles (including SARS-CoV-2 and its constituent subcomponents), non-viral COVID-19-mediated nanoparticles, and circulating glycoprotein-containing exosomes.

[0204] In some embodiments, the devices, systems, and methods of the present invention include one or more hollow fiber cartridges containing an affinity agent, the affinity agent being a lectin, preferably snowdrop agglutinin (GNA). Other lectins include daffodil agglutinin (NPA), concanavalin A, and cyanovirin. Examples of extracorporeal circulation devices containing lectins that can be used in the methods disclosed herein are described in WO2007 / 103572, WO2009 / 023332, and WO2010 / 065765 (each of which is expressly incorporated by reference in its entirety).

[0205] The extracorporeal circulation devices disclosed herein are useful for capturing circulating viral particles containing glycoproteins, such as enveloped viral particles that incorporate host cell membranes containing abundant glycoprotein and other molecular materials during replication. In the case of SARS-CoV-2 and other coronaviruses, spike (S) glycoproteins are also expressed and positioned on the viral envelope to decorate it.

[0206] The COVID-19 pandemic as a whole has revealed that many patients experience long-term side effects of SARS-CoV-2 infection and post-COVID-19 syndrome. When the body mounts an inflammatory response to combat the coronavirus, this response can lead to severe complications affecting a wide range of organs throughout the body. In some cases, the resulting inflammation can cause damage that is more severe than the infection itself. As described herein, the extracorporeal circulation devices disclosed herein are useful for treating or suppressing the long-term sequelae of coronavirus infection and can improve the prognosis of chronic sequelae of coronavirus infection. Treatment using the extracorporeal circulation devices of the present invention may include removing exosomes from the patient's body, which may contain one or more miRNAs that can negatively affect the patient even if the patient does not already have an active viral infection.

[0207] Thus, in some embodiments, the present invention relates to an extracorporeal circulation device containing a lectin for removing pathogenic organisms, their fragments, or other biological components from a patient's blood or plasma. In some embodiments, the extracorporeal circulation device includes one or more hollow fiber cartridges containing a lectin. Using hollow fiber membrane technology provided herein or known in the art, embodiments of the present invention include a size-exclusion mechanism that contacts subcellular nanoparticles (including, but not limited to, virus particles, COVID-19-mediated nanoparticles, exosomes, etc.) with an affinity matrix, restricting blood components (including cells) larger than nanoparticles from passing through the pores of the hollow fiber and entering the space outside the hollow fiber where the affinity agent is present. In some embodiments, the pore diameter is 20 to 500 nm. In some embodiments, the pore diameter is 200 nm or approximately 200 nm.

[0208] In one example, blood or plasma is passed through an extracorporeal circuit using a hollow fiber cartridge. The hollow fiber membrane is sufficiently permeable to allow subcellular nanoparticles in the blood or plasma to pass through and be expelled to a compartment outside the hollow fiber. The compartment outside the hollow fiber contains a substrate having one or more drugs (e.g., lectins) attached thereto, which can adhere to the subcellular nanoparticles expelled from the interior of the hollow fiber and substantially prevent them from returning to the interior of the hollow fiber. Those skilled in the art are familiar with the various types of hollow fiber systems available commercially. The hollow fiber system is selected based on the desired blood or plasma volume and the desired flow rate of the blood or plasma volume through the hollow fiber system. More specifically, a 250 mm long hollow fiber cartridge may be used, fitted with 535 hollow fibers sold by Amicon. The hollow fibers may have an inner diameter of 180 microns and an outer diameter of 360 microns, providing a total contact surface area within the cartridge of 750 cm. 2Alternatively, "Plasmaflux P2" hollow fiber filter cartridges (sold by Fresenius) or Plasmart PS60 cartridges (sold by Medical srl) may be used.

[0209] Regardless of the type of hollow fiber system used, the concept required for application of the present invention is that hollow fiber filters must allow blood cells to flow through the interior of the hollow fibers and allow subcellular nanoparticles to diffuse to the exterior of the hollow fibers. To allow subcellular nanoparticles to diffuse to the exterior of the hollow fibers, the pore size of the hollow fiber membrane must be set to a diameter sufficient to allow particles with a diameter of 20 nm to 500 nm to pass through, depending on the target particle. In some embodiments, the pore size of the hollow fiber membrane must be set to a diameter sufficient to allow particles with a diameter of 50 nm to 300 nm to pass through. In some embodiments, the pore size of the hollow fiber membrane must be set to a diameter sufficient to allow particles with a diameter of 80 nm to 200 nm to pass through. Those skilled in the art will recognize that when conducting experiments using various types of hollow fibers, it is useful to use particles of a similar size to subcellular nanoparticles to measure the pore size of various hollow fiber filters and quantify their performance. One method for such measurement and quantification is the use of a commercially available MACS filter with a diameter of 60 nm. TM Beads (Miltenyi Biotec) can be used. Alternatively, commercially available fluorescently labeled spherical latex beads with diameters of 25 to 1000 nm can be used (e.g., spherical latex beads sold by Duke Scientific, Palo Alto, CA).

[0210] The substrate or matrix used to practice the present invention must be permeable to sufficient flow rates so that blood components other than blood cells that enter the space outside the hollow fibers are dispersed throughout the substrate or matrix material and so that subcellular nanoparticles that permeate the hollow fiber filter can adequately contact the binding agent attached to the substrate or matrix. Suitable substrates or matrices are known to those skilled in the art. Suitable substrates or matrices include silica gel, dextran, agarose, nylon polymers, acrylic acid polymers, ethylene-maleic anhydride copolymers, aminopropyl silica, aminocelite, glass beads, diatomaceous earth, silicates containing diatomaceous earth, or other substrates or matrices known in the art. Examples of such substrates or matrices are described in U.S. Patent No. 4,708,713 to Lentz, U.S. Patent No. 5,667,684 to Motomura, U.S. Patent No. 5,041,079 to Takashima et al., and U.S. Patent No. 3,925,152 to Porath and Janson (each of which is incorporated herein by reference in its entirety). Binding agents attached to the substrate may be selected based on their known affinity for subcellular nanoparticles.

[0211] In some embodiments, the methods of the present invention are carried out using an affinity cartridge with the device shown in Figure 1. In this device, blood or plasma is flowed through the lumen of a hollow fiber ultrafiltration membrane, the non-blood-wetted exterior of which is in intimate contact with immobilized lectins that bind to and immobilize viruses and other subcellular nanoparticles. Thus, the device is able to retain intact lectin-bound glycoproteins (which may be part of larger structures) while allowing other components to pass through the lumen.

[0212] While SARS-CoV-2 is the reference virus for illustrating the present invention, the present invention can be adapted for the removal of any type of coronavirus or other virus. An exemplary device, detailed in Figures 1-3, includes multiple flow channels in a hollow fiber ultrafiltration membrane that defines a filtration chamber. Inlet and outlet ports communicate with the filtration chamber. The ultrafiltration membrane is preferably an anisotropic membrane, with the dense layer or retentate side facing the bloodstream. Ultrafiltration membranes are conveniently fabricated using polymers known in the art, and any number of polymers may be used, including, for example, polysulfone, polyethersulfone, polyamide, polyimide, cellulose acetate, and polyacrylamide. The ultrafiltration membrane preferably has pores with diameters of 200–700 nm. Pores of this size allow the passage of subcellular nanoparticles (e.g., SARS-CoV-2 virions or fragments thereof, e.g., SARS-CoV-2-derived glycoproteins (e.g., SARS-CoV-2 virions with a diameter of 110 nm)) and non-viral COVID-19-mediated nanoparticles (e.g., exosomes), but not the majority of blood cells (erythrocytes: 2,000 nm diameter; lymphocytes: 7,000–12,000 nm diameter; macrophages: 10,000–18,000 nm diameter). An exemplary device is shown in Figure 1. The device includes a cartridge 10 with a blood processing chamber 12 formed of a suitable material (e.g., polycarbonate 14). The blood processing chamber 12 is surrounded by an optional outer chamber 16. Temperature-controlled fluid can be introduced through port 18, circulated through the outer chamber 16, and discharged through port 20. The device includes an inlet port 32 for introducing blood and an outlet port 34 for discharging blood. The device further includes one or more ports 48, 50 for accessing the space outside the flow channels of the cartridge. As shown in Figures 1 and 2, the blood processing chamber 12 includes a plurality of ultrafiltration membranes 22. These ultrafiltration membranes preferably have an inner pore size of 0.3 mm and an outer pore size of 0.5 mm. Figure 3 is a cross-sectional view of the flow channels 22, illustrating the anisotropy of the ultrafiltration membranes.As shown in FIG. 3, the hollow fiber membrane structure 40 is comprised of a single polymer material formed as a tubular section including a relatively dense ultrafiltration membrane 42 and a relatively porous outer portion 44, to which a lectin 46 may be immobilized. To operate the device, a solution containing lectin is loaded into the device through port 48. The loaded lectin is immobilized on the outer surface 22 of the ultrafiltration membrane, as shown in FIG. 2. Lectin that does not adhere to the outer surface 22 of the ultrafiltration membrane can be washed with saline or other solutions and recovered through port 50. The cartridge housing is made of polycarbonate, and the hollow fibers are held in place with a polyurethane-based potting material. The lectin is covalently bound to a solid resin material with a diameter of 150 to 300 microns (or larger) and resides outside the lumen (or outside the hollow fiber or flow channel). This solid resin material is composed of a porous silicon dioxide material (SiO2), preferably diatomaceous earth. The lectin-conjugated resin material (approximately 35-45 g) is filled into the space outside the hollow fibers through a polycarbonate side port in the cartridge, surrounding the hollow fibers. During operation, blood flows along the length of the hollow fibers, and plasma exits through the pores and comes into contact with the lectin attached to the solid resin matrix.

[0213] To attach lectins to an ultrafiltration membrane, the polymer of the ultrafiltration membrane is first activated using methods known in the art to make it more susceptible to chemical conjugation with proteins, for example. Any number of polymers can be used. For example, carbodiimides can be used to create reactive polyacrylic acid polymers (Valuev et al., 1998, Biomaterials, 19:41-3). Once the polymer is activated, lectins can be attached directly or via a linker to form an affinity matrix. Suitable linkers include, but are not limited to, avidin, streptavidin, biotin, protein A, or protein G. Alternatively, lectins can be directly or indirectly attached to the polymer of the ultrafiltration membrane using a coupling agent (e.g., a bifunctional reagent). In some embodiments, GNA covalently attached to agarose can be used to form the affinity matrix.

[0214] Accordingly, one aspect of the present invention is an affinity hemodialysis cartridge comprising a lectin, a filtering chamber configured to contain blood or plasma; a lectin disposed within the filtration chamber; A porous hollow fiber membrane with pores of 200 to 500 nm in diameter Including, The lectin may be bound to agarose, diatomaceous earth, or aminocelite; the lectin is selected from the group consisting of snowdrop agglutinin (GNA), daffodil agglutinin (NPA), cyanovirin and concanavalin A, and mixtures thereof; and the hemodialysis cartridge is configured to remove subcellular nanoparticles from blood or plasma; A hemodialysis cartridge is provided.

[0215] Methods that can be used to isolate lectins (e.g., GNA) are well known in the art. For example, Van Damme et al. have shown that lectins can be isolated from Galanthus nivalis (snowdrop) corms by affinity purification using mannose or other sugars (Van Damme et al. FEBS Letters (1987) 215(1):140-144). The use of purified GNA for affinity purification has previously been reported, for example, for the isolation of immunoglobulin-like glycoproteins (Shibuya et al. Archives Biochem. Biophys. (1988) 267(2):676-680). All of the above references are expressly incorporated herein by reference in their entirety.

[0216] Furthermore, the present invention provides the above-mentioned device, which further comprises a filtration chamber having an inlet port and an outlet port, a flow path of the porous hollow fiber membrane in fluid communication with the inlet port and the outlet port; The hemodialysis cartridge has an extra-flow space within the filtration chamber, the extra-flow space surrounding the porous hollow fiber membrane; and The lectin may be covalently bound to agarose, diatomaceous earth, or aminocelite disposed in a space outside the flow channel adjacent to the outer surface of the porous hollow fiber membrane. The present invention provides an apparatus characterized by:

[0217] In some methods of the present invention, blood or plasma containing subcellular nanoparticles (which may or may not contain SARS-CoV-2 viral particles) is withdrawn from a patient and contacted with an ultrafiltration membrane. In some embodiments, the blood is first separated into plasma and cellular components. The blood or plasma is then contacted with a lectin to remove the subcellular nanoparticles by binding glycoproteins to the lectin. The plasma and cellular components can then be recombined and returned to the patient. Alternatively, the cellular components can be returned to the patient separately from the plasma. Treatment can be repeated periodically until the desired response is achieved. In some embodiments, treatment can be administered for 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours, or a range of any two of these hours within a 24-hour window. In some embodiments, treatment can be repeated daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days.

[0218] In some embodiments, the methods and devices of the present invention further include a monoclonal antibody that binds to a glycoprotein from SARS-CoV-19 (e.g., the S1 spike protein described herein) as an affinity agent in the extracorporeal circulation circuit. In certain embodiments of the present invention, the methods and devices of the present invention include an affinity agent consisting of a GNA and an affinity agent consisting of a monoclonal antibody.

[0219] Those skilled in the art will appreciate that biological samples can be collected from various types of bodily fluids, including, but not limited to, peripheral blood, plasma, serum, ascites, cerebrospinal fluid (CSF), sputum, saliva, bone marrow, synovial fluid, aqueous humor, amniotic fluid, earwax, breast milk, alveolar lavage fluid, semen (including prostatic fluid), Cowper's fluid or pre-ejaculatory fluid, female ejaculatory fluid, sweat, feces, hair, tears, cyst fluid, pleural effusion, ascites, pericardial fluid, lymph, mucus, chyle, bile, interstitial fluid, menstrual fluid, pus, sebum, vomit, vaginal secretions, mucosal secretions, nasal secretions (e.g., isolated from nasal swabs), watery stool, urine, pancreatic juice, sinus lavage, bronchopulmonary aspirate, or other lavage fluid. Biological samples also include fetal or maternal samples such as the blastocyst cavity, umbilical cord blood, or maternal circulatory system. Biological samples may also be tissue samples or biopsy samples.

[0220] Therapeutic methods or uses for treating COVID-19 The present invention relates to a method for hemofiltration of blood or plasma using lectins in an extracorporeal circulation device. Accordingly, the present invention relates to a method for reducing subcellular nanoparticles (e.g., subcellular nanoparticles associated with COVID-19 or its symptoms or sequelae) from the circulatory system of an individual, comprising: obtaining blood or plasma from an individual; passing the blood or plasma through a porous hollow fiber membrane having lectin molecules immobilized on the outer porous portion; Recovering the blood or plasma that has passed through the porous hollow fiber membrane; and reinjecting the blood or plasma passed through the porous hollow fiber membrane into the individual. The present invention provides a method comprising:

[0221] In some embodiments, the device and method of the present invention can capture and physically remove the S1 (spike) protein of SARS-CoV-2 with high efficiency, but is not limited to such an embodiment. Thus, the present invention provides a method for capturing and physically removing COVID-19-mediated nanoparticles from the circulatory system of an individual, comprising: obtaining blood or plasma from an individual; passing the blood or plasma through a porous hollow fiber membrane having lectin molecules immobilized on the outer porous portion; Recovering the blood or plasma that has passed through the porous hollow fiber membrane; and reinjecting the blood or plasma passed through the porous hollow fiber membrane into the individual. The present invention provides a method comprising: However, in some embodiments, the devices and methods disclosed herein can be used in patients who no longer have an active viral infection, but who still exhibit symptoms or sequelae of the infection.

[0222] If a subject in need of the methods described herein is identified, e.g., a subject with severe COVID-19 disease, a subject at risk for severe COVID-19 disease (e.g., a subject requiring oxygen therapy), or a subject who has overcome COVID-19 but still has one or more symptoms or sequelae, the method for removing subcellular nanoparticles potentially associated with COVID-19 may include: a) providing a hollow fiber cartridge containing a lectin or other affinity binding agent that selectively binds to the outer surface of subcellular nanoparticles potentially associated with COVID-19; b) removing from the subject a biological sample (e.g., blood or plasma) containing a concentration of said subcellular nanoparticles using an extracorporeal circulation device; c) contacting the affinity binding agent with the biological sample by processing the biological sample using the hollow fiber cartridge; d) capturing and retaining at least a portion of the subcellular nanoparticles in the biological sample within the hollow fiber cartridge; and e) reintroducing the biological sample, from which the portion of the trapped subcellular nanoparticles has been removed, into the subject without removing the biological sample from the extracorporeal circulation device prior to reintroducing the biological sample into the subject. may also include: A biological sample from the subject, such as nasal secretions (e.g., isolated from a nasal swab), blood, or plasma, may be obtained from the subject before or after treatment, or both, and the biological sample is used to analyze the level or amount of subcellular nanoparticles.

[0223] Capturing SARS-CoV-2 virions from the circulation of critically ill COVID-19 patients may confer several positive benefits, including: (1) Reduction of the amount of SARS-CoV-2 in the whole body. (2) A reduction in the severity of the systemic inflammatory response (e.g., cytokine storm) associated with COVID-19 infection. (3) Improved function of immune cells, including cells with antiviral functions. (4) a reduction in persistent cellular infection, a reduction in progressive damage to affected organs, and / or a reduction in disease-related symptoms due to the virus itself and / or its inflammatory response.

[0224] As described herein, it has been demonstrated that exosomes can be captured from a patient's blood or plasma using an extracorporeal circulation device. In some embodiments, the patient may be a patient with an active coronavirus infection (e.g., COVID-19). In other embodiments, the patient may no longer have an active coronavirus infection (e.g., a reduced circulating viral load as detected by conventional methods or no circulating virus detected by conventional methods) but still exhibit symptoms or sequelae of the coronavirus infection. In some embodiments, exosomes removed by the extracorporeal circulation device may contain miR-424-5p, miR-16-2-3p, or both. These miRNAs may negatively affect a patient's coronavirus symptoms or sequelae, even if the patient no longer has an active coronavirus infection.

[0225] In some embodiments, methods are disclosed for reducing SARS-CoV-2 virions or portions thereof in a COVID-19 patient in need thereof. In some embodiments, the methods comprise: (a) introducing blood or plasma from a COVID-19 infected patient into an extracorporeal circulation device containing a lectin that binds to SARS-CoV-2 virions or portions thereof (e.g., snowdrop agglutinin (GNA), daffodil agglutinin (NPA), or cyanovirin from Nostoc ellipsosporum); (b) contacting the patient's blood or plasma with the lectin in the extracorporeal circulation device for a time sufficient to allow SARS-CoV-2 virions or portions thereof in the blood or plasma to bind to the lectin; and (c) returning to said patient the blood or plasma in which step (b) has been performed and which has a reduced amount of SARS-CoV-2 virions or a portion thereof compared to said patient's blood or plasma before step (b) has been performed. Including, (d) detecting or identifying SARS-CoV-2 virions or portions thereof in a sample (e.g., a nasal sample, a blood sample, a plasma sample, etc.) obtained from the patient before step (a) or after step (b), or both; and / or Selecting or identifying patients with COVID-19 for treatment that reduces SARS-CoV-2 virions or fragments thereof by comparing the levels or amounts to a control (e.g., the levels or amounts in a sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). may also include: In some embodiments, the patient does not have a coronavirus infection before step (a) but is experiencing symptoms or after-effects of a coronavirus infection. In some embodiments, the patient has recovered from a coronavirus infection before step (a) but is still experiencing symptoms or after-effects of a coronavirus infection. In some embodiments, the patient's blood or plasma is coronavirus-free before step (a) is performed but is still experiencing symptoms or after-effects of a coronavirus infection. In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the patient has early acute lung injury (ALI), early acute respiratory distress syndrome (ARDS), dyspnea, respiratory frequency of 30 breaths per minute or more, blood oxygen saturation of 93% or less, arterial oxygen tension to fractional inspired oxygen ratio of less than 300, pulmonary infiltrates of more than 50%, respiratory failure within 24 to 48 hours, elevated ferritin level, elevated lactate level, elevated lactate dehydrogenase (LDH) level, decreased absolute lymphocyte count (ALC), decreased platelet count, prolonged prothrombin time international normalized ratio (PT / INR), septic shock, or multiple organ dysfunction or failure, or any combination thereof. In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of IL-6 in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum IL-6 level is 2 pg / mL or greater.In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of D-dimer in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum D-dimer level is 500 ng / mL or greater. In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of troponin T in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum troponin T level is 15 ng / L or greater. In some preferred embodiments, the lectin is snowdrop agglutinin (GNA). In some embodiments, the extracorporeal circulation device includes a hollow fiber cartridge containing the lectin, and the blood or plasma flows through the hollow fibers of the hollow fiber cartridge. In some embodiments, the hollow fibers of the hollow fiber cartridge have a pore size that does not allow cellular components in the blood or plasma to pass through, so that the lectin does not come into contact with cellular components in the blood or plasma. In some embodiments, the pore size is 20 to 500 nm or approximately 20 to 500 nm. In some embodiments, the pore size is 200 nm or approximately 200 nm. In some embodiments, the lectin is immobilized or adsorbed on a solid support, and the hollow fiber cartridge includes the lectin immobilized or adsorbed on the solid support. In some embodiments, the solid support includes agarose, diatomaceous earth, or amino celite. In some embodiments, the solid support includes diatomaceous earth.In some embodiments, the method further comprises isolating coronavirus virions or portions thereof bound to the lectin contained in the extracorporeal circulation device. In some embodiments, the method further comprises isolating exosomes associated with a coronavirus infection, or a symptom or sequelae thereof, bound to the lectin contained in the extracorporeal circulation device. In some embodiments, the method further comprises examining the contents of the isolated exosomes. In some embodiments, the exosomes associated with a coronavirus infection, or a symptom or sequelae thereof, contain miR-424-5p or miR-16-2-3p, or both. In some embodiments, the method further comprises observing or measuring a decrease in the number of coronavirus virions or portions thereof, or a decrease in the number of exosomes associated with coronavirus infection or its symptoms or sequelae, in the patient's blood or plasma sample obtained after step (b) compared to the patient's blood or plasma sample obtained before step (b); or measuring the relative level or amount of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in the patient's blood or plasma sample obtained after step (b) compared to the patient's blood or plasma sample obtained before step (b). In some embodiments, the method further comprises observing an improvement in coronavirus infection or its symptoms or sequelae in the patient who has undergone step (b) or step (c), or both. In some embodiments, observing an improvement in coronavirus infection or its symptoms or sequelae comprises determining in the patient an improvement in early acute lung injury (ALI), early acute respiratory distress syndrome (ARDS), respiratory frequency, blood oxygen saturation, arterial oxygen tension to fractional inspired oxygen ratio, pulmonary infiltrates, respiratory failure, ferritin, lactate, LDH, absolute lymphocyte count (ALC), platelet count, PT / INR ratio, septic shock, or multiple organ dysfunction or failure, or any combination thereof.In some embodiments, observing improvement in coronavirus infection or its symptoms or sequelae comprises observing a decrease in the number of coronavirus virions or portions thereof, or a decrease in the number of exosomes associated with coronavirus infection or its symptoms or sequelae, in a biological sample (e.g., blood) obtained from the patient before, after, or both of the treatment; or measuring the level or amount of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in a biological sample (e.g., blood) obtained from the patient before, after, or both of the treatment. In some embodiments, the COVID-19 is caused by a SARS-CoV-2 mutant strain. In some embodiments, the SARS-CoV-2 variant strain is 20I / 501Y.V1 (alpha strain, B.1.1.7), 20H / 501Y.V2 (beta strain, B.1.351), 20J / 501Y.V3 (gamma strain, P.1), B.1.617.2 (delta strain), AY.1, AY.2, C.37 (lambda strain), B.1.621 (mu strain), B.1.1.207, VUI-202102 / 03 (B.1.525), VUI-202101 / 01 (P.2), VUI-202102 / 01 (A.23.1), VUI 202102 / 04 (B.1.1.318), VUI 202103 / 01 (B.1.324.1), B.1.427, CAL.20C (B.1.429), R.1, B.1.466.2, B.1.1.519, C.36.3, B.1.214.2, B.1.1.523, B.1.619, B.1.620, C.1.2, B.1.617.1, B.1.1.529 (Omicron strain), and B.1.526. In some embodiments, prior to performing step (a), blood clotting is prevented by priming the extracorporeal circulation device with an anticoagulant, preferably heparin.In some embodiments, the flow rate of the blood flowing through the extracorporeal circulation device is about 50 to about 600 mL / min, preferably about 200 to about 400 mL / min, preferably about 200 to about 240 mL / min or 200 to 240 mL / min, and most preferably 240 mL / min. In some embodiments, the blood flow is initiated at an initial flow rate of 100 mL / min and gradually increased to 200 mL / min (e.g., increased stepwise over 5 minutes). In some embodiments, the step of returning the blood to the patient includes flushing the extracorporeal circulation device with saline. In some embodiments, the blood or plasma is in contact with the extracorporeal circulation device for 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours, or a range of any two of these hours. In some embodiments, steps (a), (b), and (c) and optional step (d) are repeated daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days. In some embodiments, the method further comprises administering an additional antiviral therapy to the patient. In some embodiments, the additional antiviral therapy comprises administering favipiravir, favipiravir, remdesivir, tocilizumab, galidesivir, sarilumab, lopinavir, ritonavir, darunavir, ribavirin, interferon alpha, pegylated interferon alpha, interferon alpha-2b, convalescent serum, or any combination thereof.

[0226] Additionally, in some embodiments, methods are disclosed for reducing COVID-19-mediated nanoparticles in a COVID-19 patient in need thereof. In some embodiments, the methods include: (a) introducing blood or plasma from a COVID-19 infected patient into an extracorporeal circulation device containing a lectin that binds to COVID-19-mediated nanoparticles (e.g., snowdrop agglutinin (GNA), daffodil agglutinin (NPA), or cyanovirin from Nostoc ellipsosporum); (b) contacting the patient's blood or plasma with the lectin in the extracorporeal circulation device for a time sufficient for the COVID-19-mediated nanoparticles to bind to the lectin; and (c) returning to the patient the blood or plasma that has been subjected to step (b) and therefore has a reduced amount of COVID-19-mediated nanoparticles compared to the patient's blood or plasma before step (b) was performed. Including, (d) detecting or identifying SARS-CoV-2 virions or portions thereof or COVID-19-mediated nanoparticles in a sample (e.g., a nasal sample (e.g., a nasal sample obtained from a nasal swab), a blood sample, a plasma sample, etc.) obtained from the patient before step (a) or after step (b), or both; and / or Selecting or identifying patients with COVID-19 for treatment that reduces COVID-19-mediated nanoparticles by comparing the levels or amounts to a control (e.g., the levels or amounts in a sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). may also include: In some embodiments, the patient does not have a coronavirus infection before step (a) but is experiencing symptoms or after-effects of a coronavirus infection. In some embodiments, the patient has recovered from a coronavirus infection before step (a) but is still experiencing symptoms or after-effects of a coronavirus infection. In some embodiments, the patient's blood or plasma is coronavirus-free before step (a) is performed but is still experiencing symptoms or after-effects of a coronavirus infection. In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the patient has early acute lung injury (ALI), early acute respiratory distress syndrome (ARDS), dyspnea, respiratory frequency of 30 breaths per minute or more, blood oxygen saturation of 93% or less, arterial oxygen tension to fractional inspired oxygen ratio of less than 300, pulmonary infiltrates of more than 50%, respiratory failure within 24 to 48 hours, elevated ferritin level, elevated lactate level, elevated lactate dehydrogenase (LDH) level, decreased absolute lymphocyte count (ALC), decreased platelet count, prolonged prothrombin time international normalized ratio (PT / INR), septic shock, or multiple organ dysfunction or failure, or any combination thereof. In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of IL-6 in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum IL-6 level is 2 pg / mL or greater.In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of D-dimer in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum D-dimer level is 500 ng / mL or greater. In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of troponin T in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum troponin T level is 15 ng / L or greater. In some preferred embodiments, the lectin is snowdrop agglutinin (GNA). In some embodiments, the extracorporeal circulation device includes a hollow fiber cartridge containing the lectin, and the blood or plasma flows through the hollow fibers of the hollow fiber cartridge. In some embodiments, the hollow fibers of the hollow fiber cartridge have a pore size that does not allow cellular components in the blood or plasma to pass through, so that the lectin does not come into contact with cellular components in the blood or plasma. In some embodiments, the pore size is 20 to 500 nm or approximately 20 to 500 nm. In some embodiments, the pore size is 200 nm or approximately 200 nm. In some embodiments, the lectin is immobilized or adsorbed on a solid support, and the hollow fiber cartridge includes the lectin immobilized or adsorbed on the solid support. In some embodiments, the solid support includes agarose, diatomaceous earth, or amino celite. In some embodiments, the solid support includes diatomaceous earth.In some embodiments, the method further comprises isolating coronavirus virions or portions thereof bound to the lectin contained in the extracorporeal circulation device. In some embodiments, the method further comprises isolating exosomes associated with a coronavirus infection, or a symptom or sequelae thereof, bound to the lectin contained in the extracorporeal circulation device. In some embodiments, the method further comprises examining the contents of the isolated exosomes. In some embodiments, the exosomes associated with a coronavirus infection, or a symptom or sequelae thereof, contain miR-424-5p or miR-16-2-3p, or both. In some embodiments, the method further comprises observing or measuring a decrease in the number of coronavirus virions or portions thereof, or a decrease in the number of exosomes associated with coronavirus infection or its symptoms or sequelae, in a biological sample (e.g., blood or plasma) obtained from the patient before, after, or both of the treatment; or measuring the level or amount of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in a biological sample (e.g., blood or plasma) obtained from the patient before, after, or both of the treatment. In some embodiments, the method further comprises observing an improvement in coronavirus infection or its symptoms or sequelae in the patient who has undergone step (b) or step (c), or both. In some embodiments, observing an improvement in coronavirus infection or its symptoms or sequelae comprises determining in the patient an improvement in early acute lung injury (ALI), early acute respiratory distress syndrome (ARDS), respiratory frequency, blood oxygen saturation, arterial oxygen tension to fractional inspired oxygen ratio, pulmonary infiltrates, respiratory failure, ferritin, lactate, LDH, absolute lymphocyte count (ALC), platelet count, PT / INR ratio, septic shock, or multiple organ dysfunction or failure, or any combination thereof.In some embodiments, observing improvement in coronavirus infection or its symptoms or sequelae includes observing a decrease in the number of coronavirus virions or portions thereof, or a decrease in the number of exosomes associated with coronavirus infection or its symptoms or sequelae, in a biological sample (e.g., blood or plasma) obtained from the patient before, after, or both of the treatment; or measuring the level or amount of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in a biological sample (e.g., blood or plasma) obtained from the patient before, after, or both of the treatment. In some embodiments, the COVID-19 is caused by a SARS-CoV-2 mutant strain. In some embodiments, the SARS-CoV-2 variant strain is 20I / 501Y.V1 (alpha strain, B.1.1.7), 20H / 501Y.V2 (beta strain, B.1.351), 20J / 501Y.V3 (gamma strain, P.1), B.1.617.2 (delta strain), AY.1, AY.2, C.37 (lambda strain), B.1.621 (mu strain), B.1.1.207, VUI-202102 / 03 (B.1.525), VUI-202101 / 01 (P.2), VUI-202102 / 01 (A.23.1), VUI 202102 / 04 (B.1.1.318), VUI 202103 / 01 (B.1.324.1), B.1.427, CAL.20C (B.1.429), R.1, B.1.466.2, B.1.1.519, C.36.3, B.1.214.2, B.1.1.523, B.1.619, B.1.620, C.1.2, B.1.617.1, B.1.1.529 (Omicron strain), and B.1.526. In some embodiments, prior to performing step (a), blood clotting is prevented by priming the extracorporeal circulation device with an anticoagulant, preferably heparin.In some embodiments, the flow rate of the blood flowing through the extracorporeal circulation device is about 50 to about 600 mL / min, preferably about 200 to about 400 mL / min, and preferably about 200 to about 240 mL / min. In some embodiments, the blood flow is initiated at an initial flow rate of 100 mL / min and gradually increased to 200 mL / min (e.g., a stepwise increase over 5 minutes). In some embodiments, returning the blood to the patient includes flushing the extracorporeal circulation device with saline. In some embodiments, the contact time of the blood or plasma with the extracorporeal circulation device is 0.1 hours, 0.2 hours, 0.3 hours, 0.4 hours, 0.5 hours, 0.6 hours, 0.7 hours, 0.8 hours, 0.9 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours, or a range defined by any two of these hours. In some embodiments, steps (a), (b), and (c) and optional step (d) are repeated daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days. In some embodiments, the method further comprises administering an additional antiviral therapy to the patient. In some embodiments, the additional antiviral therapy comprises favipiravir, favipiravir, remdesivir, tocilizumab, galidesivir, sarilumab, lopinavir, ritonavir, darunavir, ribavirin, interferon alpha, pegylated interferon alpha, interferon alpha-2b, convalescent serum, or any combination thereof.

[0227] Additionally, in some embodiments, methods are disclosed for reducing COVID-19 antigen-containing exosomes in COVID-19 patients. In some embodiments, the methods include: (a) introducing blood or plasma from a COVID-19 infected patient into an extracorporeal circulation device containing a lectin (e.g., snowdrop agglutinin (GNA), daffodil agglutinin (NPA), or Nostoc ellipsosporum-derived cyanovirin) that binds to COVID-19 antigen-containing exosomes; (b) contacting the patient's blood or plasma with the lectin in the extracorporeal circulation device for a period of time sufficient for the COVID-19 antigen-containing exosomes to bind to the lectin; and (c) returning to the patient the blood or plasma in which the amount of COVID-19 antigen-containing exosomes has been reduced as a result of step (b) compared to the patient's blood or plasma before step (b). Including, (d) detecting or identifying SARS-CoV-2 virions or portions thereof or COVID-19 antigen-containing exosomes in a sample (e.g., a nasal sample, a blood sample, a plasma sample, etc.) obtained from the patient before step (a) or after step (b), or both; and / or Selecting or identifying patients with COVID-19 for treatment that reduces COVID-19 antigen-containing exosomes compared to a control level or amount (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). may also include: In some embodiments, the patient does not have a coronavirus infection before step (a) but is experiencing symptoms or after-effects of a coronavirus infection. In some embodiments, the patient has recovered from a coronavirus infection before step (a) but is still experiencing symptoms or after-effects of a coronavirus infection. In some embodiments, the patient's blood or plasma is coronavirus-free before step (a) is performed but is still experiencing symptoms or after-effects of a coronavirus infection. In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the patient has early acute lung injury (ALI), early acute respiratory distress syndrome (ARDS), dyspnea, respiratory frequency of 30 breaths per minute or more, blood oxygen saturation of 93% or less, arterial oxygen tension to fractional inspired oxygen ratio of less than 300, pulmonary infiltrates of more than 50%, respiratory failure within 24 to 48 hours, elevated ferritin levels, elevated lactate levels, elevated lactate dehydrogenase (LDH) levels, decreased absolute lymphocyte count (ALC), decreased platelet count, prolonged prothrombin time / INR, septic shock, or multiple organ dysfunction or failure, or any combination thereof, compared to a control level or amount (e.g., the level or amount in a sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae or a healthy patient). In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of IL-6 in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum IL-6 level is 2 pg / mL or greater.In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of D-dimer in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum D-dimer level is 500 ng / mL or greater. In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of troponin T in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum troponin T level is 15 ng / L or greater. In some preferred embodiments, the lectin is snowdrop agglutinin (GNA). In some embodiments, the extracorporeal circulation device includes a hollow fiber cartridge containing the lectin, and the blood or plasma flows through the hollow fibers of the hollow fiber cartridge. In some embodiments, the hollow fibers of the hollow fiber cartridge have a pore size that does not allow cellular components in the blood or plasma to pass through, so that the lectin does not come into contact with cellular components in the blood or plasma. In some embodiments, the pore size is 20 to 500 nm or approximately 20 to 500 nm. In some embodiments, the pore size is 200 nm or approximately 200 nm. In some embodiments, the lectin is immobilized or adsorbed on a solid support, and the hollow fiber cartridge includes the lectin immobilized or adsorbed on the solid support. In some embodiments, the solid support includes agarose, diatomaceous earth, or amino celite. In some embodiments, the solid support includes diatomaceous earth.In some embodiments, the method further comprises isolating coronavirus virions or portions thereof bound to the lectin contained in the extracorporeal circulation device. In some embodiments, the method further comprises isolating exosomes associated with a coronavirus infection, or a symptom or sequelae thereof, bound to the lectin contained in the extracorporeal circulation device. In some embodiments, the method further comprises examining the contents of the isolated exosomes. In some embodiments, the exosomes associated with a coronavirus infection, or a symptom or sequelae thereof, contain miR-424-5p or miR-16-2-3p, or both. In some embodiments, the method includes observing or measuring a decrease in the number of coronavirus virions or portions thereof, or a decrease in the number of exosomes associated with coronavirus infection or its symptoms or sequelae, in a biological sample (e.g., blood or plasma) obtained from the patient before, after, or both of the treatment; or measuring the level or amount of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in a biological sample (e.g., blood or plasma) obtained from the patient before, after, or both of the treatment. In some embodiments, the method further includes observing an improvement in coronavirus infection or its symptoms or sequelae in the patient who has undergone step (b) or step (c), or both. In some embodiments, observing an improvement in coronavirus infection or its symptoms or sequelae comprises determining in the patient an improvement in early acute lung injury (ALI), early acute respiratory distress syndrome (ARDS), respiratory frequency, blood oxygen saturation, arterial oxygen tension to fractional inspired oxygen ratio, pulmonary infiltrates, respiratory failure, ferritin, lactate, LDH, absolute lymphocyte count (ALC), platelet count, PT / INR ratio, septic shock, or multiple organ dysfunction or failure, or any combination thereof.In some embodiments, observing improvement in coronavirus infection or its symptoms or sequelae includes observing a decrease in the number of coronavirus virions or portions thereof, or a decrease in the number of exosomes associated with coronavirus infection or its symptoms or sequelae, in a biological sample (e.g., blood or plasma) obtained from the patient before, after, or both of the treatment; or measuring the level or amount of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in a biological sample (e.g., blood or plasma) obtained from the patient before, after, or both of the treatment. In some embodiments, the COVID-19 is caused by a SARS-CoV-2 mutant strain. In some embodiments, the SARS-CoV-2 variant strain is 20I / 501Y.V1 (alpha strain, B.1.1.7), 20H / 501Y.V2 (beta strain, B.1.351), 20J / 501Y.V3 (gamma strain, P.1), B.1.617.2 (delta strain), AY.1, AY.2, C.37 (lambda strain), B.1.621 (mu strain), B.1.1.207, VUI-202102 / 03 (B.1.525), VUI-202101 / 01 (P.2), VUI-202102 / 01 (A.23.1), VUI 202102 / 04 (B.1.1.318), VUI 202103 / 01 (B.1.324.1), B.1.427, CAL.20C (B.1.429), R.1, B.1.466.2, B.1.1.519, C.36.3, B.1.214.2, B.1.1.523, B.1.619, B.1.620, C.1.2, B.1.617.1, B.1.1.529 (Omicron strain), and B.1.526. In some embodiments, prior to performing step (a), blood clotting is prevented by priming the extracorporeal circulation device with an anticoagulant, preferably heparin.In some embodiments, the flow rate of the blood flowing through the extracorporeal circulation device is about 50 to about 600 mL / min, preferably about 200 to about 400 mL / min, and more preferably about 200 to about 240 mL / min, 200 to 240 mL / min, or 240 mL / min. In some embodiments, the blood flow is initiated at an initial flow rate of 100 mL / min and gradually increased to 200 mL / min (e.g., increased stepwise over 5 minutes). In some embodiments, the step of returning the blood to the patient includes flushing the extracorporeal circulation device with saline. In some embodiments, the blood or plasma is in contact with the extracorporeal circulation device for 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours, or a range of any two of these hours. In some embodiments, steps (a), (b), and (c) and optional step (d) are repeated daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days. In some embodiments, the method further comprises administering an additional antiviral therapy to the patient. In some embodiments, the additional antiviral therapy comprises favipiravir, favipiravir, remdesivir, tocilizumab, galidesivir, sarilumab, lopinavir, ritonavir, darunavir, ribavirin, interferon alpha, pegylated interferon alpha, interferon alpha-2b, convalescent serum, or any combination thereof.

[0228] Additionally, in some embodiments, methods are disclosed for reducing the level or amount of circulating interleukin 6 (IL-6) in a subject (e.g., a COVID-19 patient) compared to a patient not experiencing inflammation or COVID-19 infection or its associated sequelae or a healthy patient. In some embodiments, the methods include: (a) introducing blood or plasma from a COVID-19 infected patient into an extracorporeal circulation device containing a lectin (e.g., snowdrop agglutinin (GNA), daffodil agglutinin (NPA), or Nostoc ellipsosporum cyanovirin) that binds to SARS-CoV-2 virions or fragments thereof or COVID-19 antigen-containing exosomes; (b) contacting the patient's blood or plasma with the lectin in the extracorporeal circulation device for a time sufficient to allow SARS-CoV-2 virions or fragments thereof or COVID-19 antigen-containing exosomes to bind to the lectin; and (c) returning to the patient the blood or plasma in which the amount of SARS-CoV-2 virions or fragments thereof or COVID-19 antigen-containing exosomes has been reduced as a result of step (b) compared to the patient's blood or plasma before step (b). Including, (d) measuring the level or amount of IL-6 in a sample (e.g., a blood sample, a plasma sample, etc.) obtained from the patient before step (a) or after step (b), or both; and Selecting or identifying patients with COVID-19 for treatment that reduces the level or amount of IL-6 in the plasma or blood sample compared to a control level or amount (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). may also include: In some embodiments, the patient does not have coronavirus infection before step (a) but exhibits symptoms or sequelae of coronavirus infection. In some embodiments, the patient has recovered from coronavirus infection before step (a) but still exhibits symptoms or sequelae of coronavirus infection. In some embodiments, the patient's blood or plasma is coronavirus-free before performing step (a), but the patient still exhibits symptoms or sequelae of coronavirus infection. In some embodiments, the method further includes determining whether the patient has early acute lung injury (ALI), early acute respiratory distress syndrome (ARDS), dyspnea, a respiratory frequency of 30 breaths per minute or greater, a blood oxygen saturation of 93% or less, an arterial oxygen tension to inspired oxygen ratio of less than 300, pulmonary infiltrates greater than 50%, respiratory failure within 24 to 48 hours, septic shock, or multiple organ dysfunction or failure, or any combination thereof, before step (a) or after step (b), or both. In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of IL-6 in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or associated sequelae, or a healthy patient). In some embodiments, the elevated serum IL-6 level is 2 pg / mL or greater. In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of D-dimer in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or associated sequelae, or a healthy patient). In some embodiments, the elevated serum D-dimer level is 500 mg / mL or greater.In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of troponin T in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum troponin T level is 15 ng / L or greater. In some preferred embodiments, the lectin is snowdrop agglutinin (GNA). In some embodiments, the extracorporeal circulation device includes a hollow fiber cartridge containing the lectin, and the blood or plasma flows through the hollow fibers of the hollow fiber cartridge. In some embodiments, the hollow fibers of the hollow fiber cartridge have a pore size that does not allow cellular components in the blood or plasma to pass through, so that the lectin does not come into contact with cellular components in the blood or plasma. In some embodiments, the pore size is 20 to 500 nm or about 20 to 500 nm. In some embodiments, the pore size is 200 nm or about 200 nm. In some embodiments, the lectin is immobilized or adsorbed on a solid support, and the hollow fiber cartridge comprises the lectin immobilized or adsorbed on the solid support. In some embodiments, the solid support comprises agarose, diatomaceous earth, or aminocelite. In some embodiments, the solid support comprises diatomaceous earth. In some embodiments, the method further comprises isolating coronavirus virions or portions thereof bound to the lectin contained in the extracorporeal circulation device. In some embodiments, the method further comprises isolating exosomes associated with a coronavirus infection or symptoms or sequelae thereof bound to the lectin contained in the extracorporeal circulation device. In some embodiments, the method further comprises examining the contents of the isolated exosomes.In some embodiments, the exosomes associated with a coronavirus infection, or a symptom or sequelae thereof, comprise miR-424-5p or miR-16-2-3p, or both. In some embodiments, the method includes observing or measuring a decrease in the number of coronavirus virions or portions thereof, or a decrease in the number of exosomes associated with a coronavirus infection, or a symptom or sequelae thereof, in a biological sample (e.g., blood) obtained from the patient before, after, or both of the treatment; or measuring the level or amount of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in a biological sample (e.g., blood) obtained from the patient before, after, or both of the treatment. In some embodiments, the method further includes observing an improvement in the coronavirus infection, or a symptom or sequelae thereof, in the patient who has undergone step (b) or step (c), or both. In some embodiments, observing an improvement in coronavirus infection or its symptoms or sequelae comprises determining in the patient an improvement in early acute lung injury (ALI), early acute respiratory distress syndrome (ARDS), respiratory frequency, blood oxygen saturation, arterial oxygen tension to fractional inspired oxygen ratio, pulmonary infiltrates, respiratory failure, septic shock, or multiple organ dysfunction or failure, or any combination thereof.In some embodiments, observing improvement in coronavirus infection or its symptoms or sequelae includes observing a decrease in the number of coronavirus virions or portions thereof, or a decrease in the number of exosomes associated with coronavirus infection or its symptoms or sequelae, in a biological sample (e.g., blood or plasma) obtained from the patient before, after, or both of the treatment; or measuring the level or amount of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in a biological sample (e.g., blood or plasma) obtained from the patient before, after, or both of the treatment. In some embodiments, the COVID-19 is caused by a SARS-CoV-2 mutant strain. In some embodiments, the SARS-CoV-2 variant strain is 20I / 501Y.V1 (alpha strain, B.1.1.7), 20H / 501Y.V2 (beta strain, B.1.351), 20J / 501Y.V3 (gamma strain, P.1), B.1.617.2 (delta strain), AY.1, AY.2, C.37 (lambda strain), B.1.621 (mu strain), B.1.1.207, VUI-202102 / 03 (B.1.525), VUI-202101 / 01 (P.2), VUI-202102 / 01 (A.23.1), VUI 202102 / 04 (B.1.1.318), VUI 202103 / 01 (B.1.324.1), B.1.427, CAL.20C (B.1.429), R.1, B.1.466.2, B.1.1.519, C.36.3, B.1.214.2, B.1.1.523, B.1.619, B.1.620, C.1.2, B.1.617.1, B.1.1.529 (Omicron strain), and B.1.526. In some embodiments, prior to performing step (a), blood clotting is prevented by priming the extracorporeal circulation device with an anticoagulant, preferably heparin.In some embodiments, the flow rate of the blood through the extracorporeal circulation device is about 50 to about 600 mL / min, preferably about 200 to about 400 mL / min or 200 to 240 mL / min, and most preferably 240 mL / min. In some embodiments, the blood flow is initiated at an initial flow rate of 100 mL / min and gradually increased to 200 mL / min (e.g., a stepwise increase over 5 minutes). In some embodiments, returning the blood to the patient includes flushing the extracorporeal circulation device with saline. In some embodiments, the contact time of the blood or plasma with the extracorporeal circulation device is 0.1 hours, 0.2 hours, 0.3 hours, 0.4 hours, 0.5 hours, 0.6 hours, 0.7 hours, 0.8 hours, 0.9 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours, or a range defined by any two of these limits. In some embodiments, steps (a), (b), and (c) and optional step (d) are repeated daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days. In some embodiments, the method further comprises administering an additional antiviral therapy to the patient. In some embodiments, the additional antiviral therapy comprises favipiravir, favipiravir, remdesivir, tocilizumab, galidesivir, sarilumab, lopinavir, ritonavir, darunavir, ribavirin, interferon alpha, pegylated interferon alpha, interferon alpha-2b, convalescent serum, or any combination thereof.

[0229] Additionally, in some embodiments, methods are disclosed for reducing the level or amount of circulating D-dimer in a subject (e.g., a COVID-19 patient) compared to a patient not experiencing inflammation or COVID-19 infection or its associated sequelae or a healthy patient. In some embodiments, the methods include: (a) introducing blood or plasma from a COVID-19 infected patient into an extracorporeal circulation device containing a lectin (e.g., snowdrop agglutinin (GNA), daffodil agglutinin (NPA), or Nostoc ellipsosporum cyanovirin) that binds to SARS-CoV-2 virions or fragments thereof or COVID-19 antigen-containing exosomes; (b) contacting the patient's blood or plasma with the lectin in the extracorporeal circulation device for a time sufficient to allow SARS-CoV-2 virions or fragments thereof or COVID-19 antigen-containing exosomes to bind to the lectin; and (c) returning to the patient the blood or plasma in which the amount of SARS-CoV-2 virions or fragments thereof or COVID-19 antigen-containing exosomes has been reduced as a result of step (b) compared to the patient's blood or plasma before step (b). Including, (d) measuring the level or amount of D-dimer in a sample (e.g., a blood sample, a plasma sample, etc.) obtained from the patient before step (a) or after step (b), or both; and Selecting or identifying patients with COVID-19 for treatment that reduces the level or amount of D-dimer in the blood or plasma sample compared to a control level or amount (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). may also include: In some embodiments, the patient does not have a coronavirus infection before step (a) but is experiencing symptoms or after-effects of a coronavirus infection. In some embodiments, the patient has recovered from a coronavirus infection before step (a) but is still experiencing symptoms or after-effects of a coronavirus infection. In some embodiments, the patient's blood or plasma is coronavirus-free before step (a) is performed but is still experiencing symptoms or after-effects of a coronavirus infection. In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the patient has early acute lung injury (ALI), early acute respiratory distress syndrome (ARDS), dyspnea, respiratory frequency of 30 breaths per minute or more, blood oxygen saturation of 93% or less, arterial oxygen tension to fractional inspired oxygen ratio of less than 300, pulmonary infiltrates of more than 50%, respiratory failure within 24 to 48 hours, elevated ferritin level, elevated lactate level, elevated lactate dehydrogenase (LDH) level, decreased absolute lymphocyte count (ALC), decreased platelet count, prolonged prothrombin time international normalized ratio (PT / INR), septic shock, or multiple organ dysfunction or failure, or any combination thereof. In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of IL-6 in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum IL-6 level is 2 pg / mL or greater.In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of D-dimer in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum D-dimer level is 500 ng / mL or greater. In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of troponin T in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum troponin T level is 15 ng / L or greater. In some preferred embodiments, the lectin is snowdrop agglutinin (GNA). In some embodiments, the extracorporeal circulation device includes a hollow fiber cartridge containing the lectin, and the blood or plasma flows through the hollow fibers of the hollow fiber cartridge. In some embodiments, the hollow fibers of the hollow fiber cartridge have a pore size that does not allow cellular components in the blood or plasma to pass through, so that the lectin does not come into contact with cellular components in the blood or plasma. In some embodiments, the pore size is 20 to 500 nm or approximately 20 to 500 nm. In some embodiments, the pore size is 200 nm or approximately 200 nm. In some embodiments, the lectin is immobilized or adsorbed on a solid support, and the hollow fiber cartridge includes the lectin immobilized or adsorbed on the solid support. In some embodiments, the solid support includes agarose, diatomaceous earth, or amino celite. In some embodiments, the solid support includes diatomaceous earth.In some embodiments, the method further comprises isolating coronavirus virions or portions thereof bound to the lectin contained in the extracorporeal circulation device. In some embodiments, the method further comprises isolating exosomes associated with a coronavirus infection, or a symptom or sequelae thereof, bound to the lectin contained in the extracorporeal circulation device. In some embodiments, the method further comprises examining the contents of the isolated exosomes. In some embodiments, the exosomes associated with a coronavirus infection, or a symptom or sequelae thereof, contain miR-424-5p or miR-16-2-3p, or both. In some embodiments, the method comprises observing or measuring a decrease in the number of coronavirus virions or portions thereof, or a decrease in the number of exosomes associated with coronavirus infection or its symptoms or sequelae, in a biological sample (e.g., blood) obtained from the patient before, after, or both of the treatment; or measuring the level or amount of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in a biological sample (e.g., blood) obtained from the patient before, after, or both of the treatment. In some embodiments, the method further comprises observing an improvement in coronavirus infection or its symptoms or sequelae in the patient who has undergone step (b) or step (c), or both. In some embodiments, observing an improvement in coronavirus infection or its symptoms or sequelae comprises determining in the patient an improvement in early acute lung injury (ALI), early acute respiratory distress syndrome (ARDS), respiratory frequency, blood oxygen saturation, arterial oxygen tension to fractional inspired oxygen ratio, pulmonary infiltrates, respiratory failure, ferritin, lactate, LDH, absolute lymphocyte count (ALC), platelet count, PT / INR ratio, septic shock, or multiple organ dysfunction or failure, or any combination thereof.In some embodiments, observing improvement in coronavirus infection or its symptoms or sequelae comprises observing a decrease in the number of coronavirus virions or portions thereof, or a decrease in the number of exosomes associated with coronavirus infection or its symptoms or sequelae, in a biological sample (e.g., blood) obtained from the patient before, after, or both of the treatment; or measuring the level or amount of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in a biological sample (e.g., blood) obtained from the patient before, after, or both of the treatment. In some embodiments, the COVID-19 is caused by a SARS-CoV-2 mutant strain. In some embodiments, the SARS-CoV-2 variant strain is 20I / 501Y.V1 (alpha strain, B.1.1.7), 20H / 501Y.V2 (beta strain, B.1.351), 20J / 501Y.V3 (gamma strain, P.1), B.1.617.2 (delta strain), AY.1, AY.2, C.37 (lambda strain), B.1.621 (mu strain), B.1.1.207, VUI-202102 / 03 (B.1.525), VUI-202101 / 01 (P.2), VUI-202102 / 01 (A.23.1), VUI 202102 / 04 (B.1.1.318), VUI 202103 / 01 (B.1.324.1), B.1.427, CAL.20C (B.1.429), R.1, B.1.466.2, B.1.1.519, C.36.3, B.1.214.2, B.1.1.523, B.1.619, B.1.620, C.1.2, B.1.617.1, B.1.1.529 (Omicron strain), and B.1.526. In some embodiments, prior to performing step (a), blood clotting is prevented by priming the extracorporeal circulation device with an anticoagulant, preferably heparin.In some embodiments, the flow rate of the blood flowing through the extracorporeal circulation device is about 50 to about 600 mL / min, preferably about 200 to about 400 mL / min, preferably about 200 to about 240 mL / min or 200 to 240 mL / min, and most preferably 240 mL / min. In some embodiments, the blood flow is initiated at an initial flow rate of 100 mL / min and gradually increased to 200 mL / min (e.g., increased stepwise over 5 minutes). In some embodiments, the step of returning the blood to the patient includes flushing the extracorporeal circulation device with saline. In some embodiments, the blood or plasma is in contact with the extracorporeal circulation device for 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours, or a range of any two of these hours. In some embodiments, steps (a), (b), and (c) and optional step (d) are repeated daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days. In some embodiments, the method further comprises administering an additional antiviral therapy to the patient. In some embodiments, the additional antiviral therapy comprises favipiravir, favipiravir, remdesivir, tocilizumab, galidesivir, sarilumab, lopinavir, ritonavir, darunavir, ribavirin, interferon alpha, pegylated interferon alpha, interferon alpha-2b, convalescent serum, or any combination thereof.

[0230] Additionally, in some embodiments, methods are disclosed for reducing the level or amount of circulating Troponin T in COVID-19 patients compared to patients not experiencing inflammation or COVID-19 infection or its associated sequelae or healthy patients. In some embodiments, the methods include: (a) introducing blood or plasma from a COVID-19 infected patient into an extracorporeal circulation device containing a lectin (e.g., snowdrop agglutinin (GNA), daffodil agglutinin (NPA), or Nostoc ellipsosporum cyanovirin) that binds to SARS-CoV-2 virions or fragments thereof or COVID-19 antigen-containing exosomes; (b) contacting the patient's blood or plasma with the lectin in the extracorporeal circulation device for a time sufficient to allow SARS-CoV-2 virions or fragments thereof or COVID-19 antigen-containing exosomes to bind to the lectin; and (c) returning to the patient the blood or plasma in which the amount of SARS-CoV-2 virions or fragments thereof or COVID-19 antigen-containing exosomes has been reduced as a result of step (b) compared to the patient's blood or plasma before step (b). Including, (d) measuring the level or amount of troponin T in a sample (e.g., a blood sample, a plasma sample, etc.) obtained from the patient before step (a) or after step (b), or both; and Selecting or identifying patients with COVID-19 for treatment that reduces the level or amount of Troponin T in the blood or plasma sample compared to a control level or amount (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). may also include: In some embodiments, the patient does not have coronavirus infection before step (a) but exhibits symptoms or sequelae of coronavirus infection. In some embodiments, the patient has recovered from coronavirus infection before step (a) but still exhibits symptoms or sequelae of coronavirus infection. In some embodiments, the patient's blood or plasma is coronavirus-free before performing step (a), but the patient still exhibits symptoms or sequelae of coronavirus infection. In some embodiments, the method further includes determining whether the patient has early acute lung injury (ALI), early acute respiratory distress syndrome (ARDS), dyspnea, a respiratory frequency of 30 breaths per minute or greater, a blood oxygen saturation of 93% or less, an arterial oxygen tension to inspired oxygen ratio of less than 300, pulmonary infiltrates greater than 50%, respiratory failure within 24 to 48 hours, septic shock, or multiple organ dysfunction or failure, or any combination thereof, before step (a) or after step (b), or both. In some embodiments, the method further comprises determining whether the level or amount of IL-6 in the patient's blood or plasma sample is elevated before step (a) or after step (b), or both, compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum IL-6 level is 2 pg / mL or greater. In some embodiments, the method further comprises determining whether the level or amount of D-dimer in the patient's blood or plasma sample is elevated before step (a) or after step (b), or both. In some embodiments, the elevated serum D-dimer level is 500 ng / mL or greater. In some embodiments, the method further comprises determining whether the level or amount of troponin T in the patient's blood or plasma sample is elevated before step (a) or after step (b), or both.In some embodiments, the elevated serum troponin T level is 15 ng / L or greater. In some preferred embodiments, the lectin is snowdrop agglutinin (GNA). In some embodiments, the extracorporeal circulation device includes a hollow fiber cartridge containing the lectin, and the blood or plasma flows through the hollow fibers of the hollow fiber cartridge. In some embodiments, the hollow fibers of the hollow fiber cartridge have a pore size that does not allow cellular components in the blood or plasma to pass through, so that the lectin does not come into contact with cellular components in the blood or plasma. In some embodiments, the pore size is 20 to 500 nm or about 20 to 500 nm. In some embodiments, the pore size is 200 nm or about 200 nm. In some embodiments, the lectin is immobilized or adsorbed on a solid support, and the hollow fiber cartridge includes the lectin immobilized or adsorbed on the solid support. In some embodiments, the solid support includes agarose, diatomaceous earth, or amino celite. In some embodiments, the solid support includes diatomaceous earth. In some embodiments, the method further comprises isolating coronavirus virions or portions thereof bound to the lectin contained in the extracorporeal circulation device. In some embodiments, the method further comprises isolating exosomes associated with a coronavirus infection, or a symptom or sequelae thereof, bound to the lectin contained in the extracorporeal circulation device. In some embodiments, the method further comprises examining the contents of the isolated exosomes. In some embodiments, the exosomes associated with a coronavirus infection, or a symptom or sequelae thereof, contain miR-424-5p or miR-16-2-3p, or both.In some embodiments, the method includes observing or measuring a decrease in the number of coronavirus virions or portions thereof, or a decrease in the number of exosomes associated with coronavirus infection or its symptoms or sequelae, in a biological sample (e.g., blood or plasma) obtained from the patient before, after, or both of the treatment; or measuring the level or amount of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in a biological sample (e.g., blood or plasma) obtained from the patient before, after, or both of the treatment. In some embodiments, the method further includes observing an improvement in coronavirus infection or its symptoms or sequelae in the patient who has undergone step (b) or step (c), or both. In some embodiments, observing an improvement in coronavirus infection or its symptoms or sequelae comprises determining in the patient an improvement in early acute lung injury (ALI), early acute respiratory distress syndrome (ARDS), respiratory frequency, blood oxygen saturation, arterial oxygen tension to fractional inspired oxygen ratio, pulmonary infiltrates, respiratory failure, septic shock, or multiple organ dysfunction or failure, or any combination thereof. In some embodiments, observing improvement in a coronavirus infection or its symptoms or sequelae comprises observing a decrease in the number of coronavirus virions or portions thereof, or a decrease in the number of exosomes associated with a coronavirus infection or its symptoms or sequelae, in a biological sample (e.g., blood or plasma) obtained from the patient before and / or after the treatment; or measuring the level or amount of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in a biological sample (e.g., blood or plasma) obtained from the patient before and / or after the treatment.In some embodiments, the COVID-19 is caused by a variant strain of SARS-CoV-2. In some embodiments, the SARS-CoV-2 variant strain is 20I / 501Y.V1 (alpha strain, B.1.1.7), 20H / 501Y.V2 (beta strain, B.1.351), 20J / 501Y.V3 (gamma strain, P.1), B.1.617.2 (delta strain), AY.1, AY.2, C.37 (lambda strain), B.1.621 (mu strain), B.1.1.207, VUI-202102 / 03 (B.1.525), VUI-202101 / 01 (P.2), VUI-202102 / 01 (A.23.1), VUI 202102 / 04 (B.1.1.318), VUI 202103 / 01 (B.1.324.1), B.1.427, CAL.20C (B.1.429), R.1, B.1.466.2, B.1.1.519, C.36.3, B.1.214.2, B.1.1.523, B.1.619, B.1.620, C.1.2, B.1.617.1, B.1.1.529 (Omicron strain), and B.1.526. In some embodiments, prior to performing step (a), blood clotting is prevented by priming the extracorporeal circulation device with an anticoagulant, preferably heparin. In some embodiments, the flow rate of the blood through the extracorporeal circulation device is about 50 to about 600 mL / min, preferably about 200 to about 400 mL / min or 200 to 240 mL / min, and most preferably 240 mL / min. In some embodiments, the blood flow is initiated at an initial flow rate of 100 mL / min and gradually increased to 200 mL / min (e.g., a stepwise increase over 5 minutes). In some embodiments, returning the blood to the patient includes flushing the extracorporeal circulation device with saline. In some embodiments, the contact time of the blood or plasma with the extracorporeal circulation device is 0.1 hours, 0.2 hours, 0.3 hours, 0.4 hours, 0.5 hours, 0.6 hours, 0.7 hours, 0.8 hours, 0.9 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours, or a range defined by any two of these limits.In some embodiments, steps (a), (b), and (c) and optional step (d) are repeated daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days. In some embodiments, the method further comprises administering an additional antiviral therapy to the patient. In some embodiments, the additional antiviral therapy comprises favipiravir, favipiravir, remdesivir, tocilizumab, galidesivir, sarilumab, lopinavir, ritonavir, darunavir, ribavirin, interferon alpha, pegylated interferon alpha, interferon alpha-2b, convalescent serum, or any combination thereof.

[0231] Additionally, in some embodiments, methods of treating or suppressing a coronavirus infection or a symptom or sequelae thereof in a patient in need thereof are disclosed. In some embodiments, the methods comprise: (a) introducing blood or plasma containing a coronavirus or a portion thereof, which has been taken from a patient suffering from a coronavirus infection or its symptoms or sequelae, into an extracorporeal circulation device containing a lectin that binds to the coronavirus or a portion thereof (e.g., snowdrop agglutinin (GNA), daffodil agglutinin (NPA), or Nostoc ellipsosporum-derived cyanovirin); (b) contacting the patient's blood or plasma with the lectin in the extracorporeal circulation device for a time sufficient to allow the coronavirus or portion thereof in the blood or plasma to bind to the lectin; and (c) returning to the patient the blood or plasma in which the amount of coronavirus or a portion thereof has been reduced as a result of step (b) compared to the patient's blood or plasma before step (b) was performed. Including, (d) detecting or identifying a coronavirus or a portion thereof in a sample (e.g., a nasal sample (e.g., isolated from a nasal swab), a blood sample, a plasma sample, etc.) obtained from the patient before step (a) or after step (b), or both; and / or Selecting or identifying patients with coronavirus infection or its symptoms or sequelae for treatment to reduce the risk of the coronavirus or a portion thereof. may also include: In some embodiments, the patient does not have a coronavirus infection before step (a) but is experiencing symptoms or after-effects of a coronavirus infection. In some embodiments, the patient has recovered from a coronavirus infection before step (a) but is still experiencing symptoms or after-effects of a coronavirus infection. In some embodiments, the patient's blood or plasma is coronavirus-free before step (a) is performed but is still experiencing symptoms or after-effects of a coronavirus infection. In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the patient has early acute lung injury (ALI), early acute respiratory distress syndrome (ARDS), dyspnea, respiratory frequency of 30 breaths per minute or more, blood oxygen saturation of 93% or less, arterial oxygen tension to fractional inspired oxygen ratio of less than 300, pulmonary infiltrates of more than 50%, respiratory failure within 24 to 48 hours, elevated ferritin level, elevated lactate level, elevated lactate dehydrogenase (LDH) level, decreased absolute lymphocyte count (ALC), decreased platelet count, prolonged prothrombin time international normalized ratio (PT / INR), septic shock, or multiple organ dysfunction or failure, or any combination thereof. In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of IL-6 in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum IL-6 level is 2 pg / mL or greater.In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of serum D-dimer in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum D-dimer level is 500 ng / mL or greater. In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of troponin T in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum troponin T level is 15 ng / L or greater. In some preferred embodiments, the lectin is snowdrop agglutinin (GNA). In some embodiments, the extracorporeal circulation device includes a hollow fiber cartridge containing the lectin, and the blood or plasma flows through the hollow fibers of the hollow fiber cartridge. In some embodiments, the hollow fibers of the hollow fiber cartridge have a pore size that does not allow cellular components in the blood or plasma to pass through, so that the lectin does not come into contact with cellular components in the blood or plasma. In some embodiments, the pore size is 20 to 500 nm or approximately 20 to 500 nm. In some embodiments, the pore size is 200 nm or approximately 200 nm. In some embodiments, the lectin is immobilized or adsorbed on a solid support, and the hollow fiber cartridge includes the lectin immobilized or adsorbed on the solid support. In some embodiments, the solid support includes agarose, diatomaceous earth, or amino celite. In some embodiments, the solid support includes diatomaceous earth.In some embodiments, the method further comprises isolating coronavirus virions or portions thereof bound to the lectin contained in the extracorporeal circulation device. In some embodiments, the method further comprises isolating exosomes associated with a coronavirus infection, or a symptom or sequelae thereof, bound to the lectin contained in the extracorporeal circulation device. In some embodiments, the method further comprises examining the contents of the isolated exosomes. In some embodiments, the exosomes associated with a coronavirus infection, or a symptom or sequelae thereof, contain miR-424-5p or miR-16-2-3p, or both. In some embodiments, the method further comprises observing or measuring a decrease in the number of coronavirus virions or portions thereof, or a decrease in the number of exosomes associated with coronavirus infection or a symptom or sequelae thereof, in the patient's blood or plasma sample obtained after step (b) compared to the patient's blood or plasma sample obtained before step (b); or measuring the relative level or amount of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in the patient's blood or plasma sample obtained after step (b) compared to the patient's blood or plasma sample obtained before step (b). In some embodiments, the method further includes observing an improvement in the coronavirus infection or symptoms or sequelae thereof in the patient who has undergone step (b) or step (c), or both, compared to a control level or amount (e.g., a level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or sequelae associated therewith, or a healthy patient).In some embodiments, observing an improvement in coronavirus infection or its symptoms or sequelae comprises determining in the patient an improvement in early acute lung injury (ALI), early acute respiratory distress syndrome (ARDS), respiratory frequency, blood oxygen saturation, arterial oxygen tension to fractional inspired oxygen ratio, pulmonary infiltrates, respiratory failure, ferritin, lactate, LDH, absolute lymphocyte count (ALC), platelet count, PT / INR ratio, septic shock, or multiple organ dysfunction or failure, or any combination thereof. In some embodiments, observing improvement in a coronavirus infection or its symptoms or sequelae comprises observing a decrease in the number of coronavirus virions or portions thereof, or a decrease in the number of exosomes associated with a coronavirus infection or its symptoms or sequelae, in a biological sample (e.g., blood or plasma) obtained from the patient before and / or after the treatment; or measuring the level or amount of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in a biological sample (e.g., blood or plasma) obtained from the patient before and / or after the treatment. In some embodiments, the coronavirus infection is caused by a coronavirus selected from SARS-CoV-2, SARS-CoV-1, MERS-CoV, HCoV-229E, HCoV-OC43, HCoV NL63, and HCoV-HKU1. In some embodiments, the SARS-CoV-2 is a SARS-CoV-2 mutant strain.In some embodiments, the SARS-CoV-2 variant strain is 20I / 501Y.V1 (alpha strain, B.1.1.7), 20H / 501Y.V2 (beta strain, B.1.351), 20J / 501Y.V3 (gamma strain, P.1), B.1.617.2 (delta strain), AY.1, AY.2, C.37 (lambda strain), B.1.621 (mu strain), B.1.1.207, VUI-202102 / 03 (B.1.525), VUI-202101 / 01 (P.2), VUI-202102 / 01 (A.23.1), VUI 202102 / 04 (B.1.1.318), VUI 202103 / 01 (B.1.324.1), B.1.427, CAL.20C (B.1.429), R.1, B.1.466.2, B.1.1.519, C.36.3, B.1.214.2, B.1.1.523, B.1.619, B.1.620, C.1.2, B.1.617.1, B.1.1.529 (Omicron strain), and B.1.526. In some embodiments, the symptom or sequelae include EBV reactivation in the patient. In some embodiments, blood clotting is prevented by priming the extracorporeal circulation device with an anticoagulant (preferably heparin) prior to performing step (a). In some embodiments, the flow rate of the blood flowing through the extracorporeal circulation device is about 50 to about 600 mL / min, preferably about 200 to about 400 mL / min, preferably about 200 to about 240 mL / min or 200 to 240 mL / min, and most preferably 240 mL / min. In some embodiments, returning the blood to the patient includes flushing the extracorporeal circulation device with saline. In some embodiments, the contact time of the blood or plasma with the extracorporeal circulation device is 0.1 hours, 0.2 hours, 0.3 hours, 0.4 hours, 0.5 hours, 0.6 hours, 0.7 hours, 0.8 hours, 0.9 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours, or within a range defined by any two of these limits.In some embodiments, steps (a), (b), and (c) and optional step (d) are repeated daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days. In some embodiments, the method further comprises administering an additional antiviral therapy to the patient. In some embodiments, the additional antiviral therapy comprises favipiravir, favipiravir, remdesivir, tocilizumab, galidesivir, sarilumab, lopinavir, ritonavir, darunavir, ribavirin, interferon alpha, pegylated interferon alpha, interferon alpha-2b, convalescent serum, or any combination thereof.

[0232] Additionally, in some embodiments, methods of treating or suppressing a coronavirus infection or a symptom or sequelae thereof in a patient in need thereof are disclosed. In some embodiments, the methods comprise: (a) introducing blood or plasma containing exosomes associated with coronavirus infection or its symptoms or sequelae, which has been removed from a patient with coronavirus infection or its symptoms or sequelae, into an extracorporeal circulation device containing a lectin that binds to exosomes associated with coronavirus infection or its symptoms or sequelae; (b) contacting the patient's blood or plasma with the lectin in the extracorporeal circulation device for a period of time sufficient for the exosomes in the blood or plasma to bind to the lectin; and (c) returning to the patient the blood or plasma in which the amount of exosomes has been reduced as a result of step (b) compared to the blood or plasma of the patient before step (b). Including, (d) detecting or identifying the exosomes in a sample (e.g., a nasal sample (e.g., a nasal sample isolated from a nasal swab), a blood sample, a plasma sample, etc.) obtained from the patient before step (a) or after step (b), or both; and / or Selecting or identifying a patient with coronavirus infection or its symptoms or sequelae for treatment that reduces exosomes. may also include: In some embodiments, the patient does not have a coronavirus infection before step (a) but is experiencing symptoms or after-effects of a coronavirus infection. In some embodiments, the patient has recovered from a coronavirus infection before step (a) but is still experiencing symptoms or after-effects of a coronavirus infection. In some embodiments, the patient's blood or plasma is coronavirus-free before step (a) is performed but is still experiencing symptoms or after-effects of a coronavirus infection. In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the patient has early acute lung injury (ALI), early acute respiratory distress syndrome (ARDS), dyspnea, respiratory frequency of 30 breaths per minute or more, blood oxygen saturation of 93% or less, arterial oxygen tension to fractional inspired oxygen ratio of less than 300, pulmonary infiltrates of more than 50%, respiratory failure, elevated ferritin level, elevated lactate level, elevated lactate dehydrogenase (LDH) level, decreased absolute lymphocyte count (ALC), decreased platelet count, prolonged prothrombin time international normalized ratio (PT / INR), septic shock, or multiple organ dysfunction or failure, or any combination thereof. In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of IL-6 in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum IL-6 level is 2 pg / mL or greater.In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of D-dimer in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum D-dimer level is 500 ng / mL or greater. In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of troponin T in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum troponin T level is 15 ng / L or greater. In some preferred embodiments, the lectin is snowdrop agglutinin (GNA). In some embodiments, the extracorporeal circulation device includes a hollow fiber cartridge containing the lectin, and the blood or plasma flows through the hollow fibers of the hollow fiber cartridge. In some embodiments, the hollow fibers of the hollow fiber cartridge have a pore size that does not allow cellular components in the blood or plasma to pass through, so that the lectin does not come into contact with cellular components in the blood or plasma. In some embodiments, the pore size is 20 to 500 nm or approximately 20 to 500 nm. In some embodiments, the pore size is 200 nm or approximately 200 nm. In some embodiments, the lectin is immobilized or adsorbed on a solid support, and the hollow fiber cartridge includes the lectin immobilized or adsorbed on the solid support. In some embodiments, the solid support includes agarose, diatomaceous earth, or amino celite. In some embodiments, the solid support includes diatomaceous earth.In some embodiments, the method further comprises isolating coronavirus virions or portions thereof bound to the lectin contained in the extracorporeal circulation device. In some embodiments, the method further comprises isolating exosomes associated with a coronavirus infection, or a symptom or sequelae thereof, bound to the lectin contained in the extracorporeal circulation device. In some embodiments, the method further comprises examining the contents of the isolated exosomes. In some embodiments, the exosomes associated with a coronavirus infection, or a symptom or sequelae thereof, contain miR-424-5p or miR-16-2-3p, or both. In some embodiments, the method further comprises observing or measuring a decrease in the number of coronavirus virions or portions thereof, or a decrease in the number of exosomes associated with coronavirus infection or its symptoms or sequelae, in the patient's blood or plasma sample obtained after step (b) compared to the patient's blood or plasma sample obtained before step (b); or measuring the relative level or amount of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in the patient's blood or plasma sample obtained after step (b) compared to the patient's blood or plasma sample obtained before step (b). In some embodiments, the method further comprises observing an improvement in coronavirus infection or its symptoms or sequelae in the patient who has undergone step (b) or step (c), or both. In some embodiments, observing an improvement in coronavirus infection or its symptoms or sequelae comprises determining in the patient an improvement in early acute lung injury (ALI), early acute respiratory distress syndrome (ARDS), respiratory frequency, blood oxygen saturation, arterial oxygen tension to fractional inspired oxygen ratio, pulmonary infiltrates, respiratory failure, ferritin, lactate, LDH, absolute lymphocyte count (ALC), platelet count, PT / INR ratio, septic shock, or multiple organ dysfunction or failure, or any combination thereof.In some embodiments, observing improvement in a coronavirus infection or its symptoms or sequelae includes observing a decrease in the number of coronavirus virions or portions thereof, or a decrease in the number of exosomes associated with a coronavirus infection or its symptoms or sequelae in the patient compared to before treatment; or measuring the relative levels or amounts of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in the patient compared to before treatment. In some embodiments, the coronavirus infection is caused by a coronavirus selected from SARS-CoV-2, SARS-CoV-1, MERS-CoV, HCoV-229E, HCoV-OC43, HCoV NL63, and HCoV-HKU1. In some embodiments, the SARS-CoV-2 is a SARS-CoV-2 mutant strain. In some embodiments, the SARS-CoV-2 variant strain is 20I / 501Y.V1 (alpha strain, B.1.1.7), 20H / 501Y.V2 (beta strain, B.1.351), 20J / 501Y.V3 (gamma strain, P.1), B.1.617.2 (delta strain), AY.1, AY.2, C.37 (lambda strain), B.1.621 (mu strain), B.1.1.207, VUI-202102 / 03 (B.1.525), VUI-202101 / 01 (P.2), VUI-202102 / 01 (A.23.1), VUI 202102 / 04 (B.1.1.318), VUI 202103 / 01 (B.1.324.1), B.1.427, CAL.20C (B.1.429), R.1, B.1.466.2, B.1.1.519, C.36.3, B.1.214.2, B.1.1.523, B.1.619, B.1.620, C.1.2, B.1.617.1, B.1.1.529 (Omicron strain), and B.1.526. In some embodiments, the symptoms or sequelae comprise reactivation of EBV in the patient.In some embodiments, prior to performing step (a), blood clotting is prevented by priming the extracorporeal circulation device with an anticoagulant (preferably heparin). In some embodiments, the flow rate of the blood through the extracorporeal circulation device is about 50 to about 600 mL / min, preferably about 200 to about 400 mL / min, preferably about 200 to about 240 mL / min or 20 to 240 mL / min, and most preferably 240 mL / min. In some embodiments, returning the blood to the patient includes flushing the extracorporeal circulation device with saline. In some embodiments, the blood or plasma is in contact with the extracorporeal circulation device for 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours, or a range of any two of these hours. In some embodiments, steps (a), (b), and (c) and optional step (d) are repeated daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days. In some embodiments, the method further comprises administering an additional antiviral therapy to the patient. In some embodiments, the additional antiviral therapy comprises favipiravir, favipiravir, remdesivir, tocilizumab, galidesivir, sarilumab, lopinavir, ritonavir, darunavir, ribavirin, interferon alpha, pegylated interferon alpha, interferon alpha-2b, convalescent serum, or any combination thereof.

[0233] Additionally, in some embodiments, methods are disclosed for treating or inhibiting a coronavirus infection or a symptom or sequelae thereof in a patient in need thereof, wherein the symptom or sequelae comprises COVID-19 associated coagulation disorder (CAC). In some embodiments, the methods are more broadly directed to treating or inhibiting a coagulation disorder (CAC) in a patient in need thereof. In some embodiments, the methods comprise: (a) introducing blood or plasma containing exosomes associated with a viral infection (e.g., COVID-19) or bacterial infection or a symptom or sequelae (e.g., CAC) collected from a patient with a viral infection (e.g., COVID-19) or bacterial infection or a symptom or sequelae (e.g., CAC) into an extracorporeal circulation device containing a lectin (e.g., GNA, NPA, or cyanovirin) that binds to exosomes associated with a viral infection (e.g., COVID-19) or bacterial infection or a symptom or sequelae (e.g., CAC); (b) contacting the patient's blood or plasma with the lectin in the extracorporeal circulation device for a period of time sufficient for the exosomes in the blood or plasma to bind to the lectin; and (c) returning to the patient the blood or plasma in which the amount of exosomes has been reduced as a result of step (b) compared to the blood or plasma of the patient before step (b). Including, (d) detecting or identifying the exosomes in a sample (e.g., a nasal sample (e.g., a nasal sample isolated from a nasal swab), a blood sample, a plasma sample, etc.) obtained from the patient before step (a) or after step (b), or both; and / or Selecting or identifying a patient with a viral infection (e.g., COVID-19) or a bacterial infection or a symptom or sequela thereof (e.g., CAC) for treatment with the exosome-reducing treatment. may also include:In some embodiments, the patient does not have a viral infection (e.g., COVID-19) or bacterial infection prior to step (a), but is experiencing symptoms or sequelae of a viral infection (e.g., COVID-19) or bacterial infection (e.g., CAC). In some embodiments, the patient has recovered from the infection prior to step (a), but is still experiencing symptoms or sequelae of the infection (e.g., CAC). In some embodiments, the patient's blood or plasma is virus (e.g., COVID-19) or bacteria-free prior to performing step (a), but is still experiencing symptoms or sequelae of the infection (e.g., CAC). In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the patient has CAC, early acute lung injury (ALI), early acute respiratory distress syndrome (ARDS), dyspnea, respiratory frequency of 30 breaths per minute or more, blood oxygen saturation of 93% or less, arterial oxygen tension to fractional inspired oxygen ratio of less than 300, pulmonary infiltrates of more than 50%, respiratory failure within 24 to 48 hours, elevated ferritin level, elevated lactate level, elevated lactate dehydrogenase (LDH) level, decreased absolute lymphocyte count (ALC), decreased platelet count, prolonged prothrombin time international normalized ratio (PT / INR), septic shock, or multiple organ dysfunction or failure, or any combination thereof. In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the patient has CAC. In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of IL-6 in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum IL-6 level is 2 pg / mL or greater.In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of D-dimer in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum D-dimer level is 500 ng / mL or greater. In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of troponin T in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum troponin T level is 15 ng / L or greater. In some preferred embodiments, the lectin is snowdrop agglutinin (GNA). In some embodiments, the extracorporeal circulation device includes a hollow fiber cartridge containing the lectin, and the blood or plasma flows through the hollow fibers of the hollow fiber cartridge. In some embodiments, the hollow fibers of the hollow fiber cartridge have a pore size that does not allow cellular components in the blood or plasma to pass through, so that the lectin does not come into contact with cellular components in the blood or plasma. In some embodiments, the pore size is 20 to 500 nm or approximately 20 to 500 nm. In some embodiments, the pore size is 200 nm or approximately 200 nm. In some embodiments, the lectin is immobilized or adsorbed on a solid support, and the hollow fiber cartridge includes the lectin immobilized or adsorbed on the solid support. In some embodiments, the solid support includes agarose, diatomaceous earth, or amino celite. In some embodiments, the solid support includes diatomaceous earth.In some embodiments, the method further comprises isolating coronavirus virions or portions thereof bound to the lectin contained in the extracorporeal circulation device. In some embodiments, the method further comprises isolating exosomes associated with a coronavirus infection or a symptom or sequelae thereof (e.g., CAC) bound to the lectin contained in the extracorporeal circulation device. In some embodiments, the method further comprises examining the contents of the isolated exosomes. In some embodiments, the exosomes associated with a coronavirus infection or a symptom or sequelae thereof (e.g., CAC) contain miR-424-5p or miR-16-2-3p, or both. In some embodiments, the method further comprises observing or measuring a decrease in the number of coronavirus virions or portions thereof, or a decrease in the number of exosomes associated with coronavirus infection or a symptom or sequelae thereof, in the patient's blood or plasma sample obtained after step (b) compared to the patient's blood or plasma sample obtained before step (b); or measuring the relative level or amount of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in the patient's blood or plasma sample obtained after step (b) compared to the patient's blood sample obtained before step (b). In some embodiments, the method further comprises observing an improvement in coronavirus infection or a symptom or sequelae thereof (e.g., CAC) in the patient who has undergone step (b) or step (c), or both.In some embodiments, observing an improvement in a coronavirus infection or a symptom or sequela thereof (e.g., CAC) comprises determining in the patient an improvement in CAC, early acute lung injury (ALI), early acute respiratory distress syndrome (ARDS), respiratory frequency, blood oxygen saturation, arterial oxygen tension to fractional inspired oxygen ratio, pulmonary infiltrates, respiratory failure, ferritin, lactate, LDH, absolute lymphocyte count (ALC), platelet count, PT / INR ratio, septic shock, or multiple organ dysfunction or failure, or any combination thereof. In some embodiments, observing improvement in a coronavirus infection or its symptoms or sequelae (e.g., CAC) comprises observing a decrease in the number of coronavirus virions or portions thereof, or a decrease in the number of exosomes associated with a coronavirus infection or its symptoms or sequelae in the patient compared to before treatment; or measuring the relative levels or amounts of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in the patient compared to before treatment. In some embodiments, the coronavirus infection is caused by a coronavirus selected from SARS-CoV-2, SARS-CoV-1, MERS-CoV, HCoV-229E, HCoV-OC43, HCoV NL63, and HCoV-HKU1. In some embodiments, the SARS-CoV-2 is a SARS-CoV-2 mutant strain.In some embodiments, the SARS-CoV-2 variant strain is 20I / 501Y.V1 (alpha strain, B.1.1.7), 20H / 501Y.V2 (beta strain, B.1.351), 20J / 501Y.V3 (gamma strain, P.1), B.1.617.2 (delta strain), AY.1, AY.2, C.37 (lambda strain), B.1.621 (mu strain), B.1.1.207, VUI-202102 / 03 (B.1.525), VUI-202101 / 01 (P.2), VUI-202102 / 01 (A.23.1), VUI 202102 / 04 (B.1.1.318), VUI 202103 / 01 (B.1.324.1), B.1.427, CAL.20C (B.1.429), R.1, B.1.466.2, B.1.1.519, C.36.3, B.1.214.2, B.1.1.523, B.1.619, B.1.620, C.1.2, B.1.617.1, B.1.1.529 (Omicron strain), and B.1.526. In some embodiments, the symptom or sequelae include EBV reactivation in the patient. In some embodiments, blood clotting is prevented by priming the extracorporeal circulation device with an anticoagulant (preferably heparin) prior to performing step (a). In some embodiments, the flow rate of the blood flowing through the extracorporeal circulation device is about 50 to about 600 mL / min, preferably about 200 to about 400 mL / min, preferably about 200 to about 240 mL / min or 200 to 240 mL / min, and most preferably 240 mL / min. In some embodiments, returning the blood to the patient includes flushing the extracorporeal circulation device with saline. In some embodiments, the contact time of the blood or plasma with the extracorporeal circulation device is 0.1 hours, 0.2 hours, 0.3 hours, 0.4 hours, 0.5 hours, 0.6 hours, 0.7 hours, 0.8 hours, 0.9 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours, or within a range defined by any two of these limits.In some embodiments, steps (a), (b), and (c) and optional step (d) are repeated daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days. In some embodiments, the method further comprises administering an additional antiviral therapy to the patient. In some embodiments, the additional antiviral therapy comprises favipiravir, favipiravir, remdesivir, tocilizumab, galidesivir, sarilumab, lopinavir, ritonavir, darunavir, ribavirin, interferon alpha, pegylated interferon alpha, interferon alpha-2b, convalescent serum, or any combination thereof.

[0234] Further disclosed herein are methods for reducing the amount of SARS-CoV-2 virions or fragments thereof in COVID-19 patients. In some embodiments, the methods comprise: (a) providing an extracorporeal circulation device comprising a hollow fiber cartridge containing a lectin that selectively binds to the outer surface of the SARS-CoV-2 virion or a fragment thereof; (b) the process of drawing blood from COVID-19 patients; (c) treating the blood in the hollow fiber cartridge by contacting the blood with the lectin; (d) reducing at least a portion of the SARS-CoV-2 virions or fragments thereof in the blood by retaining at least a portion of the SARS-CoV-2 virions or fragments thereof in the hollow fiber cartridge; and (e) reintroducing into said patient the blood from which at least some of the SARS-CoV-2 virions or fragments thereof have been removed. Includes: In some embodiments, the lectin is GNA.

[0235] Further disclosed herein are methods for reducing the amount of COVID-19-mediated nanoparticles in a COVID-19 patient. In some embodiments, the methods include: (a) providing an extracorporeal circulation device comprising a hollow fiber cartridge containing a lectin that selectively binds to the outer surface of a COVID-19-mediated nanoparticle; (b) the process of drawing blood from COVID-19 patients; (c) treating the blood in the hollow fiber cartridge by contacting the blood with the lectin; (d) reducing at least a portion of the COVID-19-mediated nanoparticles in the blood by retaining at least a portion of the COVID-19-mediated nanoparticles in the hollow fiber cartridge; and (e) reintroducing into said patient the blood from which at least a portion of the COVID-19-mediated nanoparticles has been removed. Includes: In some embodiments, the lectin is GNA.

[0236] Further disclosed herein are methods for reducing the amount of COVID-19-mediated exosomes in COVID-19 patients. In some embodiments, the methods include: (a) providing an extracorporeal circulation device including a hollow fiber cartridge containing a lectin that selectively binds to the outer surface of COVID-19-mediated exosomes; (b) the process of drawing blood from COVID-19 patients; (c) treating the blood in the hollow fiber cartridge by contacting the blood with the lectin; (d) reducing at least a portion of the COVID-19-mediated exosomes in the blood by retaining at least a portion of the COVID-19-mediated exosomes in the hollow fiber cartridge; and (e) reintroducing into said patient the blood from which at least a portion of the COVID-19-mediated exosomes has been removed. Includes: In some embodiments, the lectin is GNA.

[0237] Further disclosed herein are methods for reducing the amount of IL-6 in COVID-19 patients. In some embodiments, the methods include: (a) providing an extracorporeal circulation device comprising a hollow fiber cartridge containing a lectin that selectively binds to the outer surface of a SARS-CoV-2 virion or a fragment thereof or a COVID-19-mediated exosome; (b) the process of drawing blood from COVID-19 patients; (c) measuring the level of IL-6 in the blood; (d) treating the blood in the hollow fiber cartridge by contacting the blood with the lectin; (e) reducing at least a portion of the COVID-19-mediated exosomes in the blood by retaining SARS-CoV-2 virions or fragments thereof or at least a portion of the COVID-19-mediated exosomes in the hollow fiber cartridge; (f) measuring the level of IL-6 in the blood; and (g) reintroducing into said patient the blood from which at least a portion of the SARS-CoV-2 virions or fragments thereof or COVID-19-mediated exosomes has been removed. Includes: In some embodiments, the lectin is GNA.

[0238] Further disclosed herein are methods for reducing the amount of D-dimer in COVID-19 patients. In some embodiments, the methods include: (a) providing an extracorporeal circulation device comprising a hollow fiber cartridge containing a lectin that selectively binds to the outer surface of a SARS-CoV-2 virion or a fragment thereof or a COVID-19-mediated exosome; (b) the process of drawing blood from COVID-19 patients; (c) measuring the level of D-dimer in the blood; (d) treating the blood in the hollow fiber cartridge by contacting the blood with the lectin; (e) reducing at least a portion of the COVID-19-mediated exosomes in the blood by retaining SARS-CoV-2 virions or fragments thereof or at least a portion of the COVID-19-mediated exosomes in the hollow fiber cartridge; (f) measuring the level of D-dimer in the blood; and (g) reintroducing into said patient the blood from which at least a portion of the SARS-CoV-2 virions or fragments thereof or COVID-19-mediated exosomes has been removed. Includes: In some embodiments, the lectin is GNA.

[0239] Further disclosed herein are methods for reducing the amount of troponin T in COVID-19 patients. In some embodiments, the methods include: (a) providing an extracorporeal circulation device comprising a hollow fiber cartridge containing a lectin that selectively binds to the outer surface of a SARS-CoV-2 virion or a fragment thereof or a COVID-19-mediated exosome; (b) the process of drawing blood from COVID-19 patients; (c) measuring the level of troponin T in the blood; (d) treating the blood in the hollow fiber cartridge by contacting the blood with the lectin; (e) reducing at least a portion of the COVID-19-mediated exosomes in the blood by retaining SARS-CoV-2 virions or fragments thereof or at least a portion of the COVID-19-mediated exosomes in the hollow fiber cartridge; (f) measuring the level of troponin T in the blood; and (g) reintroducing into said patient the blood from which at least a portion of the SARS-CoV-2 virions or fragments thereof or COVID-19-mediated exosomes has been removed. Includes: In some embodiments, the lectin is GNA.

[0240] Further disclosed herein is an extracorporeal circulation device comprising a lectin for use in treating or suppressing coronavirus infection or its symptoms or sequelae in a patient in need thereof; or for use in reducing the levels or amounts of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in a patient in need thereof. Further disclosed herein is an extracorporeal circulation device comprising a lectin for use in treating or suppressing COVID-19-associated coagulation disorders in a patient in need thereof. Further disclosed herein is an extracorporeal circulation device containing a lectin for use in a method for treating or suppressing coronavirus infection or its symptoms or sequelae in a patient in need thereof, the method comprising: flowing blood drawn from the patient through the extracorporeal circulation device to contact the blood with the lectin to obtain treated blood; and returning the treated blood to the patient. In some preferred embodiments, the lectin is snowdrop agglutinin (GNA). In some embodiments, the extracorporeal circulation device includes a hollow fiber cartridge containing the lectin, and the patient's blood flows through the hollow fibers of the hollow fiber cartridge. In some embodiments, the lectin is immobilized or adsorbed on a solid support, and the hollow fiber cartridge contains the lectin immobilized or adsorbed on the solid support. In some embodiments, the solid support is agarose, diatomaceous earth, or amino celite. In some embodiments, the solid support is diatomaceous earth. In some embodiments, the lectin selectively binds to a coronavirus virion or portion thereof, an exosome associated with a coronavirus infection or a symptom or sequelae thereof, or any combination thereof.In some embodiments, the coronavirus infection is caused by a coronavirus selected from SARS-CoV-2, SARS-CoV-1, MERS-CoV, HCoV-229E, HCoV-OC43, HCoV NL63, and HCoV-HKU1. In some embodiments, the SARS-CoV-2 is a SARS-CoV-2 variant. In some embodiments, the SARS-CoV-2 variant strain is 20I / 501Y.V1 (alpha strain, B.1.1.7), 20H / 501Y.V2 (beta strain, B.1.351), 20J / 501Y.V3 (gamma strain, P.1), B.1.617.2 (delta strain), AY.1, AY.2, C.37 (lambda strain), B.1.621 (mu strain), B.1.1.207, VUI-202102 / 03 (B.1.525), VUI-202101 / 01 (P.2), VUI-202102 / 01 (A.23.1), VUI 202102 / 04 (B.1.1.318), VUI 202103 / 01 (B.1.324.1), B.1.427, CAL.20C (B.1.429), R.1, B.1.466.2, B.1.1.519, C.36.3, B.1.214.2, B.1.1.523, B.1.619, B.1.620, C.1.2, B.1.617.1, B.1.1.529 (Omicron strain), and B.1.526. In some embodiments, the symptoms or sequelae comprise reactivation of EBV in the patient. In some embodiments, the extracorporeal circulation device is used for 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours per session, or for a range of any two of these hours. In some embodiments, the extracorporeal circulation device is used daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days. In some embodiments, the extracorporeal circulation device is used in conjunction with an additional antiviral therapy.In some embodiments, the additional antiviral therapy comprises favipiravir, favipiravir, remdesivir, tocilizumab, galidesivir, sarilumab, lopinavir, ritonavir, darunavir, ribavirin, interferon alpha, pegylated interferon alpha, interferon alpha-2b, convalescent serum, or any combination thereof.

[0241] Therapeutic methods or uses for treating EBV reactivation More than half of all COVID-19 patients have been found to be positive for Epstein-Barr virus (EBV) reactivation, and EBV reactivation is associated with a wide range of adverse clinical manifestations in both the acute and post-acute sequelae of COVID-19. EBV viremia during acute COVID-19 infection was one of four factors associated with the development of post-acute sequelae of COVID-19. EBV reactivation has been hypothesized to be one of the major factors determining the severity of COVID disease, and patients with EBV and COVID-19 coinfection have been found to experience significantly worsening infection and fever. In hospitalized patients, EBV reactivation has been detected in more than 80% of COVID patients after admission to the ICU, and EBV reactivation has been associated with prolonged ICU stay. Circulating EBV virion DNA can be detected in the serum of COVID-19 patients, and circulating EBV virion DNA is a more reliable marker of reactivation than detection of EBV IgM antibodies.

[0242] Disclosed herein, in some embodiments, are methods for treating Epstein-Barr virus (EBV) reactivation or reducing or suppressing EBV infection in patients with coronavirus infection. In some embodiments, the methods include: (a) introducing blood or plasma containing a coronavirus or a portion thereof and EBV or a portion thereof, which has been taken from a patient with a coronavirus infection, into an extracorporeal circulation device containing a lectin that binds to a coronavirus or a portion thereof and EBV or a portion thereof (e.g., snowdrop agglutinin (GNA), daffodil agglutinin (NPA), or Nostoc ellipsosporum-derived cyanovirin); (b) contacting the patient's blood or plasma with the lectin in the extracorporeal circulation device for a time sufficient for the coronavirus or portion thereof and EBV or portion thereof in the blood or plasma to bind to the lectin; and (c) returning to the patient the blood or plasma in which the amount of coronavirus or a part thereof and EBV or a part thereof has been reduced as a result of step (b) compared to the blood or plasma of the patient before step (b) was performed. Including, (d) detecting or identifying a coronavirus or a portion thereof and / or EBV or a portion thereof in a sample (e.g., a nasal sample (e.g., a nasal sample isolated from a nasal swab), a blood sample, a plasma sample, etc.) obtained from the patient before step (a) or after step (b), or both; and / or Selecting or identifying patients with coronavirus infection and / or EBV infection for treatment to reduce coronavirus or a portion thereof and / or EBV or a portion thereof. may also include: In some embodiments, the patient does not have a coronavirus infection and / or EBV infection before step (a), but is experiencing symptoms or sequelae of a coronavirus infection and / or EBV infection. In some embodiments, the patient has recovered from a coronavirus infection and / or EBV infection before step (a), but is still experiencing symptoms or sequelae of a coronavirus infection and / or EBV infection. In some embodiments, the patient's blood or plasma is coronavirus and / or EBV-free before performing step (a), but is still experiencing symptoms or sequelae of a coronavirus infection and / or EBV infection. In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the patient has early acute lung injury (ALI), early acute respiratory distress syndrome (ARDS), dyspnea, respiratory frequency of 30 breaths per minute or more, blood oxygen saturation of 93% or less, arterial oxygen tension to fractional inspired oxygen ratio of less than 300, pulmonary infiltrates of more than 50%, respiratory failure within 24 to 48 hours, elevated ferritin level, elevated lactate level, elevated lactate dehydrogenase (LDH) level, decreased absolute lymphocyte count (ALC), decreased platelet count, prolonged prothrombin time international normalized ratio (PT / INR), septic shock, or multiple organ dysfunction or failure, or any combination thereof. In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of IL-6 in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum IL-6 level is 2 pg / mL or greater.In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of serum D-dimer in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum D-dimer level is 500 ng / mL or greater. In some embodiments, the method further comprises determining, before step (a) or after step (b), or both, whether the level or amount of troponin T in the patient's blood or plasma sample is elevated compared to the level or amount in a control (e.g., the level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection or its associated sequelae, or a healthy patient). In some embodiments, the elevated serum troponin T level is 15 ng / L or greater. In some preferred embodiments, the lectin is snowdrop agglutinin (GNA). In some embodiments, the extracorporeal circulation device includes a hollow fiber cartridge containing the lectin, and the blood or plasma flows through the hollow fibers of the hollow fiber cartridge. In some embodiments, the hollow fibers of the hollow fiber cartridge have a pore size that does not allow cellular components in the blood or plasma to pass through, so that the lectin does not come into contact with cellular components in the blood or plasma. In some embodiments, the pore size is 20 to 500 nm or approximately 20 to 500 nm. In some embodiments, the pore size is 200 nm or approximately 200 nm. In some embodiments, the lectin is immobilized or adsorbed on a solid support, and the hollow fiber cartridge includes the lectin immobilized or adsorbed on the solid support. In some embodiments, the solid support includes agarose, diatomaceous earth, or amino celite. In some embodiments, the solid support includes diatomaceous earth.In some embodiments, the method further comprises isolating coronavirus virions or portions thereof and / or EBV or portions thereof bound to the lectin contained in the extracorporeal circulation device. In some embodiments, the method further comprises isolating exosomes associated with coronavirus infection and / or EBV infection bound to the lectin contained in the extracorporeal circulation device. In some embodiments, the method further comprises examining the contents of the isolated exosomes. In some embodiments, the exosomes associated with coronavirus infection and / or EBV infection contain miR-424-5p or miR-16-2-3p, or both. In some embodiments, the method further comprises observing or measuring a decrease in the number of coronavirus virions or portions thereof and / or EBV or portions thereof, or a decrease in the number of exosomes associated with coronavirus infection and / or EBV infection, in the patient's blood sample or plasma sample obtained after step (b) compared to the patient's blood sample or plasma sample obtained before step (b); or measuring the relative level or amount of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in the patient's blood sample or plasma sample obtained after step (b) compared to the patient's blood sample or plasma sample obtained before step (b). In some embodiments, the method further comprises observing in step (b) or step (c), or both, whether the coronavirus infection and / or EBV infection in the patient is improved compared to a control level or amount (e.g., a level or amount in a blood or plasma sample obtained from a patient not experiencing inflammation or COVID-19 infection and / or EBV infection or sequelae associated therewith, or a healthy patient).In some embodiments, observing an improvement in coronavirus infection or its symptoms or sequelae comprises determining in the patient an improvement in early acute lung injury (ALI), early acute respiratory distress syndrome (ARDS), respiratory frequency, blood oxygen saturation, arterial oxygen tension to fractional inspired oxygen ratio, pulmonary infiltrates, respiratory failure, ferritin, lactate, LDH, absolute lymphocyte count (ALC), platelet count, PT / INR ratio, septic shock, or multiple organ dysfunction or failure, or any combination thereof. In some embodiments, observing improvement in a coronavirus infection or its symptoms or sequelae comprises observing a decrease in the number of coronavirus virions or portions thereof, or a decrease in the number of exosomes associated with a coronavirus infection or its symptoms or sequelae, in a biological sample (e.g., blood or plasma) obtained from the patient before and / or after the treatment; or measuring the level or amount of IL-1, IL-6, IL-10, IL-15, CXCL10, CCL2, myeloperoxidase, VCAM-1, TNFα, C-reactive protein (CRP), D-dimer, or troponin T, or any combination thereof, in a biological sample (e.g., blood or plasma) obtained from the patient before and / or after the treatment. In some embodiments, the coronavirus infection is caused by a coronavirus selected from SARS-CoV-2, SARS-CoV-1, MERS-CoV, HCoV-229E, HCoV-OC43, HCoV NL63, and HCoV-HKU1. In some embodiments, the SARS-CoV-2 is a SARS-CoV-2 mutant strain.In some embodiments, the SARS-CoV-2 variant strain is 20I / 501Y.V1 (alpha strain, B.1.1.7), 20H / 501Y.V2 (beta strain, B.1.351), 20J / 501Y.V3 (gamma strain, P.1), B.1.617.2 (delta strain), AY.1, AY.2, C.37 (lambda strain), B.1.621 (mu strain), B.1.1.207, VUI-202102 / 03 (B.1.525), VUI-202101 / 01 (P.2), VUI-202102 / 01 (A.23.1), VUI 202102 / 04 (B.1.1.318), VUI 202103 / 01 (B.1.324.1), B.1.427, CAL.20C (B.1.429), R.1, B.1.466.2, B.1.1.519, C.36.3, B.1.214.2, B.1.1.523, B.1.619, B.1.620, C.1.2, B.1.617.1, B.1.1.529 (Omicron strain), and B.1.526. In some embodiments, the symptom or sequelae include EBV reactivation in the patient. In some embodiments, blood clotting is prevented by priming the extracorporeal circulation device with an anticoagulant (preferably heparin) prior to performing step (a). In some embodiments, the flow rate of the blood flowing through the extracorporeal circulation device is about 50 to about 600 mL / min, preferably about 200 to about 400 mL / min, preferably about 200 to about 240 mL / min or 200 to 240 mL / min, and most preferably 240 mL / min. In some embodiments, returning the blood to the patient includes flushing the extracorporeal circulation device with saline. In some embodiments, the contact time of the blood or plasma with the extracorporeal circulation device is 0.1 hours, 0.2 hours, 0.3 hours, 0.4 hours, 0.5 hours, 0.6 hours, 0.7 hours, 0.8 hours, 0.9 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours, or within a range defined by any two of these limits.In some embodiments, steps (a), (b), and (c) and optional step (d) are repeated daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days. In some embodiments, the method further comprises administering an additional antiviral therapy to the patient. In some embodiments, the additional antiviral therapy comprises favipiravir, favipiravir, remdesivir, tocilizumab, galidesivir, sarilumab, lopinavir, ritonavir, darunavir, ribavirin, interferon alpha, pegylated interferon alpha, interferon alpha-2b, convalescent serum, or any combination thereof.

[0243] Further disclosed herein is an extracorporeal circulation device containing a lectin for use in treating or suppressing EBV reactivation in patients with coronavirus infection. In some preferred embodiments, the lectin is snowdrop agglutinin (GNA). In some embodiments, the extracorporeal circulation device includes a hollow fiber cartridge containing the lectin, and the patient's blood flows through the hollow fibers of the hollow fiber cartridge. In some embodiments, the lectin is immobilized or adsorbed on a solid support, and the hollow fiber cartridge contains the lectin immobilized or adsorbed on the solid support. In some embodiments, the solid support is agarose, diatomaceous earth, or aminocelite. In some embodiments, the solid support is diatomaceous earth. In some embodiments, the lectin selectively binds to coronavirus virions or portions thereof and / or EBV or portions thereof, exosomes associated with coronavirus infection and / or EBV infection, or any combination thereof. In some embodiments, the coronavirus infection is caused by a coronavirus selected from SARS-CoV-2, SARS-CoV-1, MERS-CoV, HCoV-229E, HCoV-OC43, HCoV NL63, and HCoV-HKU1. In some embodiments, the SARS-CoV-2 is a SARS-CoV-2 variant.In some embodiments, the SARS-CoV-2 variant strain is 20I / 501Y.V1 (alpha strain, B.1.1.7), 20H / 501Y.V2 (beta strain, B.1.351), 20J / 501Y.V3 (gamma strain, P.1), B.1.617.2 (delta strain), AY.1, AY.2, C.37 (lambda strain), B.1.621 (mu strain), B.1.1.207, VUI-202102 / 03 (B.1.525), VUI-202101 / 01 (P.2), VUI-202102 / 01 (A.23.1), VUI 202102 / 04 (B.1.1.318), VUI 202103 / 01 (B.1.324.1), B.1.427, CAL.20C (B.1.429), R.1, B.1.466.2, B.1.1.519, C.36.3, B.1.214.2, B.1.1.523, B.1.619, B.1.620, C.1.2, B.1.617.1, B.1.1.529 (Omicron strain), and B.1.526. In some embodiments, the symptoms or sequelae comprise reactivation of EBV in the patient. In some embodiments, the extracorporeal circulation device is used for 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours per session, or for a range of any two of these hours. In some embodiments, the extracorporeal circulation device is used daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days. In some embodiments, the extracorporeal circulation device is used in conjunction with an additional antiviral therapy. In some embodiments, the additional antiviral therapy comprises favipiravir, favipiravir, remdesivir, tocilizumab, galidesivir, sarilumab, lopinavir, ritonavir, darunavir, ribavirin, interferon alpha, pegylated interferon alpha, interferon alpha-2b, convalescent serum, or any combination thereof.

[0244] As further disclosed herein, the extracorporeal circulation device disclosed herein may be used to treat EBV caused by coronavirus infection as well as EBV caused by other reasons.

[0245] Provided herein are methods for treating or reducing or suppressing an EBV infection in a patient in need thereof. In some embodiments, the methods comprise: a) introducing blood or plasma containing EBV or a portion thereof, taken from a patient, into an extracorporeal circulation device containing a lectin that binds to EBV or a portion thereof; b) contacting the patient's blood or plasma with the lectin in the extracorporeal circulation device for a time sufficient for EBV or a portion thereof in the blood or plasma to bind to the lectin; and c) returning to the patient the blood or plasma in which the amount of EBV or a part thereof has been reduced as a result of step (b) compared to the blood or plasma of the patient before step (b) was performed. Including, d) detecting or identifying EBV or a portion thereof in a sample (e.g., a nasal sample (e.g., a nasal sample isolated from a nasal swab), a blood sample, a plasma sample, etc.) obtained from the patient before step (a) or after step (b), or both; and / or Selecting or identifying a patient with EBV infection for treatment to reduce EBV or a portion thereof. may also include: In some embodiments, the patient has a latent EBV infection that has reactivated to develop into an active EBV infection. In some embodiments, the patient exhibits symptoms of EBV infection prior to step (a). In some embodiments, the patient's EBV infection is induced by a bacterial or viral superinfection, and may be induced by a coronavirus superinfection. In some embodiments, the coronavirus superinfection is caused by a coronavirus selected from SARS-CoV-2, SARS-CoV-1, MERS-CoV, HCoV-229E, HCoV-OC43, HCoV NL63, and HCoV-HKU1. In some embodiments, the SARS-CoV-2 is a SARS-CoV-2 mutant strain. In some embodiments, the SARS-CoV-2 variant strain is 20I / 501Y.V1 (alpha strain, B.1.1.7), 20H / 501Y.V2 (beta strain, B.1.351), 20J / 501Y.V3 (gamma strain, P.1), B.1.617.2 (delta strain), AY.1, AY.2, C.37 (lambda strain), B.1.621 (mu strain), B.1.1.207, VUI-202102 / 03 (B.1.525), VUI-202101 / 01 (P.2), VUI-202102 / 01 (A.23.1), VUI 202102 / 04 (B.1.1.318), VUI 202103 / 01 (B.1.324.1), B.1.427, CAL.20C (B.1.429), R.1, B.1.466.2, B.1.1.519, C.36.3, B.1.214.2, B.1.1.523, B.1.619, B.1.620, C.1.2, B.1.617.1, B.1.1.529 (Omicron strain), and B.1.526. In some embodiments, the EBV infection is associated with multiple sclerosis, an autoimmune disease, or a malignant cancer in the patient. In some embodiments, the malignant cancer comprises Burkitt lymphoma, Hodgkin lymphoma, T / NK cell lymphoma, gastric cancer, breast cancer, nasopharyngeal carcinoma, glioblastoma multiforme, or post-transplant lymphoproliferative disorder.In some embodiments, the method further comprises isolating EBV virions or portions thereof bound to the lectin contained in the extracorporeal circulation device. In some embodiments, the method further comprises isolating exosomes associated with EBV infection or symptoms or sequelae thereof bound to the lectin contained in the extracorporeal circulation device. In some embodiments, the method further comprises examining the contents of the isolated exosomes. Embodiments of the extracorporeal circulation device and methods of using the extracorporeal circulation device disclosed herein may be used in this method.

[0246] Further disclosed herein is an extracorporeal circulation device comprising a lectin for use in treating EBV infection in a patient in need thereof. In some embodiments, the patient has a latent EBV infection that has reactivated to develop an active EBV infection (i.e., the active EBV infection is caused by EBV reactivation). In some embodiments, the EBV reactivation in the patient is induced by a bacterial or viral superinfection, and may be induced by a coronavirus superinfection. In some embodiments, the EBV infection is associated with multiple sclerosis, an autoimmune disease, and / or a malignant cancer in the patient. In some embodiments, the malignant cancer includes Burkitt's lymphoma, Hodgkin's lymphoma, T / NK-cell lymphoma, gastric cancer, breast cancer, nasopharyngeal carcinoma, glioblastoma multiforme, or post-transplant lymphoproliferative disorder. Embodiments of the extracorporeal circulation device and methods of using the extracorporeal circulation device disclosed herein may be used for this treatment. [Example]

[0247] The following examples further disclose some aspects of the above-described embodiments of the present invention, but are not intended to limit the scope of the present disclosure in any way. Those skilled in the art will appreciate that many other embodiments are also within the scope of the present invention, as described and claimed herein.

[0248] Example 1: Preparation of an affinity matrix consisting of lectin and agarose This example demonstrates the preparation of an affinity matrix using snowdrop agglutinin (GNA) covalently bound to agarose using cyanogen bromide. Essentially following the method described by Cuatrecasas et al. (Cuatracasas et al. Proc Natl Acad Sci USA 61(2): 636-643, 1968), cyanogen bromide (CNBr)-activated agarose was used for direct coupling. Briefly, 1 ml of CNBr-activated agarose (Sigma, St. Louis, MO) was added with 1 ml of 10 mg / ml GNA in NaHCO3 (0.1 M, pH 9.5) and incubated overnight in the cold. After the reaction was complete, unreacted material was removed by aspiration, and the agarose with GNA-bound lectin was thoroughly washed with cold sterile PBS. The resulting affinity matrix consisting of lectin and agarose was stored in the cold until use. Alternatively, GNA agarose may be commercially available from Vector Laboratories (Burlingame, Calif.).

[0249] Example 2: Preparation of an affinity matrix consisting of lectin and silica This example demonstrates the preparation of a lectin-containing affinity matrix using GNA covalently coupled to glass beads via reduction with cyanoborohydride and Schiff base formation. Affinity matrices consisting of lectin and silica were prepared using a modified version of the method described by Hermanson (Hermanson. Bioconjugate Techniques: 785, 1996). GNA (lectin) was dissolved in 0.1 M sodium borate (pH 9.5) to a final concentration of 10 mg / ml and added to aldehyde-derivatized silica glass beads (BioConnexant, Austin, TX). While this reaction is most efficient at alkaline pH, in this example it was performed at pH 7–9, typically using a 2–4-fold excess of GNA relative to the coupling sites. The resulting mixture was added with 10 μl of 5 M NaCNBH3 in 1 N NaOH (Aldrich, St. Louis, MO) per ml of coupling reaction mixture, and the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete, 20 μl of 3 M ethanolamine (pH 9.5) was added per ml of reaction mixture to cap any unreacted aldehydes on the silica glass surface. After 15 minutes at room temperature, the reaction mixture was decanted and the unbound protein and reagents were removed by thorough washing with PBS. The resulting matrix was stored in a refrigerator until use.

[0250] Example 3: Preparation of an affinity matrix consisting of lectin and aminocelite This example demonstrates the preparation of GNA covalently bound to amino-Celite using glutaraldehyde. Amino-Celite was prepared by reacting Celite (a silicate containing diatomaceous earth) overnight in a 5% aqueous solution of aminopropyltriethoxysilane. The aminated Celite was washed with water and ethanol to remove excess reagent and then dried overnight to yield an off-white powder. 1 g of the resulting off-white powder was suspended in 5 ml of 5% glutaraldehyde (Sigma) and reacted for 30 minutes. The suspension was filtered and washed with water until no residual aldehyde was detected with Schiff's reagent to remove excess glutaraldehyde. The filter cake was then resuspended in 5 ml of borohydride coupling buffer (Sigma) containing 2–3 mg / ml GNA and allowed to stand overnight at room temperature for the reaction to proceed. After the reaction was complete, unreacted GNA was washed away, and unreacted aldehyde was aminated with ethanolamine as described above. Finally, the mixture was washed with sterile PBS and stored in a cool place until use.

[0251] Example 4: Preparation of an affinity matrix consisting of lectin and diatomaceous earth A lectin-containing affinity virus hemodialysis device was prepared by loading dry powder of GNA-immobilized diatomaceous earth (CHROMOSORB GAW 60 / 80; Celite Corporation, Lompoc, CA) into the outer compartment of a hollow-fiber plasma exchange column (PLASMART 60; Medica, srl, Medolla, Italy) through a funnel attached to the outlet port. This dry powder (40 g) was introduced under gravity flow and then filled into the packable space outside the hollow fibers by shaking. For therapeutic use, the cartridge containing the affinity resin was placed in a TYVEK transport pouch, heat-sealed, and sterilized by gamma irradiation at 25–40 kGy. Samples of this product were then tested for sterility and endotoxin to confirm compliance with FDA standards. The final product can be stored at room temperature in a cool, dry place for at least 6 months before use.

[0252] Example 5: Preparation of an affinity matrix cartridge containing lectins This example demonstrates the preparation of an affinity hemodialysis device containing GNA as a lectin. A slurry of particulate GNA immobilized on agarose beads or Celite, suspended in sterile PBS buffer, was syringe-injected into the outer compartment of a hollow-fiber dialysis column. For blood samples up to 15 ml, a Microkros polyethersulfone hollow-fiber dialysis cartridge equipped with a Luer fitting (inner diameter: 200 μm, outer diameter: 240 μm, pore size: 200–500 nm, internal volume: approximately 0.5 ml) purchased from Spectrum Labs (Rancho Dominguez, CA) was used. The affinity resin-containing cartridge was equilibrated by pumping 5–10 column volumes of sterile PBS.

[0253] Example 6: Binding of lectin (GNA) to the spike protein of SARS-CoV-2 The device and method of the present invention can capture and remove SARS-CoV-2 spike 1 (S1) glycoprotein from a sample. In vitro experiments were performed by loading a solution spiked with SARS-CoV-2 S1 glycoprotein into a miniature column and continuously circulating it. Briefly, 10 mL of a 1 μg / mL solution of SARS-CoV-2 S1 (i.e., SARS-CoV-2 (2019-nCoV) Spike S1-His Recombinant Protein (HPLC-Verified), Sino Biological Co., Ltd., Catalog No.: 40591-V08H) in phosphate-buffered saline was injected into a Hemopurifier packed with 0.7 g of affinity resin (containing GNA and CHROMOSORB GAW 60 / 80) and circulated at a flow rate of 50 mL / min. Fluid samples were collected at predetermined time intervals, and the capture rate of viral S1 glycoprotein was measured as the percentage of S1 remaining in solution over time. As a control, S1 glycoprotein left on the bench (i.e., S1 glycoprotein not passed through the column) was used. As shown in Figure 4, the percentage of S1 protein in the test sample removed in the first 15 minutes was over 90%, and S1 protein was no longer detectable after 60 minutes of running through the column.

[0254] Example 7: Treatment of COVID-19 using an affinity hemofiltration device containing GNA lectin This example describes a method for using a clinical hemofiltration device to treat COVID-19.A clinical trial will be conducted to evaluate the use of a lectin-containing affinity extracorporeal hemofiltration device to capture and remove COVID-19-mediated nanoparticles for the treatment of SARS-CoV-2 viral disease (COVID-19).

[0255] The device of the present invention is a single-use hollow-fiber plasma exchange cartridge modified to include an affinity matrix incorporating snowdrop agglutinin (GNA) as a lectin in the interstices between hollow fibers arranged along the length of the plasma exchange cartridge. When blood is introduced into the device, enveloped viruses in the blood are transported through the pores of the hollow fibers, which have a nominal pore size of 200 nm, by convection and diffusion, and come into contact with the affinity matrix. The GNA captures the viruses and prevents them from returning to the circulatory system. At the same time, cellular components in the blood remain within the lumen of the hollow fibers and do not come into contact with the affinity matrix. The device is connected to the subject's circulatory system using a double-lumen central venous catheter and operates using standard dialysis equipment to perform hemofiltration.

[0256] The objectives of this clinical trial are to evaluate the safety of the hemofiltration device, assess changes in circulating viral load in the blood by RT-PCR, and measure viral load by eluting viral particles from the used hemofiltration cartridges.Clinical outcome assessments include evaluation of survival rate, evaluation of time on mechanical ventilation, evaluation of incidence of multiple organ system failure, and measurement of inflammatory, coagulation, and tissue damage markers.

[0257] Subjects with the following characteristics will be enrolled in the clinical trial: those with early acute lung injury (ALI) or early acute respiratory distress syndrome (ARDS) as their characteristic illness; and / or those at risk for severe COVID-19 disease within 24-48 hours, defined as dyspnea, respiratory rate of 30 breaths per minute or greater, blood oxygen saturation of 93% or less, arterial oxygen tension to fractional inspired oxygen ratio of less than 300, and / or pulmonary infiltrates greater than 50%; and / or those with life-threatening illness, defined as respiratory failure, septic shock, and / or multiple organ dysfunction or failure, who have been diagnosed with COVID-19.

[0258] Preparing the patient for treatment with a hemofiltration device: Pretreatment assessment involves obtaining blood samples to measure cytokines, inflammatory markers, coagulation markers, and other blood biomarkers indicative of organ damage, as well as performing a blood cell count. Pretreatment blood samples may also be used to detect viral components. For example, SARS-CoV-2 RNA may be assessed by RT-PCR. Furthermore, a separate blood sample may be used to assess exosomes present in the patient's circulation before treatment and compared with posttreatment exosomes. A hemodialysis catheter is inserted into the patient to prepare for treatment.

[0259] Preparation of the hemofiltration device:

[0260] Connect the extracorporeal circuit.

[0261] Prime and rinse the extracorporeal circuit with at least 2 L of priming solution.

[0262] To prevent blood clotting within the blood circuit, an anticoagulant such as heparin is added to 1 L of the priming solution as needed.

[0263] The initial priming flow rate should be 200-250 mL / min, and then increased to 400-500 mL / min for several minutes to increase the shear stress within the hollow fiber lumen and promote the removal of microbubbles. This procedure allows air bubbles to be removed from the tubing and cartridge with just a gentle tap.

[0264] Treatment:

[0265] To use a hemofiltration device in a patient with established vascular access, the patient is connected to a dialysis machine. The patient's blood is pumped through the cartridge, and the purified blood is returned to the patient. The blood flow rate is typically maintained at 200-400 ml / min, depending on the physician's discretion. Heparin is most commonly administered to prevent blood clotting. The typical treatment time for dialysis patients is up to four hours. This time may be extended to increase the effectiveness of treatment. After treatment, the blood in the tubing and cartridge is washed with sterile saline and returned to the patient. The patient is then disconnected from the dialysis machine, and the contaminated cartridge and blood tubing are properly disposed of.

[0266] During dialysis treatment, activated clotting time (ACT) is measured to monitor anticoagulation.

[0267] Post-treatment:

[0268] After use, the hemofiltration device is removed from the blood circuit, and the blood circuit is flushed with saline to remove as much fluid as possible that has entered the cartridge.

[0269] Used hemofiltration devices are sealed in clear plastic pouches and stored in a freezer until sent to an appropriate laboratory for analysis.

[0270] Blood samples are taken from patients to assess cytokines, inflammatory markers, other blood biomarkers indicative of organ damage, and blood counts after treatment.

[0271] result:

[0272] Comparing pre-treatment and post-treatment blood samples from COVID-19 patients treated as described above has shown a significant reduction in viral RNA levels in post-treatment blood samples. SARS-CoV-2 may be detected based on viral RNA measured by RT-PCR. Enzyme-linked immunosorbent assays (ELISAs) may also be used to detect and / or quantify viral proteins (e.g., spike ("S") glycoprotein or nucleocapsid protein). Serological assays using antibodies specific for one or more conserved epitopes of SARS-CoV-2 may also be used to detect viral proteins.

[0273] To analyze the viral components captured by the hemofiltration device, one of the techniques described above for measuring viral components is performed (e.g., measuring RNA by RT-PCR) to detect SARS-CoV-2 cleared from the patient's circulation.

[0274] Analysis of used hemofiltration devices indicates that they capture SARS-CoV-2 from the circulatory system.

[0275] Blood samples taken from COVID-19 patients at various time intervals after treatment with hemofiltration devices show reduced levels of D-dimer and fibrin degradation products.

[0276] Blood samples taken from COVID-19 patients at various time intervals after hemofiltration treatment show that troponin T levels are reduced after treatment compared to before hemofiltration treatment.

[0277] Laboratory analysis of pre-treatment blood samples may show evidence of lymphopenia, specifically abnormally low levels of T cells and NK cells in the peripheral blood. Post-treatment blood samples may show partial or complete recovery of total lymphocyte, T cell, and NK cell levels days or weeks after hemofiltration treatment.

[0278] Serum samples are analyzed in the laboratory using ELISA to quantify concentrations of markers such as IL-6, IL-10, IL-15, CXCL-10, and / or CCL-2. Laboratory evaluations include complete blood count and differential count; comprehensive metabolic panel including LDH, ferritin, and C-reactive protein (CRP); concentrations of inflammatory cytokines and chemokines (IL-6, IL-10, IL-15, CXCL10, and CCL2); myeloperoxidase; VCAM-1; LDH; D-dimer; and PT-INR; detection of SARS-CoV-2 in nasopharyngeal samples; quantification of viral (SARS-CoV-2) RNA in plasma; and quantification of viral (SARS-CoV-2) RNA in hemopurifier cartridges used during treatment. COVID-19 patients treated with hemofiltration devices have decreased serum concentrations of IL-6, IL-10, IL-15, CXCL-10, and / or CCL-2.

[0279] Serum samples are analyzed in the laboratory using an ELISA to quantify C-reactive protein (CRP) levels. Patients with COVID-19 treated with hemofiltration devices have decreased serum CRP levels.

[0280] Clinical outcomes in COVID-19 patients treated with hemofiltration devices as described above show improvements in clinical parameters, which may include reduction or resolution of lung lesions based on chest CT scans, reduction in time on mechanical ventilation, and improvement in multiple organ failure.

[0281] By utilizing the hemofiltration device and its method of use of the present invention, it is possible to shorten the time spent on a ventilator, reduce the likelihood of developing acute respiratory distress syndrome, cardiac complications such as arrhythmia and heart failure, and multiple organ failure, as well as the risk of acute kidney disease, sepsis, and / or other complications. For example, in patients with severe COVID-19 accompanied by systemic inflammation, the hemofiltration device and its method of use of the present invention can suppress or reduce the production or abundance of cytokines (e.g., IL-6).

[0282] The hemofiltration device and its method of use of the present invention have been shown to reduce blood D-dimer levels, shorten prothrombin time international normalized ratio (PT / INR), and increase platelet counts, thereby improving coagulation disorders in COVID-19 patients.

[0283] Example 8: Significant improvement in clinical condition of post-infectious patients with hemofiltration using affinity matrices containing lectins The patient, infected with COVID-19, presented with severe, persistent dyspnea and an oxygen saturation of 40% to 50%. The patient showed no improvement and continued receiving 100% oxygen via mechanical ventilation. The lectin (GNA)-containing affinity matrix cartridge (using CHROMOSORB GAW 60 / 80 as a carrier) disclosed herein was approved for emergency use. The patient underwent total hemodialysis using this lectin cartridge at a flow rate of 200 mL / min for 6 hours per day for a total of 8 days. A new cartridge was used daily. Blood samples were collected before and after treatment. In a blood sample collected before treatment on Day 1, qPCR analysis of the patient's plasma revealed no circulating COVID-19 virus viremia (Figure 5). Treatment was temporarily interrupted due to blood clotting on Day 1, but no problems were observed in subsequent treatments. After hemofiltration treatment, the partial pressure of oxygen (PaO2) reached 105 mmHg, eliminating the need for pure oxygen, and the patient showed remarkable recovery.

[0284] Blood samples collected from patients and the contents of Hemopurifier cartridges were analyzed to examine components isolated from patients by hemodialysis. Eight pre-treatment plasma samples and eight post-treatment plasma samples (containing EDTA anticoagulant) were added in 700 μL aliquots to buffer AVL (Qiagen) for nucleic acid isolation and used for viral genome and miRNA detection. One mL aliquots from the eight pre-treatment plasma samples and eight post-treatment plasma samples (containing EDTA anticoagulant) were stored without further processing and used for detection of intact exosomes and exosomal cargo (including proteins and miRNA). The used Hemopurifier was treated with 1) 1 M α-methylmannoside (α-MM; a competitor for lectin binding) and then 2) TRIzol Reagent® (ThermoFisher) (to release residual nucleic acids) to elute blood components bound to the lectin GNA. Approximately 200 mL of eluate was obtained from each step and each of the four Hemopurifiers.

[0285] An overview of patient outcomes and analysis of exosomes obtained from patient samples is presented in this Example. Additional information regarding exosome analysis is provided in Examples 9-10. Table 1 summarizes the overall patient outcomes.

[0286] 1) Eight days prior to treatment (July 30, 2020), the patient had an LDH level of 2370 U / L, providing evidence of tissue damage, and a ferritin level of 3599.5 ng / ml, providing evidence of systemic inflammation.

[0287] 2) On August 1, 2020 (6 days before treatment), the patient had a D-dimer level of >7650 ng / ml, providing evidence of endothelial damage / coagulopathy.

[0288] 3) On August 3, 2020 (4 days before treatment), the patient had evidence of tissue hypoxia, as evidenced by a lactate level of 3.6 mmol / L.

[0289] 4) Total exosome concentration decreased from before treatment to after treatment (2 to 4 days after treatment).

[0290] 5) The exosome-derived miRNAs miR-424 and miR-16 decreased during the first 4 days after the end of treatment.

[0291] On August 7, 2020 (Day 1, the first day of Hemopurifier treatment), the patient's platelet count was low at 115,000 / μL and the PT-INR was prolonged to 1.2 (13.6 seconds), providing evidence of persistent endothelial damage / coagulopathy. The PaO2 / FIO2 ratio was 93 (FIO2 = 0.70 vs. PaO2 = 65 mmHg), providing evidence of acute respiratory distress syndrome (ARDS). Furthermore, the IL-6 level was 641.7 pg / mL, the total white blood cell count was 15,500 / μL, providing evidence of systemic inflammation, and the absolute lymphocyte count was 780 / μL, providing evidence of lymphopenia.

[0292] 7) On August 8, 2020 (day 2, the second day of treatment with Hemopurifier), the PaO2 / FIO2 ratio was 98 (FIO2 = 1.0 vs. PaO2 = 98 mmHg). The patient's lactate level decreased to 2.3 mmol / l.

[0293] 8) On August 9, 2020 (the third day of treatment with Hemopurifier), the PaO2 / FIO2 ratio was 75.5 (FIO2 = 0.90 vs. PaO2 = 68 mmHg).

[0294] 9) On August 10, 2020 (day 4, the fourth day of treatment with Hemopurifier), the PaO2 / FIO2 ratio was 88.57 (FIO2 = 0.70 vs. PaO2 = 62 mmHg).

[0295] 10) On August 12, 2020, before the fifth day of treatment, the D-dimer level decreased to 3703 ng / mL, the PT value shortened to 11.3 seconds (PT-INR value 1.0), and the platelet count improved to 162,000 / μL, providing evidence that the patient's COVID-19-induced coagulopathy had improved. Because increased miR-424 levels have been reported in COVID-19-associated thrombosis, it is possible that removal of exosome-derived miR-424 with Hemopurifier played a role in improving COVID-19-induced coagulopathy. Furthermore, the PaO2 / FIO2 ratio increased to 136.25 (PaO2 = 109 mmHg compared with the required FIO2 = 0.80), indicating that the patient's pulmonary function had improved. Increased miR-16 has been associated with LPS-induced acute lung injury, and increased miR-424 has been associated with ARDS. The reduction of these two exosome-derived miRNAs following Hemopurifier treatment likely played a role in improving oxygen supply to the patient's circulatory system. The decrease in ferritin levels to 622.4 ng / mL indicated improvement in systemic inflammation, and the recovery of absolute lymphocyte count (ALC) to 1180 / μL indicated resolution of lymphopenia. The decrease in LDH levels to 978 U / L indicated improvement in tissue damage. Furthermore, the return of lactate levels to normal levels of 0.8 mmol / L indicated improvement in tissue hypoxia.

[0296] 11) On August 12, 2020, decreased levels of exosome-derived miR-424 and miR-16 were observed.

[0297] 12) Total exosome concentration increased from before treatment to after treatment.

[0298] 13) From days 6 to 8 after treatment (August 13 to 15, 2020), the PaO2 / FIO2 ratio was 117.14 on day 6 after treatment, 126.6 on day 7 after treatment, and 120 on day 8 after treatment. No change in the PaO2 / FIO2 ratio was observed, and the FIO2 was maintained at 0.70 on August 15, 2020.

[0299] 14) The levels of exosome-derived miRNAs were decreased 8 days after treatment (8 days after treatment).

[0300] 15) On August 19, 2020, the PaO2 / FIO2 ratio increased to 149.23 (FIO2 = 0.65 vs. PaO2 = 92 mmHg).

[0301] 16) On August 20, 2020, the PaO2 / FIO2 ratio rose to 175 (FIO2 = 0.60 vs. PaO2 = 105 mmHg).

[0302] 17) On August 24, 2020, laboratory analysis revealed a re-elevation of the ferritin level to 1583.8 ng / mL and a CRP level above 270 mg / L, indicating the presence of significant inflammation. Furthermore, the D-dimer level reached 5595 ng / mL and the PT-INR value reached 1.3, indicating a re-exacerbation of the coagulation disorder. It should be noted that the patient's procalcitonin level rose to 2.11 ng / mL on August 24, 2020, after reaching a normal range of 0.19 ng / mL on August 12, 2020. This finding suggests the presence of a bacterial superinfection, which may have contributed to the patient's clinical deterioration. [Table 1]

[0303] Example 9: Removal of exosomes from patients by hemofiltration In Example 8, the effect of Hemopurifier treatment on the amount of circulating exosomes and exosomal cargo in COVID-19 patients treated for 8 days (6 hours per treatment) was evaluated. Plasma samples were collected from patients on days 1 through 4 of treatment and analyzed. Pre-treatment plasma samples were collected before Hemopurifier treatment. Post-treatment plasma samples were collected after 6 hours of Hemopurifier treatment. Because treatment with Hemopurifier on day 1 was temporarily interrupted due to blood clotting, there was a 13-hour gap between the pre-treatment and post-treatment blood collections. Briefly, this analytical method involves first performing particle count analysis on untreated plasma, followed by purification of isolated exosomes using a miniature size-exclusion column (mini-SEC) to remove other particles of similar size to exosomes and abundant protein contaminants from the remaining plasma components. This mini-SEC method resulted in the collection of purified exosome samples in elution fraction No. 4, which was used for comparative analysis. The yield results from 1 mL of plasma obtained from COVID-19 patients are shown in Table 2. The COVID-19 clinical samples collected are shown in Table 2. [Table 2]

[0304] Isolation of exosomes from patient plasma: Exosomes were purified from patient plasma using established methodology (Ludwig et al. Curr. Protoc. Immunol. (2019) 127:e91; expressly incorporated herein by reference in its entirety). One milliliter of patient plasma was pre-cleared by two centrifugation steps to remove plasma particles larger than exosomes, filtered through a 0.22 μm PES membrane filter, and loaded onto a 10 mL Sepharose® column. Size exclusion chromatography was performed by adding 1 mL of PBS to the Sepharose column, and exosomes were isolated from the remaining plasma components by collecting elution fraction No. 4, which contained plasma exosomes.

[0305] For reliable quantitative measurements, plasma exosome samples should be diluted with 0.22 μm filtered PBS to approximately 10 8 ~10 9 The exosome concentration had to be adjusted to approximately 100 particles / mL. After diluting the exosome sample to an appropriate concentration range and analyzing the exosome sample with the Nanosight system, approximately 20–100 exosome particles were observed per field of view. To improve detection of small exosome populations that may be present in plasma samples, nanoparticle tracking measurement data were collected at a camera level of 12 and a detection threshold of 3. Three 30-second videos of different fields of view of the homogenous exosome sample were evaluated using NTA 3.3 software to determine particle count and particle size.

[0306] The number of nanoparticles in untreated patient plasma was assessed in pre- and post-treatment samples. Overall, the total number of nanoparticles decreased after treatment (Figure 6A). Day 1 was considered an outlier because treatment was discontinued. However, the relative particle size in untreated plasma samples did not change with treatment (Figure 6B).

[0307] The plasma sample was then processed using mini-SEC to elute eight fractions. Table 3 shows the relative protein concentrations (mg / mL) of each fraction, as measured by the BCA assay. Fraction 4 appeared to contain purified exosomes. Plasma after day 1 of treatment contained higher amounts of protein than the typical protein content of 60–80 mg / mL reported in the art (Leeman et al. Anal. Bioanal. Chem. (2018); 410:4867-73). The exosomes isolated in fraction 4 represented approximately 0.1% of the total plasma protein, consistent with the exosomal protein content reported in the art (Shtam et al. J. Hematol. (2018); 7:149-53). These data suggest that treatment with Hemopurifier has little effect on the total protein content in plasma. [Table 3]

[0308] The number of exosomes in fraction 4 obtained from each plasma sample was quantified. Figure 7A shows that the amount of exosomes in plasma generally decreased after treatment. Day 1 was considered an outlier, likely due to the interruption of treatment. These results suggest that treatment with Hemopurifier does not substantially reduce the total protein content in plasma, but can significantly remove exosomes.

[0309] The relative particle size of exosomes in fraction 4 from each plasma sample was assessed. Figure 7B shows that the relative particle size of the circulating exosome population is unchanged by treatment with Hemopurifier.

[0310] Example 10: miRNAs contained in purified exosomes that may be associated with disease phenotypes Given that miRNAs are known to be associated with inflammation and disease, we evaluated the miRNA content of exosomes (as used in Example 9) purified from patient plasma samples using mini-SEC by comparing pre- and post-treatment samples, as well as normal human plasma. Normal human plasma was processed with mini-SEC in the same manner as the patient samples, and exosome-containing fraction 4 was analyzed. Table 4 lists the miRNAs tested. miRNAs were isolated from plasma exosomes using the Qiagen miRNA Easy Isolation Kit, and exogenous miRNA spike-in controls were added. The miRNAs were reverse transcribed into cDNA templates using the TaqMan Advanced miRNA cDNA synthesis kit. Specific target miRNAs were amplified using a specific TaqMan Advanced miRNA primer / probe set (ThermoFisher, No. A25576) in a Quant 3 qPCR instrument. The miRNA sequences were quantified by normalization to the cel-miR-39-3p miRNA added as an exogenous spike-in control. [Table 4]

[0311] As an exogenous spike-in control, cel-miR-39-3p miRNA (cel-39) was added to all samples to control for variability introduced by the miRNA isolation process and subsequent synthesis of the cDNA template. The cel-39 control was added at 5.6 × 10 per sample. 8 Figure 8 shows the qRT-PCR amplification plots of the cel-39 spike-in control and the range of sample-to-sample variability that needs to be controlled for. The mean Ct value of all cel-39 amplicons was used to normalize the target miRNA signal in each sample. The relative abundance of each miRNA to the spike-in control, cel-39, was calculated using the 2-ΔΔCt method (Livak & Schmittgen, Methods (2001) 25(4):402-8). The amount of miRNA measured in exosomes was further normalized to reflect the starting sample volume of 1 mL of plasma.

[0312] Each tested miRNA was quantified by qRT-PCR in fraction 4 obtained from COVID-19 patient plasma samples and human control plasma samples. Figure 9 shows an example of a qRT-PCR amplification plot of a miRNA, demonstrating how signal intensity, reflecting miRNA abundance, varies between samples collected at individual time points during treatment. Figure 10 shows the relative abundance of miRNAs in samples from days 1 through 4. Overall, the abundance of the tested miRNAs was observed to be decreased in post-treatment exosome samples compared to pre-treatment exosome samples, suggesting that treatment with Hemopurifier removed exosomes containing these miRNAs. Figure 11 shows that during the early days of treatment, the decrease in miRNA abundance was directly proportional to the amount of exosomes removed from the samples.

[0313] To compare the relative abundance and relative depletion of tested miRNAs in the exosome fraction and untreated plasma, we quantified miRNAs in whole plasma samples obtained from COVID-19 patients on day 4 (Figure 12A). Depletion of miRNAs was also observed in whole plasma samples after treatment, with greater reductions in miR-424-5p and miR-16-2-3p in the exosome fraction compared to whole plasma (Figure 12B). Overall, our results demonstrate that while miRNAs exist in various forms in plasma (e.g., as exosomal cargo associated with other biological structures or as blood-borne nucleic acids), the use of Hemopurifier cartridges with GNA as a lectin can remove all miRNAs to some extent. However, the greater depletion observed in the exosome fraction indicates that these miRNAs are more selectively eliminated by the GNA lectin, which can capture pathogenic exosomes.

[0314] After analyzing samples from days 1–4, exosomes were also isolated and analyzed from plasma samples from days 5 and 8. Due to the need to obtain a second emergency use authorization, there was a two-day gap between days 4 and 5 of treatment. Figure 13A shows 1) the abundance of miR-424 and miR-16 in exosomes isolated from plasma and 2) the abundance of exosomes in plasma samples obtained on days 1 (August 7, 2020) and 4 (August 10, 2020). Figure 13B shows the abundance of miR-424 and miR-16 in exosomes and exosomes in plasma samples obtained on days 5 (August 12, 2020) and 8 (August 15, 2020). A consistent decrease in the abundance of miR-424 and miR-16 was observed after treatment with Hemopurifier, as evidenced by the results of pre- and post-treatment samples obtained on each day.

[0315] In summary, the Hemopurifier device can remove pathogenic miRNAs by capturing disease-promoting exosomes, regardless of the total number of exosomes before and after treatment. It was able to remove miR-424 and miR-16, miRNAs associated with COVID-19-associated coagulation disorders and acute lung injury, from the circulating blood of patients with acute COVID-19.

[0316] Example 11: Isolation of material bound to Hemopurifier cartridges This example further describes a method for extracting proteins, nucleic acids, and other substances by eluting viruses and exosomes bound to a Hemopurifier cartridge after treatment of a human subject. If the extracted substance is a viral genome, the resulting sample is analyzed by qPCR to assess the viral concentration.

[0317] Used Hemopurifier devices may be stored on ice or at -20°C until further processing, but immediate transport and processing is preferred. The Hemopurifier device is transported and handled in a biohazard-labeled bag, which is then placed in a larger secondary bag. Upon receipt, the sealed Hemopurifier device should be immediately placed in a refrigerator at 2°C to 8°C.

[0318] When you are ready to process the Hemopurifier device, prepare 250–300 mL of sterile saline or filtered PBS as a rinse solution. Secure the Hemopurifier device vertically in a clamp on a laboratory stand with a support ring or other support device. Remove the twist-lock top cap from the blood port on the top of the Hemopurifier device. Attach the MPC-850-16 and MPC-865 tubing. Fill a syringe with rinse solution and connect it to the open end of the MPC-865 tubing. Next, rotate the Hemopurifier device upside down so that the other end faces upward and remove the twist-lock cap from the blood port on this end. Attach the MPC-875 tubing. Place the open end of the MPC-875 tubing in an appropriate biohazard waste container and rotate the Hemopurifier device upside down again to position it so that the open end remains in the waste container while the Hemopurifier device is being rinsed. Slowly inject the rinse fluid into the Hemopurifier device, allowing it to pass through the device and collect in a waste container. Repeat this process two to three times. It is problematic if the fluid discharged from the Hemopurifier device is red, but a slight pink color is acceptable. Next, fill a syringe with air, inject the air into the Hemopurifier device, and allow the air to pass through the device, allowing the remaining fluid to be discharged and collected in a waste container. Repeat this process two to three times to remove as much fluid as possible before storing the Hemopurifier device. Once draining is complete, remove all tubing and discard in an appropriate biohazard container. Replace the blood port cap and store the Hemopurifier device at -20°C.

[0319] Elution circuit setup:Remove the Hemopurifier device from the biohazard bag and place it on an absorbent towel or pad. Allow the Hemopurifier device to warm to room temperature (15-20 minutes). Unscrew the twist-lock caps on both ends from the blood end ports and unscrew one of the Luer-lock caps on the side dialysate port. Save the removed caps to reinstall after the elution procedure. Attach tubing with a twist-lock to one end port. Place the other end of this tubing into a glass flask or bottle and insert the tubing nearly to the bottom. Attach another piece of tubing with a twist-lock to the other end port and insert this end into the glass container. Attach a drain tube with a male Luer fitting to the uncapped side port and place the end of this drain tube into the glass container. Once all tubing is securely in place, attach tubing clamps or hemostats to all tubing. The Hemopurifier device is then mounted vertically on a laboratory stand / holder with a support ring, with the uncapped side port facing upwards. See Figure 14 for a schematic of one example of this setup.

[0320] Elution of α-methylmannoside (α-MM):Prepare 200 mL of 1 M α-methylmannoside (α-MM) in 1x PBS. Add the α-MM solution to the glass container with the tubing inserted. Start pumping to allow the α-MM solution to flow through the Hemopurifier cartridge at a flow rate of 50 mL / min. Drain the α-MM solution from one or both of the upper drain ports. Once the Hemopurifier cartridge is filled with the α-MM solution, clamp the tubing attached to the blood outlet port ("Clamp A") and allow the α-MM solution to flow through the hollow fibers of the Hemopurifier cartridge and the space outside the hollow fibers for 20 minutes. Next, remove the A clamp, clamp the tubing attached to the side port ("Clamp B"), and allow the α-MM solution to flow through the hollow fibers of the cartridge for 20 minutes. Once circulation is complete, drain the remaining α-MM solution from the hollow fibers of the Hemopurifier cartridge and the space outside the hollow fibers. The resulting eluate can be quantified or stored frozen at -20°C for later use.

[0321] TRI Reagent / TRIzol extraction:Immediately after elution with the a-MM solution is complete, insert all tubing ends into a glass container containing 200 mL of TRI Reagent® or TRIzol. This procedure should be performed in a fume hood or appropriate biosafety cabinet. Once all tubing is secured in place, begin pumping the TRI Reagent into the Hemopurifier cartridge at a flow rate of 50 mL / min. Allow the TRI Reagent solution to drain through one or both of the upper drain ports. Once the Hemopurifier cartridge is filled with the TRI Reagent solution, clamp the drain tubing at the outlet of the hollow fiber lumen ("Clamp A") and allow the TRI Reagent solution to flow through the interior and exterior spaces of the hollow fibers for 20 minutes. The TRI Reagent solution will begin to dissolve the hollow fibers within the Hemopurifier cartridge and the hollow fibers within some of the tubing connections. The system should be checked frequently for leaks. Dissolved resin material can clog the tubing. Circulation should be checked frequently to ensure a consistent flow through the system. Adjust the tubing routing to prevent blockage of the inlet tubing. If tubing becomes clogged, the pump must be stopped and the blockage removed, replacing the tubing if necessary. Next, release clamp A, clamp B, and allow the TRI reagent solution to flow through the lumen of the Hemopurifier cartridge for 20 minutes. Once circulation is complete, allow the remaining reagent to drain from the interior and exterior spaces of the hollow fibers of the Hemopurifier cartridge. The resulting eluate can be quantified or stored at -20°C for later use.

[0322] Final rinse:Immediately after the TRI Reagent step is complete, insert all tubing ends into a glass container containing 200 mL of fresh 1x PBS. Rinse the Hemopurifier cartridge with PBS at a flow rate of 50 mL / min for 5 minutes. Once circulation is complete, drain any remaining PBS solution from the interior and exterior spaces of the Hemopurifier cartridge fibers. Store the rinsed PBS solution sample at -20°C. Remove all tubing and cap all ports on the Hemopurifier cartridge. Dispose of all equipment in an appropriate biohazard waste container.

[0323] Example 12: Overview of the use of Hemopurifier in a second acute COVID-19 patient On January 14, 2021, emergency use of the Hemopurifier device was approved for another patient. The patient was a 67-year-old man with a history of tetralogy of Fallot repair surgery, coronary artery disease, and newly diagnosed diabetes. He presented to the hospital with a week of persistent cough and shortness of breath. PCR testing confirmed positive for COVID-19 and he was hospitalized. The patient was also noted to have acute kidney injury. Despite treatment with remdesivir, dexamethasone, baricitinib, convalescent plasma, and standard-dose anticoagulation, he developed and worsened multiple organ failure. The patient was mechanically ventilated with a fraction of inspired oxygen (FIO2) of 100% and a positive end-expiratory pressure (PEEP) of 12 cmH2O, administered vasopressors alone to manage hypotension, and underwent CRRT to manage acute renal failure. As the patient's condition worsened, emergency use of the Hemopurifier device was approved for "filtration of viral components and exosomes in the bloodstream."

[0324] The subjects underwent a single 6-hour, 15-minute treatment with the Hemopurifier. The hospital was initially provided with four study devices. Using one of the four devices, the following process was performed:

[0325] As shown in Figure 15A, the contents of the Hemopurifier device were eluted with TRIzol reagent and analyzed, which positively indicated the amplification of three different SARS-CoV-2 viral genome regions. Table 5 shows the cycle threshold (Ct) values ​​used for quantification. A Ct value <37 was considered positive for the presence of SARS-CoV-2 virus. [Table 5]

[0326] The amount of each target viral gene was calculated by comparing it with a positive control containing a known copy number using the 2-ΔΔCt method (Livak & Schmittgen, M...

Claims

1. An extracorporeal circulation device including a hollow fiber cartridge containing a lectin, blood or plasma flows through the hollow fibers of the hollow fiber cartridge; the hollow fibers of the hollow fiber cartridge have a pore size that does not allow the passage of cellular components in the blood or plasma, so that the lectin does not come into contact with cellular components in the blood or plasma; the lectin is immobilized or adsorbed onto a solid support; the hollow fiber cartridge contains the lectin immobilized or adsorbed on the solid support, The lectin is characterized in that it can bind to a part of a coronavirus or a part of Epstein-Barr virus (EBV), or both; wherein the part of the coronavirus or the part of the EBV is extracted from a patient, and the patient is not suffering from a coronavirus infection and / or an EBV infection at the time the part of the coronavirus or the part of the EBV is extracted, but is exhibiting symptoms or aftereffects of a coronavirus infection and / or an EBV infection.

2. The extracorporeal circulation device according to claim 1, wherein the lectin is snowdrop agglutinin (GNA).

3. The extracorporeal circulation device according to claim 1, wherein the coronavirus is SARS-CoV-2.

4. The extracorporeal circulation device of claim 1 , wherein the solid support comprises diatomaceous earth.

5. 2. The extracorporeal circulation device according to claim 1, wherein the pore size is 20 to 500 nm, or about 20 to 500 nm, or 200 nm, or about 200 nm.

6. The extracorporeal circulation device according to claim 3, wherein the SARS-CoV-2 is a SARS-CoV-2 mutant strain.

7. The extracorporeal circulation device of claim 6, wherein the SARS-CoV-2 mutant strain is selected from 20I / 501Y.V1 (B.1.1.7), 20H / 501Y.V2 (B.1.351), 20J / 501Y.V3 (P.1), B.1.1.207, VUI-202102 / 03 (B.1.525), VUI-202101 / 01 (P.2), VUI-202102 / 01 (A.23.1), VUI 202102 / 04 (B.1.1.318), VUI 202103 / 01 (B.1.324.1) and CAL.20C (B.1.429).

8. The extracorporeal circulation device according to any one of claims 1 to 7, wherein the extracorporeal circulation device is used for 0.1 hours, 0.2 hours, 0.3 hours, 0.4 hours, 0.5 hours, 0.6 hours, 0.7 hours, 0.8 hours, 0.9 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours per use, or for a period of time within a range defined by any two of these periods.

9. 8. The extracorporeal circulation device according to claim 1, wherein the extracorporeal circulation device is used daily for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, or 15 days.

10. An extracorporeal circulation device for use in binding with a portion of a coronavirus or a portion of an Epstein-Barr virus (EBV), or both, comprising: a hollow fiber cartridge containing a lectin, wherein blood or plasma flows through the hollow fibers of the hollow fiber cartridge; the hollow fibers of the hollow fiber cartridge have a pore size that does not allow the passage of cellular components in the blood or plasma, so that the lectin does not come into contact with cellular components in the blood or plasma; the lectin is immobilized or adsorbed onto a solid support; the hollow fiber cartridge contains the lectin immobilized or adsorbed on the solid support, the carrier containing the lectin is capable of binding to a part of the coronavirus or a part of the EBV, or both; wherein the part of the coronavirus or the part of the EBV is extracted from a patient, and the patient is not suffering from a coronavirus infection and / or an EBV infection at the time the part of the coronavirus or the part of the EBV is extracted, but is exhibiting symptoms or aftereffects of a coronavirus infection and / or an EBV infection.

11. The extracorporeal circulation device according to claim 10, wherein the lectin is snowdrop agglutinin.

12. The extracorporeal circulation device according to claim 10, wherein the coronavirus is SARS-CoV-2.

13. The extracorporeal circulation device according to claim 12, wherein the SARS-CoV-2 is a SARS-CoV-2 mutant strain.

14. The extracorporeal circulation device of claim 13, wherein the SARS-CoV-2 mutant strain is selected from 20I / 501Y.V1 (B.1.1.7), 20H / 501Y.V2 (B.1.351), 20J / 501Y.V3 (P.1), B.1.1.207, VUI-202102 / 03 (B.1.525), VUI-202101 / 01 (P.2), VUI-202102 / 01 (A.23.1), VUI 202102 / 04 (B.1.1.318), VUI 202103 / 01 (B.1.324.1) and CAL.20C (B.1.429).

15. The extracorporeal circulation device according to any one of claims 10 to 14, wherein the carrier containing the lectin is used for 0.1 hours, 0.2 hours, 0.3 hours, 0.4 hours, 0.5 hours, 0.6 hours, 0.7 hours, 0.8 hours, 0.9 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours per use, or for a period of time within a range defined by any two of these periods.

16. The extracorporeal circulation device according to any one of claims 10 to 14, wherein the carrier containing the lectin is used daily for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, or 15 days.

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