WO2022258252A1 - Biomarker for monitoring coronavirus disease 2019 - Google Patents

Biomarker for monitoring coronavirus disease 2019 Download PDF

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Publication number
WO2022258252A1
WO2022258252A1 PCT/EP2022/060885 EP2022060885W WO2022258252A1 WO 2022258252 A1 WO2022258252 A1 WO 2022258252A1 EP 2022060885 W EP2022060885 W EP 2022060885W WO 2022258252 A1 WO2022258252 A1 WO 2022258252A1
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level
covid
patient
group
eef
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PCT/EP2022/060885
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French (fr)
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Johannes HAYBÄCK
Christoph SCHATZ
Meike Dorothee VON LAER
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Medizinische Universität Innsbruck
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Priority to EP22725242.6A priority Critical patent/EP4352514A1/en
Publication of WO2022258252A1 publication Critical patent/WO2022258252A1/en

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56983—Viruses
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/56—Staging of a disease; Further complications associated with the disease

Definitions

  • the present invention relates to a method of monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19. Further, the present invention relates to a method of prognosing the severity of Coronavirus disease 2019 (COVID-19) in a patient. Furthermore, the present invention relates to a method of determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19. In addition, the present invention relates to a kit useful for conducting these methods.
  • Coronavirus disease (COVID-19) is an infectious disease caused by a novel virus. In particular, it is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Starting in Wuhan, China, in December 2019, SARS-CoV-2 spread to other countries and continents. The World Health Organization (WHO) declared the outbreak to be a Public Health Emergency of International Concern on 30 January 2020 and recognized it as a pandemic on 11 March 2020.
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • WHO World Health Organization declared the outbreak to be a Public Health Emergency of International Concern on 30 January 2020 and recognized it as a pandemic on 11 March 2020.
  • Coronaviruses belong to the order of Nidovirales and infect mammals and birds.
  • the RNA-positive single-strand SARS-CoV-2 is related to MERS-CoV and SARS-CoV and causes acute and severe respiratory syndromes compared to other widely distributed coronaviruses from the genus Alphacoronavirus, infecting respiratory and gastrointestinal tracts in humans.
  • Interpersonal variation and 6 different mutations in the spike glycoprotein and 2 single nucleotide variations leading to the same missense mutation has been observed with the capability to substantially change its pathogenity.
  • SARS-CoV-2 enters the cell using the ACE2 receptor on the cell surface with replication and packaging in the cytoplasm and the assembly in the Endoplasmatic reticulum and Golgi followed by the budding in the Endoplasmatic reticulum-Golgi intermediate compartment.
  • the COVID-19 leads to a respiratory disease (similar to influenza) with symptoms such as cough and fever. Less common symptoms include fatigue, respiratory sputum production (phlegm), loss of the sense of smell, shortness of breath, muscle and joint pain, sore throat, headache, chills, vomiting, hemoptysis, diarrhea, or cyanosis.
  • infected individuals may develop bilateral pneumonia, may suffer from acute respiratory failure, and may also die.
  • Pathological processes of the liver, central nervous system, kidneys, blood vessels, and heart have also been observed.
  • the severe form of COVID-19 can be life-threatening with lung failure, septic shock, or multiple organ failure. Breathing difficulties may occur. The breathing difficulties may require intensive medical care including artificial ventilation.
  • the COVID-19 is mainly transmitted by infected persons when they cough or sneeze. Protection is possible by washing hands frequently and avoiding touching the face. Also keeping a distance from people who feel unwell helps. Someone can also get infected by touching surfaces or things where the virus is present and then touching eyes, nose or mouth.
  • Symptoms of COVID-19 can be relatively non-specific and infected people may be asymptomatic over a period of time before the disease outbreaks. It is, therefore, also important to predict the severity of the disease in order to make effective therapy decisions at an early stage. Accordingly, there is a need for a method allowing the prognosis of patients suffering from COVID-19 in a fast and reliable way.
  • eukaryotic Initiation Factors eukaryotic Initiation Factors
  • eEFs eukaryotic Elongation Factors
  • the translation of mRNAs into proteins is one level of the regulations of gene expressions and is important for homeostasis and fast responses.
  • Eukaryotic Initiation Factors elFs
  • elFs are proteins that bind to the small subunit of the ribosome during the initiation of translation, a part of protein biosynthesis.
  • the main task of elongation translation factors (eEFs) is the elongation by ribosomes.
  • the present inventors identified eukaryotic Initiation Factors (elFs) as well as eukaryotic Elongation Factors (eEFs) that allow to monitor COVID-19 in a patient, that allow to prognose the severity of COVID-19 in a patient, and that allow to determine the treatment response of a patient to specific therapies of COVID-19.
  • elFs eukaryotic Initiation Factors
  • eEFs eukaryotic Elongation Factors
  • the present invention relates to a method of monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19 comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF), the level of at least one eukaryotic Elongation Factor (eEF), the level of Mitochondrial Ribosome Recycling Factor (MRRF), and/or the level of ATP -binding cassette sub-family E member 1 (ABCE1) in a biological sample from a patient suffering from COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF
  • the present invention relates to a method of monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19 comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF) and/or the level of at least one eukaryotic Elongation Factor (eEF) in a biological sample from a patient suffering from COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, e
  • the present invention relates to a method of prognosing the severity of Coronavirus disease 2019 (COVID-19) in a patient comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF), the level of at least one eukaryotic Elongation Factor (eEF), the level of Mitochondrial Ribosome Recycling Factor (MRRF), and/or the level of ATP -binding cassette sub-family E member 1 (ABCE1) in a biological sample from a patient, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C,
  • the present invention relates to a method of prognosing the severity of Coronavirus disease 2019 (COVID-19) in a patient comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF) and/or the level of at least one eukaryotic Elongation Factor (eEF) in a biological sample from a patient, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2SS3,
  • the present invention relates to a method of determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19 comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF), the level of at least one eukaryotic Elongation Factor (eEF), the level of Mitochondrial Ribosome Recycling Factor (MRRF), and/or the level of ATP -binding cassette sub-family E member 1 (ABCEl) in a biological sample from a patient suffering from COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, e
  • the present invention relates to a method of determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19 comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF) and/or the level of at least one eukaryotic Elongation Factor (eEF) in a biological sample from a patient suffering from COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, e
  • the present invention relates to the use of at least one eukaryotic Initiation Factor (elF), at least one eukaryotic Elongation Factor (eEF), Mitochondrial Ribosome Recycling Factor (MRRF), and/or ATP -binding cassette sub-family E member 1 (ABCEl) for monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19, for prognosing the severity of Coronavirus disease 2019 (COVID- 19), or for determining whether a patient suffering from Coronavirus disease 2019 (COVID- 19) responds to a therapeutic treatment of COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl,
  • the present invention relates to the use of at least one eukaryotic Initiation Factor (elF) and/or at least one eukaryotic Elongation Factor (eEF) for monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19, for prognosing the severity of Coronavirus disease 2019 (COVID-19), or for determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3
  • the present invention relates to a kit for monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19, for prognosing the severity of Coronavirus disease 2019 (COVID-19), or for determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19, wherein the kit comprises means for determining the level of at least one eukaryotic Initiation Factor (elF), the level of at least one eukaryotic Elongation Factor (eEF), the level of Mitochondrial Ribosome Recycling Factor (MRRF), and/or the level of ATP -binding cassette sub-family E member 1 (ABCEl) in a biological sample from an individual, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elF
  • the present invention relates to a kit for monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19, for prognosing the severity of Coronavirus disease 2019 (COVID-19), or for determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19, wherein the kit comprises means for determining the level of at least one eukaryotic Initiation Factor (elF) and/or the level of at least one eukaryotic Elongation Factor (eEF) in a biological sample from an individual, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2
  • This kit is suitable for conducting the methods according to the first to third aspect of the present invention.
  • the terms used herein are defined as described in “A multilingual glossary of biotechnological terms: (IUPAC Recommendations)”, Leuenberger, H.G.W, Nagel, B. and Kolbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).
  • COVID-19 refers to an infectious disease caused by a novel virus. In particular, it is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • the disease leads to a respiratory disease (similar to influenza) with symptoms such as cough and fever. Less common symptoms include fatigue, respiratory sputum production (phlegm), loss of the sense of smell, shortness of breath, muscle and joint pain, sore throat, headache, chills, vomiting, hemoptysis, diarrhea, or cyanosis.
  • severe COVID-19 cases infected individuals may develop bilateral pneumonia, may suffer from acute respiratory failure, and may also die.
  • COVID-19 can be life-threatening with lung failure, septic shock, or multiple organ failure. Breathing difficulties may occur. The breathing difficulties may require intensive medical care including artificial ventilation.
  • COVID-19 is mainly transmitted by infected persons when they cough or sneeze. Protection is possible by washing hands frequently and avoiding touching the face. Also keeping a distance from people who feel unwell helps. Someone can also get infected by touching surfaces or things where the virus is present and then touching eyes, nose or mouth.
  • COVID-19 can occur in a mild form, a moderate form, or a severe form. About 80% of the COVID-19 diseases are mild to moderate. 20% of the COVID-19 diseases are severe forms of COVID-19. The severe form of COVID-19 can be life-threatening (with lung failure, septic shock, or multiple organ failure).
  • COVID- 19 pathological processes of the liver, central nervous system, kidneys, blood vessels, and heart have also been observed. Thus, the severe form of COVID- 19 can be life-threatening.
  • life-threatening form of COVID-19 refers to COVID-19 associated with lung failure, septic shock, and/or multiple organ failure.
  • determining the course of COVID-19 in a patient means determining the development of COVID-19 in a patient over time, e.g. whether COVID-19 worsens in the patient, does not worsen/is stable in the patient, or improves in the patient over time.
  • prognosing the severity of COVID-19 in a patient means prognosing the development of COVID-19 in a patient.
  • prognosing the severity of COVID-19 in a patient means prognosing the seriousness of COVID-19 in a patient.
  • prognosing the severity of COVID-19 in a patient suffering from a mild form of COVID-19 means determining whether (it is likely that) the patient will develop a moderate form of COVID-19 or a severe form of COVID-19.
  • prognosing the severity of COVID-19 in a patient suffering from a moderate form of COVID-19 means determining whether (it is likely that) the patient will develop a severe form of COVID-19.
  • the severe form of COVID-19 can be life-threatening.
  • determining whether a patient suffering from COVID-19 responds to a therapeutic treatment of COVID-19 means evaluating whether a therapeutic approach is effective in a patient or not.
  • treatment refers to any therapy which improves the health status and/or prolongs (increases) the lifespan of a patient suffering from COVID-19.
  • Said therapy may eliminate COVID-19 in a patient, arrest or slow the development of COVID-19 in a patient, inhibit the development of COVID-19 in a patient, decrease the severity of symptoms in a patient suffering from COVID-19, and/or decrease the recurrence in a patient who currently has or who previously has had COVID-19.
  • the treatment of COVID-19 described herein includes, but is not limited to, the administration of a drug.
  • the drug is preferably selected from the group consisting of an antiviral drug, an antibacterial drug, an anti-inflammatory drug, an antifungal drug, and an antipyretic agent.
  • the antiviral drug is more preferably selected from the group consisting of chloroquine, remdesivir, darunavir, favipiravir, lopinavir, and ritonavir. Combinations of these drugs are also encompassed.
  • the antiviral drug is even more preferably selected from the group consisting of remdesivir, darunavir, or a combination of lopinavir and ritonavir.
  • the antibacterial drug is more preferably selected from the group consisting of ceftriaxone, amoxicillin/clavulanic acid, piperacillin/tazobactam, and azithromycin. Combinations of these drugs are also encompassed.
  • the anti-inflammatory drug is more preferably selected from the group consisting of ibuprofen and metamizole. Combinations of these drugs are also encompassed.
  • the antifungal drug is more preferably selected from the group consisting of voriconazole and isavuconazole. Combinations of these drugs are also encompassed.
  • the antipyretic agent is more preferably paracetamol. However, also another treatment than the administration of a drug is possible. The other form of therapeutic treatment is preferably ventilation.
  • the ventilation is selected from the group consisting of non-invasive ventilation and invasive ventilation.
  • the non-invasive ventilation is carried out through a face mask, nasal mask, or a helmet, or the invasive ventilation is a mechanic ventilation, e.g. carried out through a positive pressure ventilator or negative pressure ventilator.
  • eukaryotic Initiation Factors refers to molecules which are involved in the initiation phase of eukaryotic translation. These factors help to stabilize the formation of the functional ribosome around the start codon and also provide regulatory mechanisms in translation initiation.
  • eukaryotic Initiation Factors covers elF RNA transcripts (RNA transcript variants) such as mRNAs including splice variants of these transcripts and elF proteins encoded thereby.
  • the level of the elFs may be determined by measuring mRNA or protein levels.
  • eukaryotic Initiation Factors elFs
  • elFs eukaryotic Initiation Factors
  • elF isoforms are members of a set of highly similar molecules, in particular proteins, that perform the same or similar biological role.
  • the present inventors identified eukaryotic Initiation Factors (elFs) that allow to monitor COVID-19 in a patient, that allow to prognose the severity of COVID-19 in a patient, and that allow to determine the treatment response of a patient to specific therapies of COVID-19.
  • elFs eukaryotic Initiation Factors
  • the specific elFs identified by the present inventors are selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5.
  • the elFs are preferably human elFs.
  • Elongation Factors refers to molecules that function at the ribosome, during protein synthesis, to facilitate translational elongation from the formation of the first to the last peptide bond of a growing polypeptide. Elongation is the most rapid step in translation. In eukaryotes, it proceeds at a rate of two amino acids per second (about 6 nucleotides read per second). Elongation factors play a role in orchestrating the events of this process and in ensuring the high accuracy translation at these speeds.
  • eukaryotic Elongation Factors covers eEF RNA transcripts (RNA transcript variants) such as mRNAs including splice variants of these transcripts and eEF proteins encoded thereby. Thus, the level of the eEFs may be determined by measuring mRNA or protein levels.
  • eukaryotic Elongation Factors eEFs
  • eEFs also covers eEF isoforms. These eEF isoforms are members of a set of highly similar molecules, in particular proteins, that perform the same or similar biological role.
  • the present inventors identified eukaryotic Elongation Factors (eEFs) that allow to monitor COVID-19 in a patient, that allow to prognose the severity of COVID-19 in a patient, and that allow to determine the treatment response of a patient to specific therapies of COVID-19.
  • the specific eEFs identified by the present inventors are selected from the group consisting of eEFlAl, eEFIG, eEF2, eEFID, and eEFlB2.
  • the eEFs are preferably human eEFs.
  • MRRF Mitochondrial Ribosome Recycling Factor
  • ATP -binding cassette sub-family E member 1 refers to a molecule which is a member of the superfamily of ATP -binding cassette (ABC) transporters.
  • ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABCl, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the OABP subfamily. Alternatively referred to as the RNase L inhibitor, this protein functions to block the activity of ribonuclease L. Activation of ribonuclease L leads to inhibition of protein synthesis in the 2-5A/RNase L system, the central pathway for viral interferon action.
  • the term “patient”, as used herein, refers to any subject suffering from COVID-19, i.e. diseased.
  • the patient may be a patient for whom it is desired to know how COVID-19 develops in said patient over time (COVID-19 monitoring).
  • the patient may further be a patient for whom it is desired to know whether the patient will (likely) develop an advanced form of COVID-19, e.g. a moderate or severe form of COVID-19 (prognosis of COVID-19 severity).
  • the patient may further be prognosed to (likely) develop an advanced form of COVID-19, e.g. a moderate or severe form of COVID-19.
  • the patient may also be a patient for whom it is desired to know whether a therapeutic treatment of COVID-19 is effective or not (COVID-19 treatment monitoring).
  • the term “patient”, as used herein, refers to a subject which is affected by COVID-19, i.e. diseased.
  • the patient may also be retested for COVID-19 in a monitoring process and may be diagnosed to be still affected by COVID-19, i.e. diseased, or not affected by COVID-19 anymore, i.e. healthy, for example after therapeutic intervention.
  • the term “patient”, as used herein, also covers an individual participating in a mass screening.
  • a patient that is diagnosed as being healthy, i.e. not suffering from COVID-19, may possibly suffer from another disease not tested/known.
  • the patient may be any mammal, including both a human and another mammal, e.g. an animal such as a monkey. Human patients are particularly preferred.
  • control subject refers to a subject known to be not affected by/infected with COVID-19 (negative control), i.e. healthy. Specifically, a (control) subject being healthy has no COVID-19 symptoms and no antibodies against COVID-19.
  • control subject also refers to a subject known to be affected by/infected with COVID-19 (positive control), i.e. diseased.
  • control subject further refers to a subject known to suffer from a specific form of COVID-19, e.g. a mild, moderate, or severe form of COVID-19.
  • a comparison of patient data with data of (control) subjects allows the prognosis of the severity of COVID-19, e.g. whether the patient will (likely) develop a moderate or severe form of COVID-19 disease.
  • a comparison of patient data with data of (control) subjects allows to determine how COVID-19 develops in the patient, e.g. whether COVID-19 worsens in the patient or improves in the patient.
  • control subject which is known to be healthy, i.e. not suffering from COVID-19, may possibly suffer from another disease not tested/known.
  • the (control) subject may be any mammal, including both a human and another mammal, e.g. an animal such as a monkey. Human (control) subjects are particularly preferred.
  • biological sample refers to any biological sample from a patient or (control) subject containing the at least one elF and/or the at least one eEF described herein.
  • the biological sample may be a body fluid sample, a body gas sample, a body tissue sample, or a body cell sample.
  • biological samples encompassed by the present invention are tissue (e.g. section or explant) samples, single cell samples, cell colony samples, cell culture samples, blood (e.g. whole blood or blood fraction such as blood cell fraction, serum or plasma) samples, urine samples, or samples from other peripheral sources.
  • Said biological samples may be mixed or pooled, e.g. a sample may be a mixture of a blood sample and a urine sample.
  • Said biological samples may be provided by removing a body fluid, cell(s), cell colonies, an explant, or a section from a patient or (control) subject, but may also be provided by using a previously isolated sample.
  • a tissue sample may be removed from a patient or (control) subject by conventional biopsy techniques or a blood sample may be taken from a patient or (control) subject by conventional blood collection techniques.
  • the biological sample e.g. urine sample, tissue sample or blood sample, may be obtained from a patient or (control) subject prior to the initiation of a therapeutic treatment, during the therapeutic treatment, and/or after the therapeutic treatment. If the biological sample is obtained from one or more (control) subjects, e.g.
  • the reference biological sample is from the same source than the biological sample of the patient to be tested, e.g. both are blood samples, cerebrospinal fluid (CSF) samples, or urine samples. It is further preferred that both are from the same species, e.g. from a human. It is also (alternatively or additionally) preferred that the measurements of the reference biological sample and the biological sample of the patient to be tested are identical, e.g. both have an identical volume. It is particularly preferred that the reference biological sample and the biological sample are from patients/(control) subjects of the same sex and age.
  • CSF cerebrospinal fluid
  • body fluid sample refers to any liquid sample derived from the body of a patient or (control) subject containing the at least one elF and/or the at least one eEF described herein.
  • Said body fluid sample may be a urine sample, blood sample, sputum sample, breast milk sample, cerebrospinal fluid (CSF) sample, cerumen (earwax) sample, gastric juice sample, mucus sample, endolymph fluid sample, perilymph fluid sample, peritoneal fluid sample, pleural fluid sample, saliva sample, sebum (skin oil) sample, semen sample, sweat sample, tears sample, cheek swab, vaginal secretion sample, liquid biopsy, or vomit sample including components or fractions thereof.
  • CSF cerebrospinal fluid
  • cerumen earwax
  • gastric juice sample mucus sample
  • endolymph fluid sample perilymph fluid sample
  • peritoneal fluid sample pleural fluid sample
  • saliva sample sebum (skin oil) sample
  • body fluid sample also encompasses body fluid fractions”, e.g. blood fractions or sputum fractions.
  • the body fluid samples may be mixed or pooled.
  • a body fluid sample may be a mixture of a blood and a urine sample or a mixture of a blood and cerebrospinal fluid sample.
  • Said body fluid sample may be provided by removing a body liquid from a patient or (control) subject, but may also be provided by using previously isolated body fluid sample material.
  • the body fluid sample allows for a non-invasive analysis of a patient.
  • the body fluid sample has a volume of between 0.01 and 20 ml, more preferably of between 0.1 and 10 ml, even more preferably of between 0.5 and 8 ml, and most preferably of between 1 and 5 ml. If the body fluid sample is obtained from one or more control subjects, e.g. from at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 400, 500, 1.000, 2.000, 3.000, 4.000, 5.000, or 10.000 control subject(s), it is designated as “reference body fluid sample”.
  • blood sample encompasses a whole blood sample or a blood fraction sample such as a blood cell fraction, blood serum, or blood plasma sample.
  • Blood cells also known as hemopoietic cells, may be used. Said blood cells may be erythrocytes, leukocytes, and/or thrombocytes, e.g. mixtures thereof.
  • Peripheral blood mononuclear cells (PBMCs) such as lymphocytes, monocytes, or macrophages may also be used.
  • PBMCs Peripheral blood mononuclear cells
  • the blood serum or plasma sample has a volume of between 0.01 and 20 ml, more preferably of between 0.1 and 10 ml, even more preferably of between 0.5 and 8 ml and most preferably of between 1 and 5 ml.
  • body gas sample refers to any gas sample derived from the body of a patient or (control) subject containing the at least one elF and/or the at least one eEF described herein. Said body gas sample encompasses exhaled condensate and exhaled gas. If the body gas sample is obtained from one or more control subjects, e.g. from at least 1, 2, 3, 4,
  • body tissue sample refers to any tissue sample derived from the body of a patient or (control) subject containing the at least one elF and/or the at least one eEF described herein.
  • Said body tissue sample encompasses skin flake, skin biopsy, hair follicle, biopsy tissue, tissue explant, and tissue section.
  • the tissue sample from a patient or (control) subject has a weight of between 0.1 and 500 mg, more preferably of between 0.5 and 250 mg, and most preferably of between 1 and 50 mg, i.e. 0.1, 0.2, 0.3, 0.4, 0.5, 0.6,
  • the body tissue sample is obtained from one or more control subjects, e.g. from at least
  • level refers to an amount (measured for example in grams, mole, or ion counts) or concentration (e.g. absolute or relative concentration) of the at least one elF and/or the at least one eEF claimed herein.
  • level also comprises scaled, normalized, or scaled and normalized amounts or values.
  • the level may also be a cut-off level.
  • the level is an expression level.
  • kit of parts in short: kit
  • kit is understood to be any combination of at least some of the components identified herein, which are combined, coexisting spatially, to a functional unit, and which can contain further components.
  • POCT point-of-care testing
  • POCT is often accomplished through the use of transportable, portable, and handheld instruments and test kits.
  • Small bench analyzers or fixed equipment can also be used when a handheld device is not available - the goal is to collect the specimen and obtain the results in a very short period of time at or near the location of the individual so that the treatment plan can be adjusted as necessary before the individual leaves the hospital.
  • eukaryotic Initiation Factors eukaryotic Initiation Factors
  • eEFs eukaryotic Elongation Factors
  • the translation of mRNAs into proteins is one level of the regulations of gene expressions and is important for homeostasis and fast responses.
  • Eukaryotic Initiation Factors elFs
  • elFs are proteins that bind to the small subunit of the ribosome during the initiation of translation, a part of protein biosynthesis.
  • the main task of elongation translation factors (eEFs) is the elongation by ribosomes.
  • the present inventors identified eukaryotic Initiation Factors (elFs) as well as eukaryotic Elongation Factors (eEFs) that allow to monitor COVID-19 in a patient, that allow to prognose the severity of COVID-19 in a patient, and that allow to determine the treatment response of a patient to specific therapies of COVID-19.
  • elFs eukaryotic Initiation Factors
  • eEFs eukaryotic Elongation Factors
  • the present invention relates to a method of monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19 comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF), the level of at least one eukaryotic Elongation Factor (eEF), the level of Mitochondrial Ribosome Recycling Factor (MRRF), and/or the level of ATP -binding cassette sub-family E member 1 (ABCE1) in a biological sample from a patient suffering from COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A,
  • the present invention relates to a method of monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19 comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF) and/or the level of at least one eukaryotic Elongation Factor (eEF) in a biological sample from a patient suffering from COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, e
  • the elF is selected from the group consisting of elFlAX, elFl, eIF5, eIF5B, and eIF2B5. More particularly, the elF is elFl AX. Combinations of the preferred elFs, namely elFlAX, elFl, eIF5, eIF5B, and eIF2B5, can be taken from Figure 1.
  • the level of at least one of elFlAX, elFl, eIF2A, eIF2B4, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, eIF5B, eEFlAl, eEFIG, and eEFlB2 is determined.
  • the level of at least one elF selected from the group consisting of elFlAX, elFl, eIF2A, eIF2B4, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B is determined and/or the level of at least one eEF selected from the group consisting of eEFlAl, eEFIG, and/or eEFlB2 is determined.
  • the above method allows to control COVID-19 or allows to determine the course of COVID-19 in a patient suffering from COVID-19 over time.
  • the above method allows to determine whether COVID-19 worsens, improves, or is stable in a patient suffering from COVID-19 over time.
  • worsening means that a patient suffering from a mild form of COVID-19 has developed a moderate or severe form of COVID-19 (over time) or that a patient suffering from a moderate form of COVID-19 has developed a severe form of COVID-19 (over time).
  • the severe form of COVID-19 can be life-threatening. In any case, the disease can progress from mild, to moderate, to severe.
  • improving means that a patient suffering from a severe form of COVID-19 has developed a moderate form of COVID-19 (over time), that a patient suffering from a moderate form of COVID-19 has developed a mild form of COVID-19 (over time), or that a patient suffering from a mild form of COVID-19 has recovered overtime.
  • the course of recovery can progress from a severe form of COVID-19, to a moderate and mild form of COVID-19 to complete recovery.
  • ICU intensive care unit
  • the level of the at least one elF is compared to a reference level of said at least one elF
  • the level of the at least one eEF is compared to a reference level of said at least one eEF
  • the level of MRRF is compared to a reference level of said MRRF
  • the level of ABCEl is compared to a reference level of said ABCEl.
  • the method of monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19 comprises the steps of:
  • elF eukaryotic Initiation Factor
  • eEF eukaryotic Elongation Factor
  • MRRF Mitochondrial Ribosome Recycling Factor
  • ABCEl ATP -binding cassette sub-family E member 1
  • the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2
  • the level of the at least one elF is compared to a reference level of said at least one elF and/or the level of the at least one eEF is compared to a reference level of said at least one eEF.
  • the method of monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19 comprises the steps of:
  • the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF
  • the reference level represents a level that allows to determine whether COVID-19 worsens, improves, or is stable in the patient.
  • the reference level is the level determined by measuring one or more, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
  • reference biological sample per subject for analysis. If additional reference biological samples are required, e.g. to determine the reference level in different reference biological samples, the same subject may be (re)tested.
  • Said reference level may be an average reference level. It may be determined by measuring reference levels and calculating the “average” value (e.g. mean, median or modal value) thereof.
  • a level above or below the reference level may indicate that COVID-19 worsens in the patient, a level comparable with the reference level may indicate that COVID-19 is unchanged in the patient, or a level above or below the reference level may indicate that COVID-19 improves in the patient.
  • the reference level is the level determined by measuring one or more reference biological samples from one or more subjects having a mild form of COVID-19 and wherein
  • the level of the at least one elF selected from the group consisting of eIF3C, eIF4E, and eIF2S2 above the reference level indicates that COVID-19 is worsening in the patient
  • the level of the at least one elF selected from the group consisting of eIF3C, eIF4E, and eIF2S2 comparable with the reference level indicates that COVID-19 is stable/not progressing in the patient
  • the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2 below the reference level indicates that COVID-19 is worsening in the patient
  • the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2 above the reference level indicates that COVID-19 is improving in the patient, and/or
  • the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2 comparable with the reference level indicates that COVID- 19 is stable/not progressing in the patient.
  • the reference level is the level determined by measuring one or more reference biological samples from one or more subjects having a moderate form of COVID-19 and wherein
  • the level of the at least one elF selected from the group consisting of elFlAX, elFl, eIF2A, eIF2B4, eIF2B5, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B above the reference level indicates that COVID-19 is improving in the patient,
  • the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 below the reference level indicates that COVID-19 is worsening in the patient
  • the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 above the reference level indicates that COVID-19 is improving in the patient
  • the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 comparable with the reference level indicates that COVID-19 is stable/not progressing in the patient
  • the reference level is the level determined by measuring one or more reference biological samples from one or more subjects having a severe form of
  • the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 above the reference level indicates that COVID-19 is improving in the patient
  • the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 comparable with the reference level indicates that COVID-19 is stable in the patient
  • the reference level may also be the level determined by measuring one or more reference biological samples from one or more subjects having a moderate/severe form of COVID-19 and wherein
  • the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2 above the reference level indicates that COVID-19 is improving in the patient.
  • the reference level may be an average level of a moderate and severe form of COVID-19.
  • the level of the at least one elF and/or the level of the at least one eEF is at least 0.6-fold or 0.7-fold, more preferably at least 0.8-fold or 0.9-fold, even more preferably at least 1.2-fold or 1.5-fold, and most preferably at least 2.0-fold or 3.0-fold below/above the reference level.
  • the level of the at least one elF and/or the level of the at least one eEF is at least 0.6-fold, at least 0.7-fold, at least 0.8-fold, at least 0.9-fold, at least 1.0-fold, at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.6- fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, at least 2.1-fold, at least 2.2-fold, at least 2.3-fold, at least 2.4-fold, at least 2.5-fold, at least 2.6-fold, at least 2.7- fold, at least 2.8-fold, at least 2.9-fold, or at least 3.0-fold below/above the reference level.
  • said determining comprises determining the level of the at least one elF, the level of the at least one eEF, the level of MRRF, and/or the level of ABCEl in a biological sample (from a patient) at a first point in time and in at least one further biological sample (from the (same) patient) at a later point in time and comparing said levels determined at the different time points.
  • the method of monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19 comprises the steps of:
  • the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2, wherein MRRF means Mitochondrial
  • said determining comprises determining the level of the at least one elF and/or the level of the at least one eEF in a biological sample (from a patient) at a first point in time and in at least one further biological sample (from the (same) patient) at a later point in time and comparing said levels determined at the different time points.
  • the method of monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19 comprises the steps of:
  • the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEFID, and eEFlB2.
  • An increase or decrease of the level over time may indicate that COVID-19 is worsening in the patient, a level that does not change over time may indicate that the patient is stable or COVID-19 is not progressing in the patient, or an increase or decrease of the level over time may indicate that COVID-19 is improving in the patient.
  • elFlAX the level of the at least one elF selected from the group consisting of elFlAX, elFl, eIF2A, eIF2B4, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B which decreases over time indicates that COVID-19 is worsening in the patient
  • the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 which increases over time indicates that COVID-19 is improving in the patient, and/or
  • the term “comparable with” means that the level varies over time between 0 and ⁇ 20%, e.g. 0, 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, 19.9, 19.99, or 19.999%.
  • the term “comparable with” in this respect can also mean that the detected level variation is within the accuracy of a measurement. The accuracy of a measurement depends on the measurement method used. Preferably, the level is constant over time.
  • the time period between the first point in time and the later point(s) in time preferably amounts to at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days (1 week), at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 1 month, or at least 2 months.
  • the individual may be routinely checked, e.g. every day or one times per week.
  • the patient may be (re)tested at 2, 3, 4, 5, 6 7, 8, 9, or 10 time points (first point in time and further point(s) in time).
  • the patient tested with the method of the first aspect may be a patient which will receive, receives, has received, or had received a treatment of COVID-19.
  • the patient may (timely) receive a therapeutic treatment for this disease state.
  • the therapeutic treatment may be in the form of the administration of a drug and/or in the form of a therapeutic treatment different from the administration of a drug, e.g. ventilation.
  • the therapeutic treatment may be reduced or finished.
  • the therapeutic treatment may be continued. In this respect, it is also referred to the third aspect of the present invention.
  • the present invention relates to a method of prognosing the severity of Coronavirus disease 2019 (COVID-19) in a patient comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF), the level of at least one eukaryotic Elongation Factor (eEF), the level of Mitochondrial Ribosome Recycling Factor (MRRF), and/or the level of ATP -binding cassette sub-family E member 1 (ABCE1) in a biological sample from a patient, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C,
  • the present invention relates to a method of prognosing the severity of Coronavirus disease 2019 (COVID-19) in a patient comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF) and/or the level of at least one eukaryotic Elongation Factor (eEF) in a biological sample from a patient, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2SS3,
  • the elF is selected from the group consisting of elFlAX, elFl, eIF5, eIF5B, and eIF2B5. More particularly, the elF is elFlAX. Combinations of the preferred elFs, namely elFlAX, elFl, eIF5, eIF5B, and eIF2B5, can be taken from Figure 1.
  • the level of at least one of elFlAX, elFl, eIF2A, eIF2B4, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, eIF5B, eEFlAl, eEFIG, and eEFlB2 is determined.
  • the level of at least one elF selected from the group consisting of elFlAX, elFl, eIF2A, eIF2B4, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B is determined and/or the level of at least one eEF selected from the group consisting of eEFlAl, eEFIG, and/or eEFlB2 is determined.
  • the above method allows to prognose the development of COVID-19 in a patient.
  • the above method allows to prognose the seriousness of COVID-19 in a patient.
  • prognosing the severity of COVID-19 in a patient suffering from a mild form of COVID-19 means determining whether (it is likely that) the patient will develop a moderate form of COVID-19 or a severe form of COVID-19.
  • prognosing the severity of COVID- 19 in a patient suffering from a moderate form of COVID-19 means determining whether (it is likely that) the patient will develop a severe form of COVID-19.
  • the severe form of COVID- 19 can be life-threatening.
  • Prognosing the severity of COVID-19 also allows to determine whether the patient will need treatment in a hospital (moderate or severe form of COVID-19) or not (mild form of COVID-19). In addition, prognosing the severity of COVID-19 also allows to determine whether the patient will need intensive medical care (severe form of COVID-19) or not (moderate form of COVID-19). Especially, prognosing the severity of COVID-19 also allows to determine whether the patient will need intensive medical care in a hospital (severe form of COVID-19) but not intensive medical care (moderate form of COVID-19). Usually, a patient suffering from a moderate form of COVID-19 has to be hospitalized, while a patient suffering from a severe form of COVID-19 has to be treated in an intensive care unit (ICU).
  • ICU intensive care unit
  • the level of the at least one elF is compared to a reference level of said at least one elF
  • the level of the at least one eEF is compared to a reference level of said at least one eEF
  • the level of MRRF is compared to a reference level of said MRRF
  • the level of ABCE1 is compared to a reference level of said ABCE1.
  • the method of prognosing the severity of Coronavirus disease 2019 (COVID-19) in a patient comprises the steps of:
  • elF eukaryotic Initiation Factor
  • eEF eukaryotic Elongation Factor
  • MRRF Mitochondrial Ribosome Recycling Factor
  • ABCE1 ATP -binding cassette sub-family E member 1
  • the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2
  • the level of at least one elF is compared to a reference level of said at least one elF and/or the level of at least one eEF is compared to a reference level of said at least one eEF.
  • the method of prognosing the severity of Coronavirus disease 2019 (COVID-19) in a patient comprises the steps of:
  • the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF
  • the reference level represents a level that allows to predict whether the patient suffering from COVID-19 will (likely) develop a moderate or severe form of COVID-19.
  • the severe form of COVID-19 can be life-threatening.
  • the reference level is the level determined by measuring one or more, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,
  • reference biological sample per subject for analysis. If additional reference biological samples are required, e.g. to determine the reference level in different reference biological samples, the same subject may be (re)tested.
  • Said reference level may be an average reference level. It may be determined by measuring reference levels and calculating the “average” value (e.g. mean, median or modal value) thereof.
  • the reference level is the level determined by measuring one or more reference biological samples from one or more subjects having a mild form of COVID-19 and wherein
  • the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2 below the reference level indicates that the patient will (likely) develop a moderate or severe form of COVID-19.
  • the reference level is the level determined by measuring one or more reference biological samples from one or more subjects having a moderate form of COVID-19 and wherein
  • the level of the at least one elF selected from the group consisting of elFl AY and eIF3C above the reference level indicates that the patient will (likely) develop a severe form of COVID-19,
  • the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 below the reference level indicates that the patient will (likely) develop a severe form of COVID-19,
  • the level of the at least one elF and/or the level of the at least one eEF is at least 0.6-fold or 0.7-fold, more preferably at least 0.8-fold or 0.9-fold, even more preferably at least 1.2-fold or 1.5-fold, and most preferably at least 2.0-fold or 3.0-fold below/above the reference level.
  • the level of the at least one elF and/or the level of the at least one eEF is at least 0.6-fold, at least 0.7-fold, at least 0.8-fold, at least 0.9-fold, at least 1.0-fold, at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.6- fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, at least 2.1-fold, at least 2.2-fold, at least 2.3-fold, at least 2.4-fold, at least 2.5-fold, at least 2.6-fold, at least 2.7- fold, at least 2.8-fold, at least 2.9-fold, or at least 3.0-fold below/above the reference level.
  • the reference level may also be the level determined by measuring one or more reference biological samples from one or more subjects being COVID-19 negative.
  • the reference level determined by measuring one or more reference biological samples from one or more subjects being COVID-19 negative is used for comparative purposes.
  • the patient tested with the method of the second aspect may be a patient which will receive, receives, has received, or had received a treatment of COVID-19.
  • the patient may (timely) receive a therapeutic treatment for this disease state.
  • the therapeutic treatment may be in the form of the administration of a drug and/or in the form of a therapeutic treatment different from the administration of a drug, e.g. ventilation.
  • the therapeutic treatment may be changed, e.g. the dose of the drug may be increased or another drug may be administered and/or a therapeutic treatment different from the administration of a drug may be applied/administered, e.g. ventilation.
  • the present invention relates to a method of determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19 comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF), the level of at least one eukaryotic Elongation Factor (eEF), the level of Mitochondrial Ribosome Recycling Factor (MRRF), and/or the level of ATP -binding cassette sub-family E member 1 (ABCE1) in a biological sample from a patient suffering from COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF
  • the present invention relates to a method of determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19 comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF) and/or the level of at least one eukaryotic Elongation Factor (eEF) in a biological sample from a patient suffering from COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, e
  • the elF is selected from the group consisting of elFlAX, elFl, eIF5, eIF5B, and eIF2B5. More particularly, the elF is elFlAX. Combinations of the preferred elFs, namely elFlAX, elFl, eIF5, eIF5B, and eIF2B5, can be taken from Figure 1.
  • the level of at least one of elFlAX, elFl, eIF2A, eIF2B4, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, eIF5B, eEFlAl, eEFIG, and eEFlB2 is determined.
  • the level of at least one elF selected from the group consisting of elFlAX, elFl, eIF2A, eIF2B4, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B is determined and/or the level of at least one eEF selected from the group consisting of eEFlAl, eEFIG, and/or eEFlB2 is determined.
  • the above method allows to evaluate whether a therapeutic approach is effective in a patient or not.
  • the patient is a patient to whom at least once (1, 2, or 3 times) a drug to be used in said therapeutic treatment is administered, has been administered, or had been administered, and/or another form of therapeutic treatment (than the administration of a drug) is administered, has been administered, or had been administered.
  • the way of administration may be oral, nasal, rectal, parenteral, vaginal, or topical.
  • Parental administration includes subcutaneous, intracutaneous, intramuscular, intravenous or intraperitoneal administration.
  • the biological sample is isolated from the patient after at least the first (e.g. first, second, or third) administration of said drug and/or administration of another form of therapeutic treatment (than the administration of a drug).
  • the biological sample is isolated from the patient in a time period of between 2 weeks and 1 day after at least the first (e.g. first, second, or third) administration of said drug and/or administration of another form of therapeutic treatment (than the administration of a drug).
  • the biological sample is isolated from the patient in a time period of between 1 weeks and 1 day after at least the first (e.g. first, second, or third) administration of said drug and/or administration of another form of therapeutic treatment (than the administration of a drug).
  • the biological sample is isolated from the patient 1, 2, 3, 4, 5, 6, day(s), 1, 2, 3 week(s) after at least the first (e.g. first, second, or third) administration of said drug and/or administration of another form of therapeutic treatment (than the administration of a drug).
  • the level of at least one elF is compared to a reference level of said at least one elF
  • the level of at least one eEF is compared to a reference level of said at least one eEF
  • the level of MRRF is compared to a reference level of said MRRF
  • the level of ABCE1 is compared to a reference level of said ABCE1.
  • the reference level is the level determined in a reference biological sample from the (same) patient prior to the administration of said drug, and/or administration of another form of therapeutic treatment.
  • the level of the at least one elF selected from the group consisting of elFlAX, elFl, eIF2A, eIF2B4, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, and eIF5B above the reference level indicates that the patient responds to said treatment of COVID-19,
  • the level of the at least one elF selected from the group consisting of elFl AY and eIF3C below the reference level indicates that the patient responds to said treatment of COVID- 19, and/or
  • the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 above the reference level indicates that the patient responds to said treatment of COVID-19.
  • the patient itself is the reference and provides the reference level.
  • the reference level is the level determined by measuring one or more, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,
  • reference biological sample per subject for analysis. If additional reference biological samples are required, e.g. to determine the reference level in different reference biological samples, the same subject may be (re)tested.
  • Said reference level may be an average reference level. It may be determined by measuring reference levels and calculating the “average” value (e.g. mean, median or modal value) thereof.
  • the reference level is the level determined by measuring one or more reference biological samples from one or more subjects having a mild form of COVID-19 and wherein
  • the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2 above the reference level indicates that the patient responds to said treatment of COVID-19.
  • the reference level is the level determined by measuring one or more reference biological samples from one or more subjects having a moderate form of COVID-19 and wherein
  • the level of the at least one elF selected from the group consisting of elFlAX, elFl, eIF2A, eIF2B4, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B above the reference level indicates that the patient responds to said treatment of COVID-19,
  • the level of the at least one elF selected from the group consisting of eIF3C, eIF4E, and eIF2S2 below the reference level indicates that the patient responds to said treatment of COVID-19, and/or
  • the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 above the reference level indicates that the patient responds to said treatment of COVID-19.
  • the reference level is the level determined by measuring one or more reference biological samples from one or more subjects having a severe form of COVID-19 and wherein
  • the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 above the reference level indicates that the patient responds to said treatment of COVID-19,
  • the level of MRRF above the reference level indicates that the patient responds to said treatment of COVID-19, and/or
  • control subjects are the reference and provide the reference level.
  • the reference level may also be the level determined by measuring one or more reference biological samples from one or more subjects having a moderate/severe form of COVID-19 and wherein
  • the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2 above the reference level indicates that the patient responds to said treatment of COVID-19.
  • the reference level may be an average level of a moderate and severe form of COVID-19.
  • the level of the at least one elF and/or the level of the at least one eEF is preferably at least 0.6-fold or 0.7-fold, more preferably at least 0.8-fold or 0.9-fold, even more preferably at least 1.2-fold or 1.5-fold, and most preferably at least 2.0-fold or 3.0-fold below/above the reference level.
  • the level of the at least one elF and/or the level of the at least one eEF is at least 0.6-fold, at least 0.7-fold, at least 0.8-fold, at least 0.9-fold, at least 1.0-fold, at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5- fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, at least 2.1-fold, at least 2.2-fold, at least 2.3-fold, at least 2.4-fold, at least 2.5-fold, at least 2.6- fold, at least 2.7-fold, at least 2.8-fold, at least 2.9-fold, or at least 3.0-fold below/above the reference level.
  • a drug to be used in said therapeutic treatment is administered, has been administered, or had been administered and/or another form of therapeutic treatment (different from the administration of a drug) is administered, has been administered, or had been administered.
  • the drug is preferably selected from the group consisting of an antiviral drug, an antibacterial drug, an anti-inflammatory drug, an antifungal drug, and an antipyretic agent.
  • the antiviral drug is more preferably selected from the group consisting of chloroquine, remdesivir, darunavir, favipiravir, lopinavir, and ritonavir. Combinations of these drugs are also encompassed.
  • the antiviral drug is even more preferably selected from the group consisting of remdesivir, darunavir, or a combination of lopinavir and ritonavir.
  • the antibacterial drug is more preferably selected from the group consisting of ceftriaxone, amoxicillin/clavulanic acid, piperacillin/tazobactam, and azithromycin. Combinations of these drugs are also encompassed.
  • the anti-inflammatory drug is more preferably selected from the group consisting of ibuprofen and metamizole. Combinations of these drugs are also encompassed.
  • the antifungal drug is more preferably selected from the group consisting of voriconazole and isavuconazole. Combinations of these drugs are also encompassed.
  • the antipyretic agent is more preferably paracetamol.
  • the other form of therapeutic treatment is ventilation.
  • the ventilation is selected from the group consisting of non-invasive ventilation and invasive ventilation.
  • the non-invasive ventilation is carried out through a face mask, nasal mask, or a helmet, or the invasive ventilation is a mechanic ventilation carried out through a positive pressure ventilator or negative pressure ventilator.
  • the drug administration may be continued, the dose of the drug may be reduced, or the drug administration may be stopped. If the treatment encompasses the administration of a drug and the patient does not respond to said treatment, the dose of the drug may be increased, the drug may be changed, or the therapy mode may be changed.
  • Coronavirus disease 2019 (COVID-19), referred to in the first to third aspect of the present invention, is associated with an acute infectious lung disease/acute respiratory syndrome. It is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • the patient is preferably a mammal, more preferably a human.
  • the biological sample is preferably selected from the group consisting of a body fluid sample, a body tissue sample, and a body gas sample. More preferably,
  • the body fluid sample is selected from the group consisting of blood, cerebrospinal fluid (CSF), urine, sputum, breast milk, cerumen (earwax), endolymph fluid, perilymph fluid, pleural fluid, peritoneal fluid, gastric juice, mucus, saliva, semen, sweat, cheek swab, tears, and liquid biopsy,
  • CSF cerebrospinal fluid
  • urine urine
  • sputum breast milk
  • cerumen earwax
  • endolymph fluid perilymph fluid
  • pleural fluid peritoneal fluid
  • gastric juice mucus
  • saliva semen
  • sweat cheek swab
  • tears tears
  • the body tissue sample is selected from the group consisting of skin flake, skin biopsy, hair follicle, biopsy tissue, tissue explant, and tissue section, or
  • the body gas sample is selected from the group consisting of exhaled condensate and exhaled gas.
  • the blood sample is whole blood or a blood fraction.
  • the blood fraction may be a blood cell fraction, blood serum, or blood plasma.
  • the level of the at least one elF and/or eEF is determined by measuring mRNA and/or protein levels.
  • the level of the at least one elF and/or eEF can be determined either by measuring the mRNA molecule encoding said elF and/or eEF or by measuring said elF and/or eEF as such in form of a protein.
  • Methods to determine mRNA levels and protein levels in a biological sample are well known.
  • mRNA expression levels are usually measured by polymerase chain reaction (PCR), in particular by reverse transcription quantitative polymerase chain reaction (RT-PCR and qPCR) or real-time PCR. RT-PCR is used to create a cDNA from the mRNA.
  • the cDNA may be used in a qPCR assay to produce fluorescence as the DNA amplification process progresses. This fluorescence is proportional to the original mRNA amount in the samples.
  • Other methods to be used include Northern blots, Fluorescence in situ hybridization (FISH), microarrays, and RT-PCR combined with capillary electrophoresis.
  • FISH Fluorescence in situ hybridization
  • microarrays microarrays
  • RT-PCR combined with capillary electrophoresis.
  • protein levels of elFs and/or eEFs are determined using immunoassays. Such methods are based on the binding of an antibody, a derivative or a fragment thereof to its corresponding target (i.e. elF or eEF).
  • Polyclonal and monoclonal antibodies can be used in such methods.
  • Derivatives or fragments of antibodies include Fab fragments, F(ab') 2 fragments, Fv fragments, single chain antibodies and single domain antibodies.
  • Preferred immunoassays include Western blot, Immunohistochemistry, ELISA (enzyme-linked immunosorbent assay), radioimmunoassays, fluorescence resonance energy transfer (FRET) or time resolved-FRET (TR-FRET). It is particularly preferred to use antibodies and derivatives or fragments of antibodies which have been obtained from a non human source. These antigen binding molecules can be of porcine, rabbit, murine, camel or rat origin. Of course, it is also possible to use antibodies and derivatives or fragments thereof which are recombinantly produced in plants or cell cultures, in particular microbial cell cultures (e.g. bacteria, yeast).
  • microbial cell cultures e.g. bacteria, yeast
  • the level of the at least one elF and/or at least one eEF is determined by sequencing, polymerase chain reaction (PCR), spectrometry, chromatography, an enzymatic method, an immunochemical method, a gravimetric method, a chemosensoric method, or a combination thereof.
  • the method according to the first to third aspect of the present invention is preferably carried out in vitro.
  • the present invention relates to the ⁇ in vitro ) use of at least one eukaryotic Initiation Factor (elF), at least one eukaryotic Elongation Factor (eEF), Mitochondrial Ribosome Recycling Factor (MRRF), and/or ATP -binding cassette sub-family E member 1 (ABCE1) for monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19, for prognosing the severity of Coronavirus disease 2019 (COVID-19), or for determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, e
  • the present invention relates to the ⁇ in vitro ) use of at least one eukaryotic Initiation Factor (elF) and/or at least one eukaryotic Elongation Factor (eEF) for monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19, for prognosing the severity of Coronavirus disease 2019 (COVID-19), or for determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF
  • the use is preferably an in vitro use.
  • the patient is preferably a mammal, more preferably a human.
  • the level of the at least one elF and/or eEF is determined in a biological sample from a patient to be tested.
  • the biological sample is preferably selected from the group consisting of a body fluid sample, a body tissue sample, and a body gas sample. More preferably,
  • the body fluid sample is selected from the group consisting of blood, cerebrospinal fluid (CSF), urine, sputum, breast milk, cerumen (earwax), endolymph fluid, perilymph fluid, pleural fluid, peritoneal fluid, gastric juice, mucus, saliva, semen, sweat, cheek swab, tears, and liquid biopsy,
  • CSF cerebrospinal fluid
  • urine urine
  • sputum breast milk
  • cerumen earwax
  • endolymph fluid perilymph fluid
  • pleural fluid peritoneal fluid
  • gastric juice mucus
  • saliva semen
  • sweat cheek swab
  • tears tears
  • the body tissue sample is selected from the group consisting of skin flake, skin biopsy, hair follicle, biopsy tissue, tissue explant, and tissue section, or
  • the body gas sample is selected from the group consisting of exhaled condensate and exhaled gas.
  • the blood sample is whole blood or a blood fraction.
  • the blood fraction may be a blood cell fraction, blood serum, or blood plasma.
  • the present invention relates to (the ⁇ in vitro ) use of) a kit for monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19, for prognosing the severity of Coronavirus disease 2019 (COVID-19), or for determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19, wherein the kit comprises means for determining the level of at least one eukaryotic Initiation Factor (elF), the level of at least one eukaryotic Elongation Factor (eEF), the level of Mitochondrial Ribosome Recycling Factor (MRRF), and/or the level of ATP -binding cassette sub-family E member 1 (ABCE1) in a biological sample from an individual, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B
  • the present invention relates to (the ⁇ in vitro ) use of) a kit for monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19, for prognosing the severity of Coronavirus disease 2019 (COVID-19), or for determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19
  • the kit comprises means for determining the level of at least one eukaryotic Initiation Factor (elF) and/or the level of at least one eukaryotic Elongation Factor (eEF) in a biological sample from an individual, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, e
  • the kit is used in vitro.
  • the patient is a mammal, more preferably a human.
  • the biological sample is selected from the group consisting of a body fluid sample, a body tissue sample, and a body gas sample. More preferably,
  • the body fluid sample is selected from the group consisting of blood, cerebrospinal fluid (CSF), urine, sputum, breast milk, cerumen (earwax), endolymph fluid, perilymph fluid, pleural fluid, peritoneal fluid, gastric juice, mucus, saliva, semen, sweat, cheek swab, tears, and liquid biopsy
  • the body tissue sample is selected from the group consisting of skin flake, skin biopsy, hair follicle, biopsy tissue, tissue explant, and tissue section, or
  • the body gas sample is selected from the group consisting of exhaled condensate and exhaled gas.
  • the blood sample is whole blood or a blood fraction.
  • the blood fraction may be a blood cell fraction, blood serum, or blood plasma.
  • Said means may be primers or primer pairs allowing the detecting of the at least one elF and/or the at least one eEF on the RNA transcript, e.g. mRNA, level and/or antibodies, antibody derivatives or fragments of antibodies allowing the detection of the at least one elF and/or the at least one eEF on the protein level.
  • said means encompass dip strips or dipsticks, e.g. urine or blood dipstrips or dipsticks.
  • Said means are tools used to determine changes in patient’s urine or blood.
  • a dip strip or dipstick comprises different chemical pads or reagents which react (e.g. change color, in particular by applying an immune assay) when immersed in (e.g. blood or urine), and then removed from the biological sample (e.g. urine or blood sample). The result can be read after a few minutes, preferably after a few seconds.
  • the kit may further comprise
  • Said data carrier may be a non-el ectronical data carrier, e.g. a graphical data carrier such as an information leaflet, an information sheet, a bar code or an access code, or an electronical data carrier such as a floppy disk, a compact disk (CD), a digital versatile disk (DVD), a microchip or another semiconductor-based electronical data carrier.
  • the access code may allow the access to a database, e.g. an internet database, a centralized, or a decentralized database.
  • the access code may also allow access to an application software that causes a computer to perform tasks for computer users or a mobile app which is a software designed to run on smartphones and other mobile devices.
  • Said data carrier may further comprise a reference level of the at least one elF and/or at least one eEF referred to herein.
  • the data carrier comprises an access code which allows the access to a database
  • said reference level is deposited in this database.
  • the data carrier may comprise information or instructions on how to carry out the methods of the first to third aspect of the present invention.
  • Said kit may also comprise materials desirable from a commercial and user standpoint including a buffer(s), a reagent(s) and/or a diluent(s) for determining the level mentioned above.
  • the kit is useful for conducting the methods of the first to third aspect of the present invention.
  • Figure 1 Shows preferred elFs and elF combinations.
  • Figure 2 Shows the arithmetic mean raw count for healthy and each COVID-19 severity from mild, moderate to severe for the eukaryotic initiation factors (elFs) and eukaryotic elongation factors (eEFs) EIF4B, EIF4H, EIF1AX, EIF2B4, EIF3B, EIF3L, EEF1A1, EEF1G, EIF1AY, EIF1, EIF5, EIF5B, EIF2A, EIF2S3, EIF2B5, EIF3A, EIF3C, EIF3D, EIF3H, EIF3I, EIF3M, EIF4G1, EIF5A, EEF2, EEF1D and EEF1B2.
  • eEFs eukaryotic initiation factors
  • eEFs eukaryotic elongation factors
  • Figure 3 Shows the arithmetic mean raw count for each COVID-19 severity from mild, moderate to severe for the eukaryotic initiation factors (elFs), eukaryotic elongation factors (eEFs), EEF1A1, EEF1B2, EEF1G, EIF2A, EIF2B2, EIF2B3, EIF2S1, EIF2S2, EIF2S3, EIF3H, EIF3J, EIF3L, EIF4B, EIF4E, Mitochondrial Ribosome Recycling Factor (MRRF), and ATP -binding cassette sub-family E member 1 (ABCEl).
  • elFs eukaryotic initiation factors
  • eEFs eukaryotic elongation factors
  • Figure 4 Shows the p-values of ElFs deregulated between a MILD and a SEVERE form of COVID-19.
  • both p-values are ⁇ 0.05.
  • Figure 5 Shows the p-values of EIFs, EEFs, MRRF, and ABCE1 deregulated between a MODERATE and a SEVERE form of COVID-19. The p-values of all markers are ⁇ 0.05.
  • the raw data is based on a study from Ischgl with the primary goal to detect how many infected and non-infected inhabitants have developed antibodies.
  • the main groups Seronegative, Seropositive, Negative, not exposed as controls were classified and each eukaryotic initiation and elongation factor was compared between the groups using the R function wilcox.test, called from a C# script via RDotNet.
  • the Wilcoxon test is a non-parametric, robust test not depending on normal distributions. Each translation factor with a p-value below 0.05 was considered significant.
  • the sequencing data combined with clinical data contains the following groups:
  • the distribution of the raw counts of each group was compared against the distribution of the raw counts of each other group (healthy, mild, moderate, severe) to find significantly differently expressed translation factors between each paired group using Wilcox. test.
  • the Ischgl cohort dataset was combined with the GEO dataset GSE152418 containing samples from 34 patients/individuals, available under https://www.ncbi.nlm.nih. 52418 (Arunachalam PS,
  • the GSE152418 dataset contains the following groups:
  • eukaryotic initiation factors were identified as being (significantly) deregulated between the different forms of COVID-19 (mild, moderate, and/or severe) and also between healthy and the different forms of COVID-19 (mild, moderate, and severe): elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, and eIF2B5.
  • eEFs eukaryotic elongation factors
  • Table 1 elFs and eEFs identified as being deregulated between the different forms of COVID- 19 (mild, moderate, and/or severe) and also between healthy and the different forms of COVID- 19 (mild, moderate, and/or severe).
  • elFs as well as eEFs were identified as allowing to distinguish between a mild and a moderate or severe form of COVID-19: elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B5, eIF3C, eEFlAl, eEFIG, eEF2, eEFID, and eEF!B2 (see also Figure 2).
  • elFs were identified as allowing to distinguish between a moderate and a severe form of COVID-19: e!FlAX, e!Fl, eIF5, eIF5B, and eIF3C (see also Figure 2).
  • Table 3 elFs and eEFs which were significantly deregulated between a mild and severe form of COVID-19
  • the elFs EIFl AX, EIF1 AY, and EIF5B were also significantly deregulated between a moderate and severe form of COVID-19.
  • EIF3L, EIF4B, and EEF1A1 are significantly deregulated between healthy and a severe or moderate form of COVID-19
  • EIF4H is significantly deregulated between healthy and a moderate form of COVID-19
  • EIF2B4 and EIF3B are significantly deregulated between healthy and a mild form of COVID-19.
  • Table 4 elFs and eEFs which were significantly deregulated between healthy and a mild, moderate or severe form of COVID-19.
  • elFs and eEFs are, thus, biomarkers allowing to prognose the severity of Coronavirus disease 2019 (COVID-19) in a patient. They also allow to monitor the course of Coronavirus disease 2019 (COVID-19) in a patient. The determination of the treatment response is also possible with these markers.
  • the data is based on the published GEO dataset GSE190680 with additional, not published clinical information from the principal investigator regarding the Coronavirus disease 2019 (COVID-19) disease course.
  • the dataset GSE190680 containing mRNA expression values was used. Groups were built based on additional clinicopathological information regarding the course severity. The expressions of the categories 'mild', 'moderate' and 'critically severe' were compared with each other using Wilcox.test for significant distribution differences p-values below 0.05 were considered as significant.
  • the bars show the expression values per gene depending on the severity course.
  • the biomarkers shown in Table 5 and Figure 4 were significantly deregulated between a MILD and SEVERE form of COVID-19. These markers allow to prognose whether the patient will (likely) develop a MODERATE/SEVERE Coronavirus disease 2019 (COVID-19). They also allow to monitor the course of Coronavirus disease 2019 (COVID-19) in a patient. The determination of the treatment response is also possible with these biomarkers.
  • Table 5 elFs which were significantly deregulated between a MILD and SEVERE form of COVID-19.
  • the biomarkers shown in Table 6 and in Figure 5 were significantly deregulated between a MODERATE and SEVERE form of COVID-19. These markers allow to prognose whether the patient will (likely) develop a SEVERE Coronavirus disease 2019 (COVID-19). They also allow to monitor the course of Coronavirus disease 2019 (COVID-19) in a patient. The determination of the treatment response is also possible with these biomarkers.
  • biomarkers are best suited for the monitoring of Coronavirus disease 2019 (COVID-19) in a patient.

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Abstract

The present invention relates to a method of monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19. Further, the present invention relates to a method of prognosing the severity of Coronavirus disease 2019 (COVID-19) in a patient. Furthermore, the present invention relates to a method of determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19. In addition, the present invention relates to a kit useful for conducting these methods.The biomarkers for these purposes are a eukaryotic Initiation Factor (elF), a eukaryotic Elongation Factor (eEF), Mitochondrial Ribosome Recycling Factor (MRRF) and ATP-binding cassette sub-family E member 1 (ABCE1).

Description

BIOMARKER FOR MONITORING CORONAVIRUS DISEASE 2019
The present invention relates to a method of monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19. Further, the present invention relates to a method of prognosing the severity of Coronavirus disease 2019 (COVID-19) in a patient. Furthermore, the present invention relates to a method of determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19. In addition, the present invention relates to a kit useful for conducting these methods.
BACKGROUND OF THE INVENTION
Coronavirus disease (COVID-19) is an infectious disease caused by a novel virus. In particular, it is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Starting in Wuhan, China, in December 2019, SARS-CoV-2 spread to other countries and continents. The World Health Organization (WHO) declared the outbreak to be a Public Health Emergency of International Concern on 30 January 2020 and recognized it as a pandemic on 11 March 2020.
In early March 2020 an outbreak of SARS-CoV-2 emerged from a bar in a ski resort in Ischgl and departing tourists from the cluster infected others in Europe. Inhabitations were isolated from villages nearby and a lockdown of the communities in the state of Tyrol was decreed. 42.4% of the inhabitants of Ischgl showed antibodies against SARS-CoV-2.
By 20 May 2021, more than 164 million people worldwide had already been infected, with more than 3.4 million deaths related to the virus.
Coronaviruses belong to the order of Nidovirales and infect mammals and birds. The RNA-positive single-strand SARS-CoV-2 is related to MERS-CoV and SARS-CoV and causes acute and severe respiratory syndromes compared to other widely distributed coronaviruses from the genus Alphacoronavirus, infecting respiratory and gastrointestinal tracts in humans. Interpersonal variation and 6 different mutations in the spike glycoprotein and 2 single nucleotide variations leading to the same missense mutation has been observed with the capability to substantially change its pathogenity. SARS-CoV-2 enters the cell using the ACE2 receptor on the cell surface with replication and packaging in the cytoplasm and the assembly in the Endoplasmatic reticulum and Golgi followed by the budding in the Endoplasmatic reticulum-Golgi intermediate compartment.
The COVID-19 leads to a respiratory disease (similar to influenza) with symptoms such as cough and fever. Less common symptoms include fatigue, respiratory sputum production (phlegm), loss of the sense of smell, shortness of breath, muscle and joint pain, sore throat, headache, chills, vomiting, hemoptysis, diarrhea, or cyanosis. In severe COVID-19 cases, infected individuals may develop bilateral pneumonia, may suffer from acute respiratory failure, and may also die. Pathological processes of the liver, central nervous system, kidneys, blood vessels, and heart have also been observed. Thus, the severe form of COVID-19 can be life-threatening with lung failure, septic shock, or multiple organ failure. Breathing difficulties may occur. The breathing difficulties may require intensive medical care including artificial ventilation.
The COVID-19 is mainly transmitted by infected persons when they cough or sneeze. Protection is possible by washing hands frequently and avoiding touching the face. Also keeping a distance from people who feel unwell helps. Someone can also get infected by touching surfaces or things where the virus is present and then touching eyes, nose or mouth.
It has turned out that COVID-19 can deteriorate dramatically in a short period of time. It is, therefore, important to monitor the patients continuously. Accordingly, there is a need for a method allowing the determination of the course of COVID-19 in a patient suffering from COVID-19 in a fast and reliable way.
Symptoms of COVID-19 can be relatively non-specific and infected people may be asymptomatic over a period of time before the disease outbreaks. It is, therefore, also important to predict the severity of the disease in order to make effective therapy decisions at an early stage. Accordingly, there is a need for a method allowing the prognosis of patients suffering from COVID-19 in a fast and reliable way.
Only a few drugs are known to treat COVID-19. There is a large number of drugs under discussion whose efficacy has yet to be tested in patients. It would, therefore, be desirable to provide a procedure to determine whether a patient is responding to therapy or not. This allows fast treatment decisions and the adaptation of the treatment strategy. Accordingly, there is a need for a method allowing treatment response monitoring in an effective and a reliable way.
To limit the economic loss and the medical harm of SARS-CoV-2, the present inventors found evidence that eukaryotic Initiation Factors (elFs) and eukaryotic Elongation Factors (eEFs) are regulated differently in SARS-CoV-2 and, thus, can function as biomarkers. The translation of mRNAs into proteins is one level of the regulations of gene expressions and is important for homeostasis and fast responses. Eukaryotic Initiation Factors (elFs) are proteins that bind to the small subunit of the ribosome during the initiation of translation, a part of protein biosynthesis. The main task of elongation translation factors (eEFs) is the elongation by ribosomes. The present inventors identified eukaryotic Initiation Factors (elFs) as well as eukaryotic Elongation Factors (eEFs) that allow to monitor COVID-19 in a patient, that allow to prognose the severity of COVID-19 in a patient, and that allow to determine the treatment response of a patient to specific therapies of COVID-19.
SUMMARY OF THE INVENTION
In a first aspect, the present invention relates to a method of monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19 comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF), the level of at least one eukaryotic Elongation Factor (eEF), the level of Mitochondrial Ribosome Recycling Factor (MRRF), and/or the level of ATP -binding cassette sub-family E member 1 (ABCE1) in a biological sample from a patient suffering from COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2.
Preferably, the present invention relates to a method of monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19 comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF) and/or the level of at least one eukaryotic Elongation Factor (eEF) in a biological sample from a patient suffering from COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEFID, and eEFlB2.
In a second aspect, the present invention relates to a method of prognosing the severity of Coronavirus disease 2019 (COVID-19) in a patient comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF), the level of at least one eukaryotic Elongation Factor (eEF), the level of Mitochondrial Ribosome Recycling Factor (MRRF), and/or the level of ATP -binding cassette sub-family E member 1 (ABCE1) in a biological sample from a patient, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEFID, and eEFlB2.
Preferably, the present invention relates to a method of prognosing the severity of Coronavirus disease 2019 (COVID-19) in a patient comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF) and/or the level of at least one eukaryotic Elongation Factor (eEF) in a biological sample from a patient, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEFID, and eEFlB2.
In a third aspect, the present invention relates to a method of determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19 comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF), the level of at least one eukaryotic Elongation Factor (eEF), the level of Mitochondrial Ribosome Recycling Factor (MRRF), and/or the level of ATP -binding cassette sub-family E member 1 (ABCEl) in a biological sample from a patient suffering from COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEFID, and eEFlB2.
Preferably, the present invention relates to a method of determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19 comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF) and/or the level of at least one eukaryotic Elongation Factor (eEF) in a biological sample from a patient suffering from COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEFID, and eEFlB2.
In a fourth aspect, the present invention relates to the use of at least one eukaryotic Initiation Factor (elF), at least one eukaryotic Elongation Factor (eEF), Mitochondrial Ribosome Recycling Factor (MRRF), and/or ATP -binding cassette sub-family E member 1 (ABCEl) for monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19, for prognosing the severity of Coronavirus disease 2019 (COVID- 19), or for determining whether a patient suffering from Coronavirus disease 2019 (COVID- 19) responds to a therapeutic treatment of COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEFID, and eEFlB2.
Preferably, the present invention relates to the use of at least one eukaryotic Initiation Factor (elF) and/or at least one eukaryotic Elongation Factor (eEF) for monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19, for prognosing the severity of Coronavirus disease 2019 (COVID-19), or for determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEFID, and eEFlB2.
In a fifth aspect, the present invention relates to a kit for monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19, for prognosing the severity of Coronavirus disease 2019 (COVID-19), or for determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19, wherein the kit comprises means for determining the level of at least one eukaryotic Initiation Factor (elF), the level of at least one eukaryotic Elongation Factor (eEF), the level of Mitochondrial Ribosome Recycling Factor (MRRF), and/or the level of ATP -binding cassette sub-family E member 1 (ABCEl) in a biological sample from an individual, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEFID, and eEFlB2.
Preferably, the present invention relates to a kit for monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19, for prognosing the severity of Coronavirus disease 2019 (COVID-19), or for determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19, wherein the kit comprises means for determining the level of at least one eukaryotic Initiation Factor (elF) and/or the level of at least one eukaryotic Elongation Factor (eEF) in a biological sample from an individual, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEFID, and eEFlB2.
This kit is suitable for conducting the methods according to the first to third aspect of the present invention.
This summary of the invention does not necessarily describe all features of the present invention. Other embodiments will become apparent from a review of the ensuing detailed description.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
Before the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.
Preferably, the terms used herein are defined as described in “A multilingual glossary of biotechnological terms: (IUPAC Recommendations)”, Leuenberger, H.G.W, Nagel, B. and Kolbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).
Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, GenBank Accession Number sequence submissions etc.), whether supra or infra, is hereby incorporated by reference in its entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. In the event of a conflict between the definitions or teachings of such incorporated references and definitions or teachings recited in the present specification, the text of the present specification takes precedence.
The term “comprise” or variations such as “comprises” or “comprising” according to the present invention means the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. The term “consisting essentially of’ according to the present invention means the inclusion of a stated integer or group of integers, while excluding modifications or other integers which would materially affect or alter the stated integer. The term “consisting of’ or variations such as “consists of’ according to the present invention means the inclusion of a stated integer or group of integers and the exclusion of any other integer or group of integers.
The terms “a” and “an” and “the” and similar reference used in the context of describing the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
The term “Coronavirus disease (COVID-19)”, as used herein, refers to an infectious disease caused by a novel virus. In particular, it is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease leads to a respiratory disease (similar to influenza) with symptoms such as cough and fever. Less common symptoms include fatigue, respiratory sputum production (phlegm), loss of the sense of smell, shortness of breath, muscle and joint pain, sore throat, headache, chills, vomiting, hemoptysis, diarrhea, or cyanosis. In severe COVID-19 cases, infected individuals may develop bilateral pneumonia, may suffer from acute respiratory failure, and may also die. Pathological processes of the liver, central nervous system, kidneys, blood vessels, and heart have also been observed. Thus, the severe form of COVID- 19 can be life-threatening with lung failure, septic shock, or multiple organ failure. Breathing difficulties may occur. The breathing difficulties may require intensive medical care including artificial ventilation. COVID-19 is mainly transmitted by infected persons when they cough or sneeze. Protection is possible by washing hands frequently and avoiding touching the face. Also keeping a distance from people who feel unwell helps. Someone can also get infected by touching surfaces or things where the virus is present and then touching eyes, nose or mouth. COVID-19 can occur in a mild form, a moderate form, or a severe form. About 80% of the COVID-19 diseases are mild to moderate. 20% of the COVID-19 diseases are severe forms of COVID-19. The severe form of COVID-19 can be life-threatening (with lung failure, septic shock, or multiple organ failure).
The term “mild form of COVID-19”, as used herein, refers to COVID-19 without signs of pneumonia. The term “moderate form of COVID-19”, as used herein, refers to COVID-19 associated with a mild pneumonia, which is radiologically limited to less than half of the lungs, no respiratory distress and an oxygen saturation in the blood of over 93 %. The term “severe form of COVID-19”, as used herein, refers to COVID-19 associated with shortness of breath, oxygen saturation below 94 %, or lung infiltrates in more than half of the lungs. In severe COVID-19 cases, infected individuals may develop bilateral pneumonia, may suffer from acute respiratory failure, and may also die. Pathological processes of the liver, central nervous system, kidneys, blood vessels, and heart have also been observed. Thus, the severe form of COVID- 19 can be life-threatening. The term “life-threatening form of COVID-19”, as used herein, refers to COVID-19 associated with lung failure, septic shock, and/or multiple organ failure.
The term “determining the course of COVID-19 in a patient”, as used herein, means determining the development of COVID-19 in a patient over time, e.g. whether COVID-19 worsens in the patient, does not worsen/is stable in the patient, or improves in the patient over time.
The term “prognosing the severity of COVID-19 in a patient”, as used herein, means prognosing the development of COVID-19 in a patient. In other words, the term “prognosing the severity of COVID-19 in a patient”, as used herein, means prognosing the seriousness of COVID-19 in a patient.
For example, prognosing the severity of COVID-19 in a patient suffering from a mild form of COVID-19 means determining whether (it is likely that) the patient will develop a moderate form of COVID-19 or a severe form of COVID-19. In addition, prognosing the severity of COVID-19 in a patient suffering from a moderate form of COVID-19 means determining whether (it is likely that) the patient will develop a severe form of COVID-19. The severe form of COVID-19 can be life-threatening.
The term “determining whether a patient suffering from COVID-19 responds to a therapeutic treatment of COVID-19”, as used herein, means evaluating whether a therapeutic approach is effective in a patient or not.
The term “treatment”, in particular “therapeutic treatment”, as used herein, refers to any therapy which improves the health status and/or prolongs (increases) the lifespan of a patient suffering from COVID-19. Said therapy may eliminate COVID-19 in a patient, arrest or slow the development of COVID-19 in a patient, inhibit the development of COVID-19 in a patient, decrease the severity of symptoms in a patient suffering from COVID-19, and/or decrease the recurrence in a patient who currently has or who previously has had COVID-19.
The treatment of COVID-19 described herein includes, but is not limited to, the administration of a drug. The drug is preferably selected from the group consisting of an antiviral drug, an antibacterial drug, an anti-inflammatory drug, an antifungal drug, and an antipyretic agent. The antiviral drug is more preferably selected from the group consisting of chloroquine, remdesivir, darunavir, favipiravir, lopinavir, and ritonavir. Combinations of these drugs are also encompassed. The antiviral drug is even more preferably selected from the group consisting of remdesivir, darunavir, or a combination of lopinavir and ritonavir. The antibacterial drug is more preferably selected from the group consisting of ceftriaxone, amoxicillin/clavulanic acid, piperacillin/tazobactam, and azithromycin. Combinations of these drugs are also encompassed. The anti-inflammatory drug is more preferably selected from the group consisting of ibuprofen and metamizole. Combinations of these drugs are also encompassed. The antifungal drug is more preferably selected from the group consisting of voriconazole and isavuconazole. Combinations of these drugs are also encompassed. The antipyretic agent is more preferably paracetamol. However, also another treatment than the administration of a drug is possible. The other form of therapeutic treatment is preferably ventilation. More preferably, the ventilation is selected from the group consisting of non-invasive ventilation and invasive ventilation. Even more preferably, the non-invasive ventilation is carried out through a face mask, nasal mask, or a helmet, or the invasive ventilation is a mechanic ventilation, e.g. carried out through a positive pressure ventilator or negative pressure ventilator.
The term “eukaryotic Initiation Factors (elFs)”, as used herein, refers to molecules which are involved in the initiation phase of eukaryotic translation. These factors help to stabilize the formation of the functional ribosome around the start codon and also provide regulatory mechanisms in translation initiation. The term “eukaryotic Initiation Factors (elFs)”, as used herein, covers elF RNA transcripts (RNA transcript variants) such as mRNAs including splice variants of these transcripts and elF proteins encoded thereby. Thus, the level of the elFs may be determined by measuring mRNA or protein levels. The term “eukaryotic Initiation Factors (elFs)”, as used herein, also covers elF isoforms. These elF isoforms are members of a set of highly similar molecules, in particular proteins, that perform the same or similar biological role.
The present inventors identified eukaryotic Initiation Factors (elFs) that allow to monitor COVID-19 in a patient, that allow to prognose the severity of COVID-19 in a patient, and that allow to determine the treatment response of a patient to specific therapies of COVID-19. The specific elFs identified by the present inventors are selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5. The elFs are preferably human elFs.
The term “eukaryotic Elongation Factors (elFs)”, as used herein, refers to molecules that function at the ribosome, during protein synthesis, to facilitate translational elongation from the formation of the first to the last peptide bond of a growing polypeptide. Elongation is the most rapid step in translation. In eukaryotes, it proceeds at a rate of two amino acids per second (about 6 nucleotides read per second). Elongation factors play a role in orchestrating the events of this process and in ensuring the high accuracy translation at these speeds. The term “eukaryotic Elongation Factors (eEFs)”, as used herein, covers eEF RNA transcripts (RNA transcript variants) such as mRNAs including splice variants of these transcripts and eEF proteins encoded thereby. Thus, the level of the eEFs may be determined by measuring mRNA or protein levels. The term “eukaryotic Elongation Factors (eEFs)”, as used herein, also covers eEF isoforms. These eEF isoforms are members of a set of highly similar molecules, in particular proteins, that perform the same or similar biological role.
The present inventors identified eukaryotic Elongation Factors (eEFs) that allow to monitor COVID-19 in a patient, that allow to prognose the severity of COVID-19 in a patient, and that allow to determine the treatment response of a patient to specific therapies of COVID-19. The specific eEFs identified by the present inventors are selected from the group consisting of eEFlAl, eEFIG, eEF2, eEFID, and eEFlB2. The eEFs are preferably human eEFs.
The term “Mitochondrial Ribosome Recycling Factor (MRRF)”, as used herein, refers to a molecule which plays essential roles in mitochondrial physiology, including protein synthesis, and it has been implicated in human genetic diseases. The MRRF is among the few protein molecules that carry their N-terminal signal peptide sequence into the mitochondrial matrix that is required for the interaction of MRRF with the mitoribosome.
The term “ATP -binding cassette sub-family E member 1 (ABCE1)”, as used herein, refers to a molecule which is a member of the superfamily of ATP -binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABCl, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the OABP subfamily. Alternatively referred to as the RNase L inhibitor, this protein functions to block the activity of ribonuclease L. Activation of ribonuclease L leads to inhibition of protein synthesis in the 2-5A/RNase L system, the central pathway for viral interferon action.
The term “patient”, as used herein, refers to any subject suffering from COVID-19, i.e. diseased. The patient may be a patient for whom it is desired to know how COVID-19 develops in said patient over time (COVID-19 monitoring). The patient may further be a patient for whom it is desired to know whether the patient will (likely) develop an advanced form of COVID-19, e.g. a moderate or severe form of COVID-19 (prognosis of COVID-19 severity). In other words, the patient may further be prognosed to (likely) develop an advanced form of COVID-19, e.g. a moderate or severe form of COVID-19. The patient may also be a patient for whom it is desired to know whether a therapeutic treatment of COVID-19 is effective or not (COVID-19 treatment monitoring). As mentioned above, the term “patient”, as used herein, refers to a subject which is affected by COVID-19, i.e. diseased. The patient may also be retested for COVID-19 in a monitoring process and may be diagnosed to be still affected by COVID-19, i.e. diseased, or not affected by COVID-19 anymore, i.e. healthy, for example after therapeutic intervention. The term “patient”, as used herein, also covers an individual participating in a mass screening.
It should be noted that a patient that is diagnosed as being healthy, i.e. not suffering from COVID-19, may possibly suffer from another disease not tested/known. The patient may be any mammal, including both a human and another mammal, e.g. an animal such as a monkey. Human patients are particularly preferred.
The term “(control) subject”, as used herein, refers to a subject known to be not affected by/infected with COVID-19 (negative control), i.e. healthy. Specifically, a (control) subject being healthy has no COVID-19 symptoms and no antibodies against COVID-19. The term “(control) subject, as used herein, also refers to a subject known to be affected by/infected with COVID-19 (positive control), i.e. diseased. The term “(control) subject”, as used herein, further refers to a subject known to suffer from a specific form of COVID-19, e.g. a mild, moderate, or severe form of COVID-19. For example, a comparison of patient data with data of (control) subjects allows the prognosis of the severity of COVID-19, e.g. whether the patient will (likely) develop a moderate or severe form of COVID-19 disease. In addition, a comparison of patient data with data of (control) subjects allows to determine how COVID-19 develops in the patient, e.g. whether COVID-19 worsens in the patient or improves in the patient.
It should be noted that a (control) subject which is known to be healthy, i.e. not suffering from COVID-19, may possibly suffer from another disease not tested/known. The (control) subject may be any mammal, including both a human and another mammal, e.g. an animal such as a monkey. Human (control) subjects are particularly preferred.
The term “biological sample”, as used herein, refers to any biological sample from a patient or (control) subject containing the at least one elF and/or the at least one eEF described herein. The biological sample may be a body fluid sample, a body gas sample, a body tissue sample, or a body cell sample. For example, biological samples encompassed by the present invention are tissue (e.g. section or explant) samples, single cell samples, cell colony samples, cell culture samples, blood (e.g. whole blood or blood fraction such as blood cell fraction, serum or plasma) samples, urine samples, or samples from other peripheral sources. Said biological samples may be mixed or pooled, e.g. a sample may be a mixture of a blood sample and a urine sample. Said biological samples may be provided by removing a body fluid, cell(s), cell colonies, an explant, or a section from a patient or (control) subject, but may also be provided by using a previously isolated sample. For example, a tissue sample may be removed from a patient or (control) subject by conventional biopsy techniques or a blood sample may be taken from a patient or (control) subject by conventional blood collection techniques. The biological sample, e.g. urine sample, tissue sample or blood sample, may be obtained from a patient or (control) subject prior to the initiation of a therapeutic treatment, during the therapeutic treatment, and/or after the therapeutic treatment. If the biological sample is obtained from one or more (control) subjects, e.g. from at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 400, 500, 1.000, 2.000, 3.000, 4.000, 5.000, or 10.000 (control) subject(s), it is designated as “reference biological sample”. Preferably, the reference biological sample is from the same source than the biological sample of the patient to be tested, e.g. both are blood samples, cerebrospinal fluid (CSF) samples, or urine samples. It is further preferred that both are from the same species, e.g. from a human. It is also (alternatively or additionally) preferred that the measurements of the reference biological sample and the biological sample of the patient to be tested are identical, e.g. both have an identical volume. It is particularly preferred that the reference biological sample and the biological sample are from patients/(control) subjects of the same sex and age.
The term “body fluid sample”, as used herein, refers to any liquid sample derived from the body of a patient or (control) subject containing the at least one elF and/or the at least one eEF described herein. Said body fluid sample may be a urine sample, blood sample, sputum sample, breast milk sample, cerebrospinal fluid (CSF) sample, cerumen (earwax) sample, gastric juice sample, mucus sample, endolymph fluid sample, perilymph fluid sample, peritoneal fluid sample, pleural fluid sample, saliva sample, sebum (skin oil) sample, semen sample, sweat sample, tears sample, cheek swab, vaginal secretion sample, liquid biopsy, or vomit sample including components or fractions thereof. The term “body fluid sample” also encompasses body fluid fractions”, e.g. blood fractions or sputum fractions. The body fluid samples may be mixed or pooled. Thus, a body fluid sample may be a mixture of a blood and a urine sample or a mixture of a blood and cerebrospinal fluid sample. Said body fluid sample may be provided by removing a body liquid from a patient or (control) subject, but may also be provided by using previously isolated body fluid sample material. The body fluid sample allows for a non-invasive analysis of a patient. It is further preferred that the body fluid sample has a volume of between 0.01 and 20 ml, more preferably of between 0.1 and 10 ml, even more preferably of between 0.5 and 8 ml, and most preferably of between 1 and 5 ml. If the body fluid sample is obtained from one or more control subjects, e.g. from at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 400, 500, 1.000, 2.000, 3.000, 4.000, 5.000, or 10.000 control subject(s), it is designated as “reference body fluid sample”. The term “blood sample”, as used herein, encompasses a whole blood sample or a blood fraction sample such as a blood cell fraction, blood serum, or blood plasma sample. Blood cells, also known as hemopoietic cells, may be used. Said blood cells may be erythrocytes, leukocytes, and/or thrombocytes, e.g. mixtures thereof. Peripheral blood mononuclear cells (PBMCs) such as lymphocytes, monocytes, or macrophages may also be used. It is preferred that the blood serum or plasma sample has a volume of between 0.01 and 20 ml, more preferably of between 0.1 and 10 ml, even more preferably of between 0.5 and 8 ml and most preferably of between 1 and 5 ml.
The term “body gas sample”, as used herein, refers to any gas sample derived from the body of a patient or (control) subject containing the at least one elF and/or the at least one eEF described herein. Said body gas sample encompasses exhaled condensate and exhaled gas. If the body gas sample is obtained from one or more control subjects, e.g. from at least 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 400, 500, 1.000, 2.000, 3.000, 4.000, 5.000, or 10.000 control subject(s), it is designated as “reference body gas sample”.
The term “body tissue sample”, as used herein, refers to any tissue sample derived from the body of a patient or (control) subject containing the at least one elF and/or the at least one eEF described herein. Said body tissue sample encompasses skin flake, skin biopsy, hair follicle, biopsy tissue, tissue explant, and tissue section. Preferably, the tissue sample from a patient or (control) subject has a weight of between 0.1 and 500 mg, more preferably of between 0.5 and 250 mg, and most preferably of between 1 and 50 mg, i.e. 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, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or 500 mg. If the body tissue sample is obtained from one or more control subjects, e.g. from at least
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 400, 500,
1.000, 2.000, 3.000, 4.000, 5.000, or 10.000 control subject(s), it is designated as “reference body tissue sample”.
The term “level”, as used herein, refers to an amount (measured for example in grams, mole, or ion counts) or concentration (e.g. absolute or relative concentration) of the at least one elF and/or the at least one eEF claimed herein.
The term “level”, as used herein, also comprises scaled, normalized, or scaled and normalized amounts or values. The level may also be a cut-off level.
In a preferred embodiment, the level is an expression level. In the context of the present invention, the term “kit of parts (in short: kit)” is understood to be any combination of at least some of the components identified herein, which are combined, coexisting spatially, to a functional unit, and which can contain further components.
The term “point-of-care testing (POCT)”, as used herein, refers to a medical diagnostic testing at or near the point of care that is the time and place of individual care. This contrasts with the historical pattern in which testing was wholly or mostly confined to the medical laboratory, which entailed sending off specimens away from the point of care and then waiting hours or days to learn the results, during which time care must continue without the desired information. Point-of-care tests are simple medical tests that can be performed at the bedside. The driving notion behind POCT is to bring the test conveniently and immediately to the individual to be tested. This increases the likelihood that the individual, physician, and care team will receive the results quicker, which allows for immediate clinical management decisions to be made. POCT is often accomplished through the use of transportable, portable, and handheld instruments and test kits. Small bench analyzers or fixed equipment can also be used when a handheld device is not available - the goal is to collect the specimen and obtain the results in a very short period of time at or near the location of the individual so that the treatment plan can be adjusted as necessary before the individual leaves the hospital.
Embodiments of the invention
The present invention will now be further described. In the following passages different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous, unless clearly indicated to the contrary.
To limit the economic loss and the medical harm of SARS-CoV-2, the present inventors found evidence that eukaryotic Initiation Factors (elFs) and eukaryotic Elongation Factors (eEFs) are regulated differently in SARS-CoV-2 and, thus, can function as biomarkers. The translation of mRNAs into proteins is one level of the regulations of gene expressions and is important for homeostasis and fast responses. Eukaryotic Initiation Factors (elFs) are proteins that bind to the small subunit of the ribosome during the initiation of translation, a part of protein biosynthesis. The main task of elongation translation factors (eEFs) is the elongation by ribosomes. The present inventors identified eukaryotic Initiation Factors (elFs) as well as eukaryotic Elongation Factors (eEFs) that allow to monitor COVID-19 in a patient, that allow to prognose the severity of COVID-19 in a patient, and that allow to determine the treatment response of a patient to specific therapies of COVID-19.
Thus, in a first aspect, the present invention relates to a method of monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19 comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF), the level of at least one eukaryotic Elongation Factor (eEF), the level of Mitochondrial Ribosome Recycling Factor (MRRF), and/or the level of ATP -binding cassette sub-family E member 1 (ABCE1) in a biological sample from a patient suffering from COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2.
Preferably, the present invention relates to a method of monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19 comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF) and/or the level of at least one eukaryotic Elongation Factor (eEF) in a biological sample from a patient suffering from COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2.
Particularly, the elF is selected from the group consisting of elFlAX, elFl, eIF5, eIF5B, and eIF2B5. More particularly, the elF is elFl AX. Combinations of the preferred elFs, namely elFlAX, elFl, eIF5, eIF5B, and eIF2B5, can be taken from Figure 1. In an alternative, it is particularly preferred that the level of at least one of elFlAX, elFl, eIF2A, eIF2B4, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, eIF5B, eEFlAl, eEFIG, and eEFlB2 is determined. More particularly, the level of at least one elF selected from the group consisting of elFlAX, elFl, eIF2A, eIF2B4, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B is determined and/or the level of at least one eEF selected from the group consisting of eEFlAl, eEFIG, and/or eEFlB2 is determined.
The above method allows to control COVID-19 or allows to determine the course of COVID-19 in a patient suffering from COVID-19 over time. In particular, the above method allows to determine whether COVID-19 worsens, improves, or is stable in a patient suffering from COVID-19 over time.
Specifically, worsening means that a patient suffering from a mild form of COVID-19 has developed a moderate or severe form of COVID-19 (over time) or that a patient suffering from a moderate form of COVID-19 has developed a severe form of COVID-19 (over time). The severe form of COVID-19 can be life-threatening. In any case, the disease can progress from mild, to moderate, to severe.
Alternatively, improving means that a patient suffering from a severe form of COVID-19 has developed a moderate form of COVID-19 (over time), that a patient suffering from a moderate form of COVID-19 has developed a mild form of COVID-19 (over time), or that a patient suffering from a mild form of COVID-19 has recovered overtime. In any case, the course of recovery can progress from a severe form of COVID-19, to a moderate and mild form of COVID-19 to complete recovery.
Usually, a patient suffering from a moderate form of COVID-19 has to be hospitalized, while a patient suffering from a severe form of COVID-19 has to be treated in an intensive care unit (ICU).
In one embodiment, the level of the at least one elF is compared to a reference level of said at least one elF, the level of the at least one eEF is compared to a reference level of said at least one eEF, the level of MRRF is compared to a reference level of said MRRF, and/or the level of ABCEl is compared to a reference level of said ABCEl.
Thus, in one particular embodiment, the method of monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19 comprises the steps of:
(i) determining the level of at least one eukaryotic Initiation Factor (elF), the level of at least one eukaryotic Elongation Factor (eEF), the level of Mitochondrial Ribosome Recycling Factor (MRRF), and/or the level of ATP -binding cassette sub-family E member 1 (ABCEl) in a biological sample from a patient suffering from COVID-19, and
(ii) comparing the level of the at least one elF to a reference level of said at least one elF, the level of the at least one eEF to a reference level of said at least one eEF, the level of MRRF to a reference level of said MRRF, and/or the level of ABCE1 to a reference level of said ABCE1, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEFID, and eEFlB2.
In one preferred embodiment, the level of the at least one elF is compared to a reference level of said at least one elF and/or the level of the at least one eEF is compared to a reference level of said at least one eEF.
Thus, in one particular embodiment, the method of monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19 comprises the steps of:
(i) determining the level of at least one eukaryotic Initiation Factor (elF) and/or the level of at least one eukaryotic Elongation Factor (eEF) in a biological sample from a patient suffering from COVID-19, and
(ii) comparing the level of the at least one elF to a reference level of said at least one elF and/or the level of the at least one eEF to a reference level of said at least one eEF, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEFID, and eEFlB2.
As to the above embodiments, it is preferred that the reference level represents a level that allows to determine whether COVID-19 worsens, improves, or is stable in the patient.
It is more preferred that the reference level is the level determined by measuring one or more, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 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, 95, 96, 97, 98, 99, 100, 500, 1.000, 2.000, 3.000, 4.000, 5.000, or 10.000, reference biological samples from one or more, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 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, 95, 96, 97, 98, 99, 100, 500
1.000, 2.000, 3.000, 4.000, 5.000, or 10.000, subjects being healthy (in particular not infected with COVID-19) or subjects having COVID-19, in particular a mild form, a moderate form, or a severe form of COVID-19.
It is practicable to take one reference biological sample per subject for analysis. If additional reference biological samples are required, e.g. to determine the reference level in different reference biological samples, the same subject may be (re)tested. Said reference level may be an average reference level. It may be determined by measuring reference levels and calculating the “average” value (e.g. mean, median or modal value) thereof.
A level above or below the reference level may indicate that COVID-19 worsens in the patient, a level comparable with the reference level may indicate that COVID-19 is unchanged in the patient, or a level above or below the reference level may indicate that COVID-19 improves in the patient.
It is even more preferred that the reference level is the level determined by measuring one or more reference biological samples from one or more subjects having a mild form of COVID-19 and wherein
(i) the level of the at least one elF selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3D, eIF3H, eIF3I, eIF2S3, and eIF2B5 below the reference level indicates that COVID-19 is worsening in the patient,
(ii) the level of the at least one elF selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3D, eIF3H, eIF3I, eIF2S3, and eIF2B5 above the reference level indicates that COVID-19 is improving in the patient,
(iii) the level of the at least one elF selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3D, eIF3H, eIF3I, eIF2S3, and eIF2B5 comparable with the reference level indicates that COVID-19 is stable/not progressing in the patient,
(iv) the level of the at least one elF selected from the group consisting of eIF3C, eIF4E, and eIF2S2 above the reference level indicates that COVID-19 is worsening in the patient,
(v) the level of the at least one elF selected from the group consisting of eIF3C, eIF4E, and eIF2S2 comparable with the reference level indicates that COVID-19 is stable/not progressing in the patient, (vi) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2 below the reference level indicates that COVID-19 is worsening in the patient,
(vii) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2 above the reference level indicates that COVID-19 is improving in the patient, and/or
(viii) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2 comparable with the reference level indicates that COVID- 19 is stable/not progressing in the patient.
Alternatively or additionally, the reference level is the level determined by measuring one or more reference biological samples from one or more subjects having a moderate form of COVID-19 and wherein
(i) the level of the at least one elF selected from the group consisting of elFlAX, elFl, eIF2A, eIF2B2, eIF2B3, eIF2B4, eIF2B5, eIF2Sl, eIF2S3, eIF3H, eIF3J, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B below the reference level indicates that COVID-19 is worsening in the patient,
(ii) the level of the at least one elF selected from the group consisting of elFlAX, elFl, eIF2A, eIF2B4, eIF2B5, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B above the reference level indicates that COVID-19 is improving in the patient,
(iii) the level of the at least one elF selected from the group consisting of elFlAX, elFl, eIF2A, eIF2B2, eIF2B3, eIF2B4, eIF2B5, eIF2Sl, eIF2S3, eIF3H, eIF3J, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B comparable with the reference level indicates that COVID-19 is stable/not progressing in the patient,
(iv) the level of eIF3C above the reference level indicates that COVID-19 is worsening in the patient,
(v) the level of eIF3C below the reference level indicates that COVID-19 is improving in the patient,
(vi) the level of eIF3C comparable with the reference level indicates that COVID-19 is stable/not progressing in the patient,
(vii) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 below the reference level indicates that COVID-19 is worsening in the patient, (viii) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 above the reference level indicates that COVID-19 is improving in the patient,
(ix) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 comparable with the reference level indicates that COVID-19 is stable/not progressing in the patient,
(x) the level of MRRF below the reference level indicates that COVID-19 is worsening in the patient,
(xi) the level of MRRF comparable with the reference level indicates that COVID-19 is stable/not progressing in the patient,
(xii) the level of ABCEl below the reference level indicates that COVID-19 is worsening in the patient, and/or
(xiii) the level of ABCEl comparable with the reference level indicates that COVID-19 is stable/not progressing in the patient.
Alternatively or additionally, the reference level is the level determined by measuring one or more reference biological samples from one or more subjects having a severe form of
COVID-19 and wherein
(i) the level of the at least one elF selected from the group consisting of elFlAX, elFl, eIF2A, eIF2B2, eIF2B3, eIF2B4, eIF2B5, eIF2Sl, eIF2S3, eIF3H, eIF3J, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B above the reference level indicates that COVID-19 is improving in the patient,
(ii) the level of the at least one elF selected from the group consisting of elFlAX, elFl, eIF2A, eIF2B2, eIF2B3, eIF2B4, eIF2B5, eIF2Sl, eIF2S3, eIF3H, eIF3J, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B comparable with the reference level indicates that COVID-19 is stable in the patient,
(iii) the level of eIF3C below the reference level indicates that COVID-19 is improving in the patient,
(iv) the level of eIF3C comparable with the reference level indicates that COVID-19 is stable in the patient,
(v) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 above the reference level indicates that COVID-19 is improving in the patient, (vi) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 comparable with the reference level indicates that COVID-19 is stable in the patient,
(vii) the level of MRRF above the reference level indicates that COVID-19 is improving in the patient,
(viii) the level of MRRF comparable with the reference level indicates that COVID-19 is stable in the patient,
(ix) the level of ABCE1 above the reference level indicates that COVID-19 is improving in the patient, and/or
(x) the level of ABCE1 comparable with the reference level indicates that COVID-19 is stable in the patient.
The reference level may also be the level determined by measuring one or more reference biological samples from one or more subjects having a moderate/severe form of COVID-19 and wherein
(i) the level of the at least one elF selected from the group consisting of eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, eIF2A, eIF3A, eIF3D, eIF3H, eIF3I, and eIF2S3 above the reference level indicates that COVID-19 is improving in the patient, and/or
(ii) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2 above the reference level indicates that COVID-19 is improving in the patient.
In this case, the reference level may be an average level of a moderate and severe form of COVID-19.
Preferably, the level of the at least one elF and/or the level of the at least one eEF is at least 0.6-fold or 0.7-fold, more preferably at least 0.8-fold or 0.9-fold, even more preferably at least 1.2-fold or 1.5-fold, and most preferably at least 2.0-fold or 3.0-fold below/above the reference level. For example, the level of the at least one elF and/or the level of the at least one eEF is at least 0.6-fold, at least 0.7-fold, at least 0.8-fold, at least 0.9-fold, at least 1.0-fold, at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.6- fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, at least 2.1-fold, at least 2.2-fold, at least 2.3-fold, at least 2.4-fold, at least 2.5-fold, at least 2.6-fold, at least 2.7- fold, at least 2.8-fold, at least 2.9-fold, or at least 3.0-fold below/above the reference level.
In one another embodiment, said determining comprises determining the level of the at least one elF, the level of the at least one eEF, the level of MRRF, and/or the level of ABCEl in a biological sample (from a patient) at a first point in time and in at least one further biological sample (from the (same) patient) at a later point in time and comparing said levels determined at the different time points.
Thus, in one particular embodiment, the method of monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19 comprises the steps of:
(i) determining the level of the at least one elF, the level of the at least one eEF, the level of MRRF, and/or the level of ABCE1 in a biological sample (from a patient) at a first point in time and in at least one further biological sample (from the (same) patient) at a later point in time, and
(ii) comparing said levels determined at the different time points, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2, wherein MRRF means Mitochondrial Ribosome Recycling Factor, and wherein ABCE1 means ATP -binding cassette sub-family E member 1.
In one another preferred embodiment, said determining comprises determining the level of the at least one elF and/or the level of the at least one eEF in a biological sample (from a patient) at a first point in time and in at least one further biological sample (from the (same) patient) at a later point in time and comparing said levels determined at the different time points. Thus, in one particular embodiment, the method of monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19 comprises the steps of:
(i) determining the level of at least one eukaryotic Initiation Factor (elF) and/or the level of at least one eukaryotic Elongation Factor (eEF) in a biological sample (from a patient) at a first point in time and in at least one further biological sample (from the (same) patient) at a later point in time, and
(ii) comparing said levels determined at the different time points, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEFID, and eEFlB2.
An increase or decrease of the level over time may indicate that COVID-19 is worsening in the patient, a level that does not change over time may indicate that the patient is stable or COVID-19 is not progressing in the patient, or an increase or decrease of the level over time may indicate that COVID-19 is improving in the patient.
As to the above embodiments, it is preferred that
(i) the level of the at least one elF selected from the group consisting of elFlAX, elFl, eIF2A, eIF2B4, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B which decreases over time indicates that COVID-19 is worsening in the patient,
(ii) the level of the at least one elF selected from the group consisting of elFlAX, elFl, eIF2A, eIF2B4, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B which increases over time indicates that COVID-19 is improving in the patient,
(iii) the level of the at least one elF selected from the group consisting of elFlAX, elFl, eIF2A, eIF2B4, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B which does not change over time indicates that COVID-19 is stable/not progressing in the patient,
(iv) the level of eIF3C which increases over time indicates that COVID-19 is worsening in the patient,
(v) the level of eIF3C which decreases over time indicates that COVID-19 is improving in the patient,
(vi) the level of eIF3C which does not change over time indicates that COVID-19 is stable/not progressing in the patient
(vii) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 which decreases over time indicates that COVID-19 is worsening in the patient,
(viii) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 which increases over time indicates that COVID-19 is improving in the patient, and/or
(ix) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 which does not change over time indicates that COVID-19 is stable/not progressing in the patient.
In particular, the term “comparable with” means that the level varies over time between 0 and < 20%, e.g. 0, 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, 19.9, 19.99, or 19.999%. The term “comparable with” in this respect can also mean that the detected level variation is within the accuracy of a measurement. The accuracy of a measurement depends on the measurement method used. Preferably, the level is constant over time.
The time period between the first point in time and the later point(s) in time preferably amounts to at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days (1 week), at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 1 month, or at least 2 months. For example, the individual may be routinely checked, e.g. every day or one times per week. The patient may be (re)tested at 2, 3, 4, 5, 6 7, 8, 9, or 10 time points (first point in time and further point(s) in time).
The patient tested with the method of the first aspect may be a patient which will receive, receives, has received, or had received a treatment of COVID-19. For example, in case COVID- 19 is worsening in the patient, the patient may (timely) receive a therapeutic treatment for this disease state. The therapeutic treatment may be in the form of the administration of a drug and/or in the form of a therapeutic treatment different from the administration of a drug, e.g. ventilation. Further, in case COVID-19 improves in the patient, the therapeutic treatment may be reduced or finished. Furthermore, in case COVID-19 is stable/does not progress in the patient, the therapeutic treatment may be continued. In this respect, it is also referred to the third aspect of the present invention.
In a second aspect, the present invention relates to a method of prognosing the severity of Coronavirus disease 2019 (COVID-19) in a patient comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF), the level of at least one eukaryotic Elongation Factor (eEF), the level of Mitochondrial Ribosome Recycling Factor (MRRF), and/or the level of ATP -binding cassette sub-family E member 1 (ABCE1) in a biological sample from a patient, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2.
Preferably, the present invention relates to a method of prognosing the severity of Coronavirus disease 2019 (COVID-19) in a patient comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF) and/or the level of at least one eukaryotic Elongation Factor (eEF) in a biological sample from a patient, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2.
Particularly, the elF is selected from the group consisting of elFlAX, elFl, eIF5, eIF5B, and eIF2B5. More particularly, the elF is elFlAX. Combinations of the preferred elFs, namely elFlAX, elFl, eIF5, eIF5B, and eIF2B5, can be taken from Figure 1. In an alternative, it is particularly preferred that the level of at least one of elFlAX, elFl, eIF2A, eIF2B4, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, eIF5B, eEFlAl, eEFIG, and eEFlB2 is determined. More particularly, the level of at least one elF selected from the group consisting of elFlAX, elFl, eIF2A, eIF2B4, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B is determined and/or the level of at least one eEF selected from the group consisting of eEFlAl, eEFIG, and/or eEFlB2 is determined.
The above method allows to prognose the development of COVID-19 in a patient. In other words, the above method allows to prognose the seriousness of COVID-19 in a patient. In particular, prognosing the severity of COVID-19 in a patient suffering from a mild form of COVID-19 means determining whether (it is likely that) the patient will develop a moderate form of COVID-19 or a severe form of COVID-19. Further, prognosing the severity of COVID- 19 in a patient suffering from a moderate form of COVID-19 means determining whether (it is likely that) the patient will develop a severe form of COVID-19. The severe form of COVID- 19 can be life-threatening.
Prognosing the severity of COVID-19 also allows to determine whether the patient will need treatment in a hospital (moderate or severe form of COVID-19) or not (mild form of COVID-19). In addition, prognosing the severity of COVID-19 also allows to determine whether the patient will need intensive medical care (severe form of COVID-19) or not (moderate form of COVID-19). Especially, prognosing the severity of COVID-19 also allows to determine whether the patient will need intensive medical care in a hospital (severe form of COVID-19) but not intensive medical care (moderate form of COVID-19). Usually, a patient suffering from a moderate form of COVID-19 has to be hospitalized, while a patient suffering from a severe form of COVID-19 has to be treated in an intensive care unit (ICU).
In one embodiment, the level of the at least one elF is compared to a reference level of said at least one elF, the level of the at least one eEF is compared to a reference level of said at least one eEF, the level of MRRF is compared to a reference level of said MRRF, and/or the level of ABCE1 is compared to a reference level of said ABCE1.
Thus, in one particular embodiment, the method of prognosing the severity of Coronavirus disease 2019 (COVID-19) in a patient comprises the steps of:
(i) determining the level of at least one eukaryotic Initiation Factor (elF), the level of at least one eukaryotic Elongation Factor (eEF), the level of Mitochondrial Ribosome Recycling Factor (MRRF), and/or the level of ATP -binding cassette sub-family E member 1 (ABCE1) in a biological sample from a patient, and
(ii) comparing the level of the at least one elF to a reference level of said at least one elF, the level of the at least one eEF to a reference level of said at least one eEF, the level of MRRF to a reference level of said MRRF, and/or the level of ABCE1 to a reference level of said ABCE1, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2.
In one preferred embodiment, the level of at least one elF is compared to a reference level of said at least one elF and/or the level of at least one eEF is compared to a reference level of said at least one eEF.
Thus, in one particular embodiment, the method of prognosing the severity of Coronavirus disease 2019 (COVID-19) in a patient comprises the steps of:
(i) determining the level of at least one eukaryotic Initiation Factor (elF) and/or the level of at least one eukaryotic Elongation Factor (eEF) in a biological sample from a patient suffering from COVID-19, and
(ii) comparing the level of the at least one elF to a reference level of said at least one elF and/or the level of the at least one eEF to a reference level of said at least one eEF, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEFID, and eEFlB2.
It is preferred that the reference level represents a level that allows to predict whether the patient suffering from COVID-19 will (likely) develop a moderate or severe form of COVID-19. The severe form of COVID-19 can be life-threatening.
It is more preferred that the reference level is the level determined by measuring one or more, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 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, 95, 96, 97, 98, 99, 100,
500, 1.000, 2.000, 3.000, 4.000, 5.000, or 10.000, reference biological samples from one or more, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 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, 95, 96, 97, 98, 99, 100
500, 1.000, 2.000, 3.000, 4.000, 5.000, or 10.000, subjects being healthy (in particular not infected with COVID-19) or subjects having COVID-19, in particular a mild form, a moderate form, or a severe form of COVID-19.
It is practicable to take one reference biological sample per subject for analysis. If additional reference biological samples are required, e.g. to determine the reference level in different reference biological samples, the same subject may be (re)tested. Said reference level may be an average reference level. It may be determined by measuring reference levels and calculating the “average” value (e.g. mean, median or modal value) thereof.
As to the above embodiments, it is even more preferred that the reference level is the level determined by measuring one or more reference biological samples from one or more subjects having a mild form of COVID-19 and wherein
(i) the level of the at least one elF selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3D, eIF3H, eIF3I, eIF2S3, and eIF2B5 below the reference level indicates that the patient will (likely) develop a moderate or severe form of COVID-19, (ii) the level of the at least one elF selected from the group consisting of eIF3C, eIF4E, and eIF2S2 above the reference level indicates that the patient will (likely) develop a moderate or severe form of COVID-19, and/or
(iii) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2 below the reference level indicates that the patient will (likely) develop a moderate or severe form of COVID-19.
Alternatively or additionally, the reference level is the level determined by measuring one or more reference biological samples from one or more subjects having a moderate form of COVID-19 and wherein
(i) the level of the at least one elF selected from the group consisting of elFlAX, elFl, eIF2A, eIF2B2, eIF2B3, eIF2B4, eIF2Sl, eIF2S3, eIF3H, eIF3J, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B below the reference level indicates that the patient will (likely) develop a severe form of COVID-19,
(ii) the level of the at least one elF selected from the group consisting of elFl AY and eIF3C above the reference level indicates that the patient will (likely) develop a severe form of COVID-19,
(iii) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 below the reference level indicates that the patient will (likely) develop a severe form of COVID-19,
(iv) the level of MRRF below the reference level indicates that the patient will (likely) develop a severe form of COVID-19, and/or
(v) the level of ABCEl below the reference level indicates that the patient will (likely) develop a severe form of COVID-19.
Preferably, the level of the at least one elF and/or the level of the at least one eEF is at least 0.6-fold or 0.7-fold, more preferably at least 0.8-fold or 0.9-fold, even more preferably at least 1.2-fold or 1.5-fold, and most preferably at least 2.0-fold or 3.0-fold below/above the reference level. For example, the level of the at least one elF and/or the level of the at least one eEF is at least 0.6-fold, at least 0.7-fold, at least 0.8-fold, at least 0.9-fold, at least 1.0-fold, at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.6- fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, at least 2.1-fold, at least 2.2-fold, at least 2.3-fold, at least 2.4-fold, at least 2.5-fold, at least 2.6-fold, at least 2.7- fold, at least 2.8-fold, at least 2.9-fold, or at least 3.0-fold below/above the reference level.
The reference level may also be the level determined by measuring one or more reference biological samples from one or more subjects being COVID-19 negative. Thus, in a specific embodiment, the reference level determined by measuring one or more reference biological samples from one or more subjects being COVID-19 negative is used for comparative purposes.
The patient tested with the method of the second aspect may be a patient which will receive, receives, has received, or had received a treatment of COVID-19. For example, in case the patient will (likely) develop a moderate or severe form of COVID-19, the patient may (timely) receive a therapeutic treatment for this disease state. The therapeutic treatment may be in the form of the administration of a drug and/or in the form of a therapeutic treatment different from the administration of a drug, e.g. ventilation. Further, in case the patient will (likely) develop a moderate or severe form of COVID-19, the therapeutic treatment may be changed, e.g. the dose of the drug may be increased or another drug may be administered and/or a therapeutic treatment different from the administration of a drug may be applied/administered, e.g. ventilation.
In a third aspect, the present invention relates to a method of determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19 comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF), the level of at least one eukaryotic Elongation Factor (eEF), the level of Mitochondrial Ribosome Recycling Factor (MRRF), and/or the level of ATP -binding cassette sub-family E member 1 (ABCE1) in a biological sample from a patient suffering from COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2.
Preferably, the present invention relates to a method of determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19 comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF) and/or the level of at least one eukaryotic Elongation Factor (eEF) in a biological sample from a patient suffering from COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEFID, and eEFlB2.
Particularly, the elF is selected from the group consisting of elFlAX, elFl, eIF5, eIF5B, and eIF2B5. More particularly, the elF is elFlAX. Combinations of the preferred elFs, namely elFlAX, elFl, eIF5, eIF5B, and eIF2B5, can be taken from Figure 1. In an alternative, it is particularly preferred that the level of at least one of elFlAX, elFl, eIF2A, eIF2B4, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, eIF5B, eEFlAl, eEFIG, and eEFlB2 is determined. More particularly, the level of at least one elF selected from the group consisting of elFlAX, elFl, eIF2A, eIF2B4, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B is determined and/or the level of at least one eEF selected from the group consisting of eEFlAl, eEFIG, and/or eEFlB2 is determined.
The above method allows to evaluate whether a therapeutic approach is effective in a patient or not.
It is preferred that the patient is a patient to whom at least once (1, 2, or 3 times) a drug to be used in said therapeutic treatment is administered, has been administered, or had been administered, and/or another form of therapeutic treatment (than the administration of a drug) is administered, has been administered, or had been administered.
The way of administration may be oral, nasal, rectal, parenteral, vaginal, or topical. Parental administration includes subcutaneous, intracutaneous, intramuscular, intravenous or intraperitoneal administration.
It is further preferred that the biological sample is isolated from the patient after at least the first (e.g. first, second, or third) administration of said drug and/or administration of another form of therapeutic treatment (than the administration of a drug).
It is particularly preferred that the biological sample is isolated from the patient in a time period of between 2 weeks and 1 day after at least the first (e.g. first, second, or third) administration of said drug and/or administration of another form of therapeutic treatment (than the administration of a drug).
It is particularly more preferred that the biological sample is isolated from the patient in a time period of between 1 weeks and 1 day after at least the first (e.g. first, second, or third) administration of said drug and/or administration of another form of therapeutic treatment (than the administration of a drug).
For example, the biological sample is isolated from the patient 1, 2, 3, 4, 5, 6, day(s), 1, 2, 3 week(s) after at least the first (e.g. first, second, or third) administration of said drug and/or administration of another form of therapeutic treatment (than the administration of a drug).
It is more preferred that the level of at least one elF is compared to a reference level of said at least one elF, the level of at least one eEF is compared to a reference level of said at least one eEF, the level of MRRF is compared to a reference level of said MRRF, and/or the level of ABCE1 is compared to a reference level of said ABCE1.
It is even more preferred that the reference level is the level determined in a reference biological sample from the (same) patient prior to the administration of said drug, and/or administration of another form of therapeutic treatment.
It is still even more preferred that
(i) the level of the at least one elF selected from the group consisting of elFlAX, elFl, eIF2A, eIF2B4, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, and eIF5B above the reference level indicates that the patient responds to said treatment of COVID-19,
(ii) the level of the at least one elF selected from the group consisting of elFl AY and eIF3C below the reference level indicates that the patient responds to said treatment of COVID- 19, and/or
(iii) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 above the reference level indicates that the patient responds to said treatment of COVID-19.
In this case, the patient itself is the reference and provides the reference level.
It is also even more preferred that the reference level is the level determined by measuring one or more, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 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, 95, 96,
97, 98, 99, 100, 500, 1.000, 2.000, 3.000, 4.000, 5.000, or 10.000, reference biological samples from one or more, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 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, 95, 96, 97
98, 99, 100, 500, 1.000, 2.000, 3.000, 4.000, 5.000, or 10.000, subjects being heathy (in particular not infected with COVID-19) or subjects having COVID-19, in particular a mild form, a moderate form, or a severe form of COVID-19.
It is practicable to take one reference biological sample per subject for analysis. If additional reference biological samples are required, e.g. to determine the reference level in different reference biological samples, the same subject may be (re)tested. Said reference level may be an average reference level. It may be determined by measuring reference levels and calculating the “average” value (e.g. mean, median or modal value) thereof.
It is still even more preferred that the reference level is the level determined by measuring one or more reference biological samples from one or more subjects having a mild form of COVID-19 and wherein
(i) the level of the at least one elF selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3D, eIF3H, eIF3I, eIF2S3, and eIF2B5 above the reference level indicates that the patient responds to said treatment of COVID-19, and/or
(ii) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2 above the reference level indicates that the patient responds to said treatment of COVID-19.
Alternatively or additionally, the reference level is the level determined by measuring one or more reference biological samples from one or more subjects having a moderate form of COVID-19 and wherein
(i) the level of the at least one elF selected from the group consisting of elFlAX, elFl, eIF2A, eIF2B4, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B above the reference level indicates that the patient responds to said treatment of COVID-19,
(ii) the level of the at least one elF selected from the group consisting of eIF3C, eIF4E, and eIF2S2 below the reference level indicates that the patient responds to said treatment of COVID-19, and/or
(iii) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 above the reference level indicates that the patient responds to said treatment of COVID-19. Alternatively or additionally, the reference level is the level determined by measuring one or more reference biological samples from one or more subjects having a severe form of COVID-19 and wherein
(i) the level of the at least one elF selected from the group consisting of elFlAX, elFl, eIF2A, eIF2B2, eIF2B3, eIF2B4, eIF2Sl, eIF2S3, eIF3H, eIF3J, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B above the reference level indicates that the patient responds to said treatment of COVID-19,
(ii) the level of eIF3C below the reference level indicates that the patient responds to said treatment of COVID-19,
(iii) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 above the reference level indicates that the patient responds to said treatment of COVID-19,
(iv) the level of MRRF above the reference level indicates that the patient responds to said treatment of COVID-19, and/or
(v) the level of ABCEl above the reference level indicates that the patient responds to said treatment of COVID-19.
In this case, the (control) subjects are the reference and provide the reference level.
The reference level may also be the level determined by measuring one or more reference biological samples from one or more subjects having a moderate/severe form of COVID-19 and wherein
(i) the level of the at least one elF selected from the group consisting of eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY eIF3M, eIF4Gl, eIF5A, eIF2A, eIF3A, eIF3D, eIF3H, eIF3I, and eIF2S3 above the reference level indicates that the patient responds to said treatment of COVID-19,
(ii) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2 above the reference level indicates that the patient responds to said treatment of COVID-19.
In this case, the reference level may be an average level of a moderate and severe form of COVID-19.
In the above cases, the level of the at least one elF and/or the level of the at least one eEF is preferably at least 0.6-fold or 0.7-fold, more preferably at least 0.8-fold or 0.9-fold, even more preferably at least 1.2-fold or 1.5-fold, and most preferably at least 2.0-fold or 3.0-fold below/above the reference level. For example, the level of the at least one elF and/or the level of the at least one eEF is at least 0.6-fold, at least 0.7-fold, at least 0.8-fold, at least 0.9-fold, at least 1.0-fold, at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5- fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, at least 2.1-fold, at least 2.2-fold, at least 2.3-fold, at least 2.4-fold, at least 2.5-fold, at least 2.6- fold, at least 2.7-fold, at least 2.8-fold, at least 2.9-fold, or at least 3.0-fold below/above the reference level.
In the third aspect of the present invention, a drug to be used in said therapeutic treatment is administered, has been administered, or had been administered and/or another form of therapeutic treatment (different from the administration of a drug) is administered, has been administered, or had been administered.
The drug is preferably selected from the group consisting of an antiviral drug, an antibacterial drug, an anti-inflammatory drug, an antifungal drug, and an antipyretic agent.
The antiviral drug is more preferably selected from the group consisting of chloroquine, remdesivir, darunavir, favipiravir, lopinavir, and ritonavir. Combinations of these drugs are also encompassed. The antiviral drug is even more preferably selected from the group consisting of remdesivir, darunavir, or a combination of lopinavir and ritonavir.
The antibacterial drug is more preferably selected from the group consisting of ceftriaxone, amoxicillin/clavulanic acid, piperacillin/tazobactam, and azithromycin. Combinations of these drugs are also encompassed.
The anti-inflammatory drug is more preferably selected from the group consisting of ibuprofen and metamizole. Combinations of these drugs are also encompassed.
The antifungal drug is more preferably selected from the group consisting of voriconazole and isavuconazole. Combinations of these drugs are also encompassed.
The antipyretic agent is more preferably paracetamol.
It is alternatively or additionally preferred that the other form of therapeutic treatment (than the administration of a drug) is ventilation.
It is more preferred that the ventilation is selected from the group consisting of non-invasive ventilation and invasive ventilation.
It is even more preferred that the non-invasive ventilation is carried out through a face mask, nasal mask, or a helmet, or the invasive ventilation is a mechanic ventilation carried out through a positive pressure ventilator or negative pressure ventilator.
If the treatment encompasses the administration of a drug and the patient responds to said treatment, the drug administration may be continued, the dose of the drug may be reduced, or the drug administration may be stopped. If the treatment encompasses the administration of a drug and the patient does not respond to said treatment, the dose of the drug may be increased, the drug may be changed, or the therapy mode may be changed.
Coronavirus disease 2019 (COVID-19), referred to in the first to third aspect of the present invention, is associated with an acute infectious lung disease/acute respiratory syndrome. It is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
In the first to third aspect of the present invention, the patient is preferably a mammal, more preferably a human.
In the first to third aspect of the present invention, the biological sample is preferably selected from the group consisting of a body fluid sample, a body tissue sample, and a body gas sample. More preferably,
(i) the body fluid sample is selected from the group consisting of blood, cerebrospinal fluid (CSF), urine, sputum, breast milk, cerumen (earwax), endolymph fluid, perilymph fluid, pleural fluid, peritoneal fluid, gastric juice, mucus, saliva, semen, sweat, cheek swab, tears, and liquid biopsy,
(ii) the body tissue sample is selected from the group consisting of skin flake, skin biopsy, hair follicle, biopsy tissue, tissue explant, and tissue section, or
(iii) the body gas sample is selected from the group consisting of exhaled condensate and exhaled gas.
Even more preferably, the blood sample is whole blood or a blood fraction. The blood fraction may be a blood cell fraction, blood serum, or blood plasma.
In the first to third aspect of the present invention, the level of the at least one elF and/or eEF is determined by measuring mRNA and/or protein levels. The level of the at least one elF and/or eEF can be determined either by measuring the mRNA molecule encoding said elF and/or eEF or by measuring said elF and/or eEF as such in form of a protein. Methods to determine mRNA levels and protein levels in a biological sample are well known. mRNA expression levels are usually measured by polymerase chain reaction (PCR), in particular by reverse transcription quantitative polymerase chain reaction (RT-PCR and qPCR) or real-time PCR. RT-PCR is used to create a cDNA from the mRNA. The cDNA may be used in a qPCR assay to produce fluorescence as the DNA amplification process progresses. This fluorescence is proportional to the original mRNA amount in the samples. Other methods to be used include Northern blots, Fluorescence in situ hybridization (FISH), microarrays, and RT-PCR combined with capillary electrophoresis. In particular, protein levels of elFs and/or eEFs are determined using immunoassays. Such methods are based on the binding of an antibody, a derivative or a fragment thereof to its corresponding target (i.e. elF or eEF). Polyclonal and monoclonal antibodies can be used in such methods. Derivatives or fragments of antibodies include Fab fragments, F(ab')2 fragments, Fv fragments, single chain antibodies and single domain antibodies. Preferred immunoassays include Western blot, Immunohistochemistry, ELISA (enzyme-linked immunosorbent assay), radioimmunoassays, fluorescence resonance energy transfer (FRET) or time resolved-FRET (TR-FRET). It is particularly preferred to use antibodies and derivatives or fragments of antibodies which have been obtained from a non human source. These antigen binding molecules can be of porcine, rabbit, murine, camel or rat origin. Of course, it is also possible to use antibodies and derivatives or fragments thereof which are recombinantly produced in plants or cell cultures, in particular microbial cell cultures (e.g. bacteria, yeast).
Specifically, the level of the at least one elF and/or at least one eEF is determined by sequencing, polymerase chain reaction (PCR), spectrometry, chromatography, an enzymatic method, an immunochemical method, a gravimetric method, a chemosensoric method, or a combination thereof.
The method according to the first to third aspect of the present invention is preferably carried out in vitro.
In a fourth aspect, the present invention relates to the {in vitro ) use of at least one eukaryotic Initiation Factor (elF), at least one eukaryotic Elongation Factor (eEF), Mitochondrial Ribosome Recycling Factor (MRRF), and/or ATP -binding cassette sub-family E member 1 (ABCE1) for monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19, for prognosing the severity of Coronavirus disease 2019 (COVID-19), or for determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2.
Preferably, the present invention relates to the {in vitro ) use of at least one eukaryotic Initiation Factor (elF) and/or at least one eukaryotic Elongation Factor (eEF) for monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19, for prognosing the severity of Coronavirus disease 2019 (COVID-19), or for determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEFID, and eEFlB2.
As to the preferred elFs and elF combinations, it is referred to the first to third aspect of the present invention.
The use is preferably an in vitro use.
The patient is preferably a mammal, more preferably a human.
For the above mentioned use, the level of the at least one elF and/or eEF is determined in a biological sample from a patient to be tested. The biological sample is preferably selected from the group consisting of a body fluid sample, a body tissue sample, and a body gas sample. More preferably,
(i) the body fluid sample is selected from the group consisting of blood, cerebrospinal fluid (CSF), urine, sputum, breast milk, cerumen (earwax), endolymph fluid, perilymph fluid, pleural fluid, peritoneal fluid, gastric juice, mucus, saliva, semen, sweat, cheek swab, tears, and liquid biopsy,
(ii) the body tissue sample is selected from the group consisting of skin flake, skin biopsy, hair follicle, biopsy tissue, tissue explant, and tissue section, or
(iii) the body gas sample is selected from the group consisting of exhaled condensate and exhaled gas.
Even more preferably, the blood sample is whole blood or a blood fraction. The blood fraction may be a blood cell fraction, blood serum, or blood plasma.
As to further preferred embodiments, it is referred to the first to third aspect of the present invention.
In a fifth aspect, the present invention relates to (the {in vitro ) use of) a kit for monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19, for prognosing the severity of Coronavirus disease 2019 (COVID-19), or for determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19, wherein the kit comprises means for determining the level of at least one eukaryotic Initiation Factor (elF), the level of at least one eukaryotic Elongation Factor (eEF), the level of Mitochondrial Ribosome Recycling Factor (MRRF), and/or the level of ATP -binding cassette sub-family E member 1 (ABCE1) in a biological sample from an individual, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2.
Preferably, the present invention relates to (the {in vitro ) use of) a kit for monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19, for prognosing the severity of Coronavirus disease 2019 (COVID-19), or for determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19, wherein the kit comprises means for determining the level of at least one eukaryotic Initiation Factor (elF) and/or the level of at least one eukaryotic Elongation Factor (eEF) in a biological sample from an individual, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2.
As to the preferred elFs and elF combinations, it is referred to the first to third aspect of the present invention.
In particular, the kit is used in vitro.
Preferably, the patient is a mammal, more preferably a human.
Preferably, the biological sample is selected from the group consisting of a body fluid sample, a body tissue sample, and a body gas sample. More preferably,
(i) the body fluid sample is selected from the group consisting of blood, cerebrospinal fluid (CSF), urine, sputum, breast milk, cerumen (earwax), endolymph fluid, perilymph fluid, pleural fluid, peritoneal fluid, gastric juice, mucus, saliva, semen, sweat, cheek swab, tears, and liquid biopsy, (ii) the body tissue sample is selected from the group consisting of skin flake, skin biopsy, hair follicle, biopsy tissue, tissue explant, and tissue section, or
(iii) the body gas sample is selected from the group consisting of exhaled condensate and exhaled gas.
Even more preferably, the blood sample is whole blood or a blood fraction. The blood fraction may be a blood cell fraction, blood serum, or blood plasma.
Said means may be primers or primer pairs allowing the detecting of the at least one elF and/or the at least one eEF on the RNA transcript, e.g. mRNA, level and/or antibodies, antibody derivatives or fragments of antibodies allowing the detection of the at least one elF and/or the at least one eEF on the protein level.
In addition, said means encompass dip strips or dipsticks, e.g. urine or blood dipstrips or dipsticks. Said means are tools used to determine changes in patient’s urine or blood. A dip strip or dipstick comprises different chemical pads or reagents which react (e.g. change color, in particular by applying an immune assay) when immersed in (e.g. blood or urine), and then removed from the biological sample (e.g. urine or blood sample). The result can be read after a few minutes, preferably after a few seconds.
The kit may further comprise
(i) a container, and/or
(ii) a data carrier.
Said data carrier may be a non-el ectronical data carrier, e.g. a graphical data carrier such as an information leaflet, an information sheet, a bar code or an access code, or an electronical data carrier such as a floppy disk, a compact disk (CD), a digital versatile disk (DVD), a microchip or another semiconductor-based electronical data carrier. The access code may allow the access to a database, e.g. an internet database, a centralized, or a decentralized database. The access code may also allow access to an application software that causes a computer to perform tasks for computer users or a mobile app which is a software designed to run on smartphones and other mobile devices.
Said data carrier may further comprise a reference level of the at least one elF and/or at least one eEF referred to herein.
In case that the data carrier comprises an access code which allows the access to a database, said reference level is deposited in this database.
In addition, the data carrier may comprise information or instructions on how to carry out the methods of the first to third aspect of the present invention. Said kit may also comprise materials desirable from a commercial and user standpoint including a buffer(s), a reagent(s) and/or a diluent(s) for determining the level mentioned above.
The kit is useful for conducting the methods of the first to third aspect of the present invention.
As to further preferred embodiments, it is referred to the first to third aspect of the present invention.
Various modifications and variations of the invention will be apparent to those skilled in the art without departing from the scope of invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in the art in the relevant fields are intended to be covered by the present invention.
BRIEF DESCRIPTION OF THE FIGURE
The following Figure is merely illustrative of the present invention and should not be construed to limit the scope of the invention as indicated by the appended claims in any way.
Figure 1: Shows preferred elFs and elF combinations.
Figure 2: Shows the arithmetic mean raw count for healthy and each COVID-19 severity from mild, moderate to severe for the eukaryotic initiation factors (elFs) and eukaryotic elongation factors (eEFs) EIF4B, EIF4H, EIF1AX, EIF2B4, EIF3B, EIF3L, EEF1A1, EEF1G, EIF1AY, EIF1, EIF5, EIF5B, EIF2A, EIF2S3, EIF2B5, EIF3A, EIF3C, EIF3D, EIF3H, EIF3I, EIF3M, EIF4G1, EIF5A, EEF2, EEF1D and EEF1B2.
Figure 3: Shows the arithmetic mean raw count for each COVID-19 severity from mild, moderate to severe for the eukaryotic initiation factors (elFs), eukaryotic elongation factors (eEFs), EEF1A1, EEF1B2, EEF1G, EIF2A, EIF2B2, EIF2B3, EIF2S1, EIF2S2, EIF2S3, EIF3H, EIF3J, EIF3L, EIF4B, EIF4E, Mitochondrial Ribosome Recycling Factor (MRRF), and ATP -binding cassette sub-family E member 1 (ABCEl).
Figure 4: Shows the p-values of ElFs deregulated between a MILD and a SEVERE form of COVID-19. EIF4e: p = 0.03, EIF2S2: p = 0.0274. Thus, both p-values are < 0.05. Figure 5: Shows the p-values of EIFs, EEFs, MRRF, and ABCE1 deregulated between a MODERATE and a SEVERE form of COVID-19. The p-values of all markers are < 0.05.
EXAMPLES
The examples given below are for illustrative purposes only and do not limit the invention described above in any way.
EXAMPLE 1
1. Materials
Patients were characterized by sex, age, height, weight, BMI, allergies, family history, existing comorbidities as well as their exposure respectively their antibody/sero status.
Lee HK, Knabl L, Pipperger L, Volland A, Furth P, Kang K, Smith H, Knabl L, Bellmann R, Bernhard C, Kaiser N, Ganzer H, Strohle M, Walser A, Von Laer D, Hennighausen L. Immune transcriptomes of highly exposed SARS-CoV-2 asymptomatic seropositive versus seronegative individuals from the Ischgl community. Res Sq [Preprint] 2020 Sep 23:rs.3.rs-69657. doi: 10.21203/rs.3.rs-69657/vl. Update in: Sci Rep. 2021 Feb 19; 11(1):4243. PMID: 32995765; PMC ID: PMC7523134.
2. Methods
The raw data is based on a study from Ischgl with the primary goal to detect how many infected and non-infected inhabitants have developed antibodies. The main groups Seronegative, Seropositive, Negative, not exposed as controls were classified and each eukaryotic initiation and elongation factor was compared between the groups using the R function wilcox.test, called from a C# script via RDotNet. The Wilcoxon test is a non-parametric, robust test not depending on normal distributions. Each translation factor with a p-value below 0.05 was considered significant.
The sequencing data combined with clinical data contains the following groups:
1 - Highly exposed, no symptoms, no antibodies (52 individuals)
2 - Negative, no symptoms, no antibodies (5 individuals)
3 - Asymptomatic, antibodies (41 individuals) 4 - Mild symptoms (4 individuals)
No one had severe symptoms.
For each eukaryotic initiation and elongation factor, the distribution of the raw counts of each group was compared against the distribution of the raw counts of each other group (healthy, mild, moderate, severe) to find significantly differently expressed translation factors between each paired group using Wilcox. test.
The Ischgl cohort dataset was combined with the GEO dataset GSE152418 containing samples from 34 patients/individuals, available under https://www.ncbi.nlm.nih. 52418 (Arunachalam PS,
Figure imgf000045_0001
Wimmers F, Mok CKP, Perera RAPM et al. Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans. Science 2020 Sep 4;369(6508): 1210-1220. PMID: 32788292).
The ENSEMBL- Annotation in the matrix file was replaced by the HUGO symbol, obtained from BioMart https://www.ensembl.org/biomart/martview/ (Kinsella RJ, Kahari A, Haider S, Zamora J, Proctor G, Spudich G, Almeida-King J, Staines D, Derwent P, Kerhornou A, Kersey P, Flicek P. Ensembl BioMarts: a hub for data retrieval across taxonomic space. Database (Oxford). 2011 Jul 23;2011:bar030. doi: 10.1093/database/bar030. PMID: 21785142; PMCID: PMC3 170168).
The GSE152418 dataset contains the following groups:
Moderate (4 individuals)
Severe (8 patients + 4 Intensive Care Unit patients)
Healthy (17 individuals)
Healthy people were without an exposure to SARS-CoV-2.
Both datasets contain the unit Raw Counts.
Based on the aggregated data 4 groups were created:
Healthy (17 individuals + 52 exposed, but negative without symptoms and without antibodies + 5 negative control)
Mild (4 individuals)
Moderate (4 individuals) Severe (12 individuals)
For each eukaryotic initiation and elongation factor, the arithmetic means of the raw counts from the Ischgl cohort and the GEO dataset was calculated for the groups healthy, mild, moderate and severe (Figure 2).
3. Results
The following eukaryotic initiation factors (elFs) were identified as being (significantly) deregulated between the different forms of COVID-19 (mild, moderate, and/or severe) and also between healthy and the different forms of COVID-19 (mild, moderate, and severe): elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, and eIF2B5.
The following eukaryotic elongation factors (eEFs) were identified as being (significantly) deregulated between the different forms of COVID-19 (mild, moderate, and/or severe) and also between healthy and the different forms of COVID-19 (mild, moderate, and severe): eEFlAl, eEFIG, eEF2, eEFID, and eEFlB2.
The above-mentioned elFs and eEFs are summarized in the following Table 1:
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Table 1: elFs and eEFs identified as being deregulated between the different forms of COVID- 19 (mild, moderate, and/or severe) and also between healthy and the different forms of COVID- 19 (mild, moderate, and/or severe).
The following elFs as well as eEFs were identified as allowing to distinguish between a mild and a moderate or severe form of COVID-19: elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B5, eIF3C, eEFlAl, eEFIG, eEF2, eEFID, and eEF!B2 (see also Figure 2).
The following elFs were identified as allowing to distinguish between a moderate and a severe form of COVID-19: e!FlAX, e!Fl, eIF5, eIF5B, and eIF3C (see also Figure 2).
The following Table 2 shows the elFs and eEFs which were significantly deregulated between a mild and moderate form of COVID-19:
Figure imgf000049_0002
Figure imgf000050_0001
Table 2: elFs and eEFs which were significantly deregulated between a mild and moderate form of COVID-19
The following Table 3 shows the elFs and eEFs which were significantly deregulated between a mild and severe form of COVID-19:
Figure imgf000050_0002
Table 3: elFs and eEFs which were significantly deregulated between a mild and severe form of COVID-19 The elFs EIFl AX, EIF1 AY, and EIF5B were also significantly deregulated between a moderate and severe form of COVID-19.
It was further found that EIF3L, EIF4B, and EEF1A1 are significantly deregulated between healthy and a severe or moderate form of COVID-19, EIF4H is significantly deregulated between healthy and a moderate form of COVID-19, and EIF2B4 and EIF3B are significantly deregulated between healthy and a mild form of COVID-19.
The data are summarized in the following Table 4:
Figure imgf000051_0001
Table 4: elFs and eEFs which were significantly deregulated between healthy and a mild, moderate or severe form of COVID-19.
The above mentioned elFs and eEFs are, thus, biomarkers allowing to prognose the severity of Coronavirus disease 2019 (COVID-19) in a patient. They also allow to monitor the course of Coronavirus disease 2019 (COVID-19) in a patient. The determination of the treatment response is also possible with these markers.
EXAMPLE 2
1. Materials
The data is based on the published GEO dataset GSE190680 with additional, not published clinical information from the principal investigator regarding the Coronavirus disease 2019 (COVID-19) disease course.
2. Methods
The dataset GSE190680 containing mRNA expression values was used. Groups were built based on additional clinicopathological information regarding the course severity. The expressions of the categories 'mild', 'moderate' and 'critically severe' were compared with each other using Wilcox.test for significant distribution differences p-values below 0.05 were considered as significant.
Another comparison combined 'moderate' and 'severe' to ' severe'. Severe was compared to ' mild' the group that only contains 'mild'.
The bars show the expression values per gene depending on the severity course.
3. Results
In this new study, the following new biomarkers were identified as allowing to prognose the severity of Coronavirus disease 2019 (COVID-19) in a patient, to monitor the course of Coronavirus disease 2019 (COVID-19) in a patient, and to allow to determine the treatment response of Coronavirus disease 2019 (COVID-19) of a patient: eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3 J, and eIF4E (see Figures 3 to 5 as well as Tables 5 and 6 below).
The biomarkers shown in Table 5 and Figure 4 were significantly deregulated between a MILD and SEVERE form of COVID-19. These markers allow to prognose whether the patient will (likely) develop a MODERATE/SEVERE Coronavirus disease 2019 (COVID-19). They also allow to monitor the course of Coronavirus disease 2019 (COVID-19) in a patient. The determination of the treatment response is also possible with these biomarkers.
Figure imgf000052_0001
Table 5: elFs which were significantly deregulated between a MILD and SEVERE form of COVID-19.
The biomarkers shown in Table 6 and in Figure 5 were significantly deregulated between a MODERATE and SEVERE form of COVID-19. These markers allow to prognose whether the patient will (likely) develop a SEVERE Coronavirus disease 2019 (COVID-19). They also allow to monitor the course of Coronavirus disease 2019 (COVID-19) in a patient. The determination of the treatment response is also possible with these biomarkers.
Figure imgf000052_0002
Figure imgf000053_0001
Table 6: elFs, MRRF, and ABCEl which were significantly deregulated between a MODERATE and SEVERE form of COVID-19.
Due to the fact that new patient data were available, a deregulation of the following biomarkers between MODERATE Coronavirus disease 2019 (COVID-19) and SEVERE Coronavirus disease 2019 (COVID-19) disease could now be detected: EEF1A1, EEF1B2, EEF1G, EIF2A, EIF2S3, EIF3H, EIF3L, EIF4B, (see Figures 2 and 3). See also Table 6 and Figure 5. These biomarkers allow to prognose whether the patient will (likely) develop a MODERATE Coronavirus disease 2019 (COVID-19) or a SEVERE Coronavirus disease 2019 (COVID-19). They also allow to monitor the course of Coronavirus disease 2019 (COVID-19) in a patient. The determination of the treatment response is also possible with these markers. Because of the gradual decrease of the level of these biomarkers from MILD to MODERATE Coronavirus disease 2019 (COVID-19) and from MODERATE to SEVERE Coronavirus disease 2019 (COVID-19), said biomarkers are best suited for the monitoring of Coronavirus disease 2019 (COVID-19) in a patient.

Claims

1. A method of monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19 comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF), the level of at least one eukaryotic Elongation Factor (eEF), the level of Mitochondrial Ribosome Recycling Factor (MRRF), and/or the level of ATP -binding cassette sub-family E member 1 (ABCE1) in a biological sample from a patient suffering from COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2.
2. The method of claim 1, wherein the level of the at least one elF is compared to a reference level of said at least one elF, the level of the at least one eEF is compared to a reference level of said at least one eEF, the level of MRRF is compared to a reference level of said MRRF, and/or the level of ABCEl is compared to a reference level of said ABCEl.
3. The method of claim 2, wherein the reference level is the level determined by measuring one or more reference biological samples from one or more subjects having a mild form of COVID-19.
4. The method of claim 3, wherein
(i) the level of the at least one elF selected from the group consisting of elFl AX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3D, eIF3H, eIF3I, eIF2S3, and eIF2B5 below the reference level indicates that COVID-19 is worsening in the patient,
(ii) the level of the at least one elF selected from the group consisting of elFl AX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3D, eIF3H, eIF3I, eIF2S3, and eIF2B5 above the reference level indicates that COVID-19 is improving in the patient, (iii) the level of the at least one elF selected from the group consisting of elFl AX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3D, eIF3H, eIF3I, eIF2S3, and eIF2B5 comparable with the reference level indicates that COVID-19 is stable/not progressing in the patient,
(iv) the level of the at least one elF selected from the group consisting of eIF3C, eIF4E, and eIF2S2 above the reference level indicates that COVID-19 is worsening in the patient,
(v) the level of the at least one elF selected from the group consisting of eIF3C, eIF4E, and eIF2S2 comparable with the reference level indicates that COVID- 19 is stable/not progressing in the patient,
(vi) the level of the at least one eEF selected from the group consisting of eEFl Al, eEFIG, eEF2, eEF ID, and eEFlB2 below the reference level indicates that COVID-19 is worsening in the patient,
(vii) the level of the at least one eEF selected from the group consisting of eEFl Al, eEFIG, eEF2, eEF ID, and eEFlB2 above the reference level indicates that COVID-19 is improving in the patient, and/or
(viii) the level of the at least one eEF selected from the group consisting of eEFl Al, eEFIG, eEF2, eEF ID, and eEFlB2 comparable with the reference level indicates that COVID-19 is stable/not progressing in the patient.
5. The method of any one of claims 2 to 4, wherein the reference level is the level determined by measuring one or more reference biological samples from one or more subjects having a moderate form of COVID-19.
6. The method of claim 5, wherein
(i) the level of the at least one elF selected from the group consisting of elFl AX, elFl, eIF2A, eIF2B2, eIF2B3, eIF2B4, eIF2B5, eIF2Sl, eIF2S3, eIF3H, eIF3J, eIF3L, eIF4B, eIF3M, eIF5, and eIF5B below the reference level indicates that COVID-19 is worsening in the patient,
(ii) the level of the at least one elF selected from the group consisting of elFl AX, elFl, eIF2A, eIF2B4, eIF2B5, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, and eIF5B above the reference level indicates that COVID-19 is improving in the patient, (iii) the level of the at least one elF selected from the group consisting of elFl AX, elFl, eIF2A, eIF2B2, eIF2B3, eIF2B4, eIF2B5, eIF2Sl, eIF2S3, eIF3H, eIF3J, eIF3L, eIF4B, eIF3M, eIF5, and eIF5B comparable with the reference level indicates that COVID-19 is stable/not progressing in the patient,
(iv) the level of eIF3C above the reference level indicates that COVID-19 is worsening in the patient,
(v) the level of eIF3C below the reference level indicates that COVID-19 is improving in the patient,
(vi) the level of eIF3C comparable with the reference level indicates that COVID-19 is stable/not progressing in the patient,
(vii) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 below the reference level indicates that COVID-19 is worsening in the patient,
(viii) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 above the reference level indicates that COVID-19 is improving in the patient,
(ix) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 comparable with the reference level indicates that COVID- 19 is stable/not progressing in the patient,
(x) the level of MRRF below the reference level indicates that COVID-19 is worsening in the patient,
(xi) the level of MRRF comparable with the reference level indicates that COVID- 19 is stable/not progressing in the patient,
(xii) the level of ABCEl below the reference level indicates that COVID-19 is worsening in the patient, and/or
(xiii) the level of ABCEl comparable with the reference level indicates that COVID- 19 is stable/not progressing in the patient.
7. The method of any one of claims 2 to 6, wherein the reference level is the level determined by measuring one or more reference biological samples from one or more subjects having a severe form of COVID-19.
8 The method of claim 7, wherein (i) the level of the at least one elF selected from the group consisting of elFl AX, elFl, eIF2A, eIF2B2, eIF2B3, eIF2B4, eIF2B5, eIF2Sl, eIF2S3, eIF3H, eIF3J, eIF3L, eIF4B, eIF3M, eIF5, and eIF5B above the reference level indicates that COVID-19 is improving in the patient,
(ii) the level of the at least one elF selected from the group consisting of elFl AX, elFl, eIF2A, eIF2B2, eIF2B3, eIF2B4, eIF2B5, eIF2Sl, eIF2S3, eIF3H, eIF3J, eIF3L, eIF4B, eIF3M, eIF5, and eIF5B comparable with the reference level indicates that COVID-19 is stable in the patient,
(iii) the level of eIF3C below the reference level indicates that COVID-19 is improving in the patient,
(iv) the level of eIF3C comparable with the reference level indicates that COVID-19 is stable in the patient,
(v) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 above the reference level indicates that COVID-19 is improving in the patient,
(vi) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 comparable with the reference level indicates that COVID- 19 is stable in the patient,
(vii) the level of MRRF above the reference level indicates that COVID-19 is improving in the patient,
(viii) the level of MRRF comparable with the reference level indicates that COVID- 19 is stable in the patient,
(ix) the level of ABCEl above the reference level indicates that COVID-19 is improving in the patient, and/or
(x) the level of ABCEl comparable with the reference level indicates that COVID- 19 is stable in the patient.
9. The method of any one of claims 1 to 8, wherein said determining comprises determining the level of the at least one elF, the level of the at least one eEF, the level of MRRF, and/or the level of ABCEl in a biological sample at a first point in time and in at least one further biological sample at a later point in time and comparing said levels determined at the different time points.
10. The method of claim 9, wherein (i) the level of the at least one elF selected from the group consisting of elFl AX, elFl, eIF2A, eIF2B4, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B which decreases over time indicates that COVID-19 is worsening in the patient,
(ii) the level of the at least one elF selected from the group consisting of elFl AX, elFl, eIF2A, eIF2B4, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B which increases over time indicates that COVID-19 is improving in the patient,
(iii) the level of the at least one elF selected from the group consisting of elFl AX, elFl, eIF2A, eIF2B4, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B which does not change over time indicates that COVID-19 is stable/not progressing in the patient,
(iv) the level of eIF3C which increases over time indicates that COVID-19 is worsening in the patient,
(v) the level of eIF3C which decreases over time indicates that COVID-19 is improving in the patient,
(vi) the level of eIF3C which does not change over time indicates that COVID-19 is stable/not progressing in the patient,
(vii) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 which decreases over time indicates that COVID-19 is worsening in the patient,
(viii) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 which increases over time indicates that COVID-19 is improving in the patient, and/or
(ix) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 which does not change over time indicates that COVID-19 is stable/not progressing in the patient.
11. The method of any one of claims 1 to 10, wherein the patient will receive, receives, has received, or had received a treatment of COVID-19.
12. A method of prognosing the severity of Coronavirus disease 2019 (COVID-19) in a patient comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF), the level of at least one eukaryotic Elongation Factor (eEF), the level of Mitochondrial Ribosome Recycling Factor (MRRF), and/or the level of ATP -binding cassette sub-family E member 1 (ABCE1) in a biological sample from a patient, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2.
13. The method of claim 12, wherein the level of at least one elF is compared to a reference level of said at least one elF, the level of at least one eEF is compared to a reference level of said at least one eEF, the level of MRRF is compared to a reference level of said MRRF, and/or the level of ABCEl is compared to a reference level of said ABCEl.
14. The method of claim 13, wherein the reference level is the level determined by measuring one or more reference biological samples from one or more subjects having a mild form of COVID-19.
15. The method of claim 14, wherein
(i) the level of the at least one elF selected from the group consisting of elFl AX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3D, eIF3H, eIF3I, eIF2S3, and eIF2B5 below the reference level indicates that the patient will (likely) develop a moderate or severe form of COVID-19,
(ii) the level of the at least one elF selected from the group consisting of eIF3C, eIF4E, and eIF2S2 above the reference level indicates that the patient will (likely) develop a moderate or severe form of COVID-19, and/or
(iii) the level of the at least one eEF selected from the group consisting of eEFl Al, eEFIG, eEF2, eEF ID, and eEFlB2 below the reference level indicates that the patient will (likely) develop a moderate or severe form of COVID-19.
16. The method of any one of claims 13 to 15, wherein the reference level is the level determined by measuring one or more reference biological samples from one or more subjects having a moderate form of COVID-19.
17. The method of claim 16, wherein
(i) the level of the at least one elF selected from the group consisting of elFl AX, elFl, eIF2A, eIF2B2, eIF2B3, eIF2B4, eIF2Sl, eIF2S3, eIF3H, eIF3J, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B below the reference level indicates that the patient will (likely) develop a severe form of COVID-19,
(ii) the level of the at least one elF selected from the group consisting of elFlAY and eIF3C above the reference level indicates that the patient will (likely) develop a severe form of COVID-19,
(iii) the level of the at least one eEF selected from the group consisting of eEFlAl, eEFIG, and eEFlB2 below the reference level indicates that the patient will (likely) develop a severe form of COVID-19,
(iv) the level of MRRF below the reference level indicates that the patient will (likely) develop a severe form of COVID-19, and/or
(v) the level of ABCEl below the reference level indicates that the patient will (likely) develop a severe form of COVID-19.
18. A method of determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19 comprising the step of: determining the level of at least one eukaryotic Initiation Factor (elF), the level of at least one eukaryotic Elongation Factor (eEF), the level of Mitochondrial Ribosome Recycling Factor (MRRF), and/or the level of ATP -binding cassette sub-family E member 1 (ABCEl) in a biological sample from a patient suffering from COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2.
19. The method of claim 18, wherein the patient is a patient to whom at least once a drug to be used in said therapeutic treatment, and/or another form of therapeutic treatment is administered, has been administered, or had been administered.
20. The method of claims 18 or 19, wherein the biological sample is from the patient after at least the first administration of said drug and/or administration of another form of therapeutic treatment.
21. The method of any one of claims 18 to 20, wherein the level of at least one elF is compared to a reference level of said at least one elF, the level of at least one eEF is compared to a reference level of said at least one eEF, the level of MRRF is compared to a reference level of said MRRF, and/or the level of ABCE1 is compared to a reference level of said ABCE1.
22. The method of claim 21, wherein the reference level is the level determined in a reference biological sample from the (same) patient prior to the administration of said drug, and/or administration of another form of therapeutic treatment.
23. The method of claim 22, wherein
(i) the level of the at least one elF selected from the group consisting of elFl AX, elFl, eIF2A, eIF2B4, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, and eIF5B above the reference level indicates that the patient responds to said treatment of COVID-19,
(ii) the level of the at least one elF selected from the group consisting of elFlAY and eIF3C below the reference level indicates that the patient responds to said treatment of COVID-19, and/or
(iii) the level of the at least one eEF selected from the group consisting of eEFlAl, eEF 1 G, and eEF 1B2 above the reference level indicates that the patient responds to said treatment of COVID-19.
24. The method of any one of claims 21 to 23, wherein the reference level is the level determined by measuring one or more reference biological samples from one or more subjects having a mild form of COVID-19.
25. The method of claim 24, wherein
(i) the level of the at least one elF selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3D, eIF3H, eIF3I, eIF2S3, and eIF2B5 above the reference level indicates that the patient responds to said treatment of COVID- 19, and/or
(ii) the level of the at least one eEF selected from the group consisting of eEFl Al, eEFIG, eEF2, eEF ID, and eEFlB2 above the reference level indicates that the patient responds to said treatment of COVID-19.
26. The method of any one of claims 21 to 25, wherein the reference level is the level determined by measuring one or more reference biological samples from one or more subjects having a moderate form of COVID-19.
27. The method of claim 26, wherein
(i) the level of the at least one elF selected from the group consisting of elFlAX, elFl, eIF2A, eIF2B4, eIF2S3, eIF3H, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B above the reference level indicates that the patient responds to said treatment of COVID-19,
(ii) the level of the at least one elF selected from the group consisting of eIF3C, eIF4E, and eIF2S2 below the reference level indicates that the patient responds to said treatment of COVID-19, and/or
(iii) the level of the at least one eEF selected from the group consisting of eEFlAl, eEF 1 G, and eEF 1B2 above the reference level indicates that the patient responds to said treatment of COVID-19.
28. The method of any one of claims 21 to 27, wherein the reference level is the level determined by measuring one or more reference biological samples from one or more subjects having a severe form of COVID-19.
29. The method of claim 28, wherein
(i) the level of the at least one elF selected from the group consisting of elFlAX, elFl, eIF2A, eIF2B2, eIF2B3, eIF2B4, eIF2Sl, eIF2S3, eIF3H, eIF3J, eIF3L, eIF4B, eIF3M, eIF5, eIF2B5, and eIF5B above the reference level indicates that the patient responds to said treatment of COVID-19,
(ii) the level of eIF3C below the reference level indicates that the patient responds to said treatment of COVID-19,
(iii) the level of the at least one eEF selected from the group consisting of eEFlAl, eEF 1 G, and eEF 1B2 above the reference level indicates that the patient responds to said treatment of COVID-19,
(iv) the level of MRRF above the reference level indicates that the patient responds to said treatment of COVID-19, and/or
(v) the level of ABCEl above the reference level indicates that the patient responds to said treatment of COVID-19.
30. The method of any one of claims 19 to 29, wherein the drug is selected from the group consisting of an antiviral drug, an antibacterial drug, an anti-inflammatory drug, an antifungal drug, and an antipyretic agent.
31. The method of claim 30, wherein the antiviral drug is selected from the group consisting of chloroquine, remdesivir, darunavir, favipiravir, lopinavir, and ritonavir, or is a combination thereof, the antibacterial drug is selected from the group consisting of ceftriaxone, amoxicillin/clavulanic acid, piperacillin/tazobactam, and azithromycin, or is a combination thereof, the anti-inflammatory drug is selected from the group consisting of ibuprofen and metamizole, the antifungal drug is selected from the group consisting of voriconazole and isavuconazole, or the antipyretic agent is paracetamol.
32. The method of any one of claims 19 to 31, wherein the other form of therapeutic treatment is ventilation.
33. The method of claim 32, wherein the ventilation is selected from the group consisting of non-invasive ventilation and invasive ventilation.
34. The method of claim 33, wherein the non-invasive ventilation is carried out through a face mask, nasal mask, or a helmet, or the invasive ventilation is a mechanic ventilation carried out through a positive pressure ventilator or negative pressure ventilator.
35. The method of any one of claims 1 to 34, wherein COVID-19 is associated with an acute infectious lung disease/acute respiratory syndrome.
36. The method of any one of claims 1 to 35, wherein the patient is a mammal, preferably a human.
37. The method of any one of claims 1 to 36, wherein the biological sample is selected from the group consisting of a body fluid sample, a body tissue sample, and a body gas sample.
38. The method of claim 37, wherein
(i) the body fluid sample is selected from the group consisting of blood, cerebrospinal fluid (CSF), urine, sputum, breast milk, cerumen (earwax), endolymph fluid, perilymph fluid, pleural fluid, peritoneal fluid, gastric juice, mucus, saliva, semen, sweat, cheek swab, tears, and liquid biopsy,
(ii) the body tissue sample is selected from the group consisting of skin flake, skin biopsy, hair follicle, biopsy tissue, tissue explant, and tissue section, or
(iii) the body gas sample is selected from the group consisting of exhaled condensate and exhaled gas.
39. The method of claim 38, wherein the blood sample is whole blood or a blood fraction.
40. The method of claim 39, wherein the blood fraction is selected from the group consisting of a blood cell fraction, blood serum, and blood plasma.
41. The method of claim 40, wherein the blood cell fraction is a fraction of erythrocytes, leukocytes, or thrombocyte.
42. Use of at least one eukaryotic Initiation Factor (elF), at least one eukaryotic Elongation Factor (eEF), Mitochondrial Ribosome Recycling Factor (MRRF), and/or ATP -binding cassette sub-family E member 1 (ABCE1) for monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19, for prognosing the severity of Coronavirus disease 2019 (COVID-19), or for determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2.
43. A kit for monitoring the course of Coronavirus disease 2019 (COVID-19) in a patient suffering from COVID-19, for prognosing the severity of Coronavirus disease 2019 (COVID-19), or for determining whether a patient suffering from Coronavirus disease 2019 (COVID-19) responds to a therapeutic treatment of COVID-19, wherein the kit comprises means for determining the level of at least one eukaryotic Initiation Factor (elF), the level of at least one eukaryotic Elongation Factor (eEF), the level of Mitochondrial Ribosome Recycling Factor (MRRF), and/or the level of ATP -binding cassette sub family E member 1 (ABCEl) in a biological sample from an individual, wherein the at least one elF is selected from the group consisting of elFlAX, eIF4B, eIF4H, eIF2B4, eIF3B, eIF3L, elFlAY, eIF3M, eIF4Gl, eIF5A, elFl, eIF5, eIF5B, eIF2A, eIF3A, eIF3C, eIF3D, eIF3H, eIF3I, eIF2S3, eIF2B2, eIF2B3, eIF2Sl, eIF2S2, eIF3J, eIF4E, and eIF2B5, and wherein the at least one eEF is selected from the group consisting of eEFlAl, eEFIG, eEF2, eEF ID, and eEFlB2.
44. The kit of claim 43, wherein the kit is useful for conducting the methods of claims 1 to
41.
45. The kit of claims 43 or 44, wherein the kit further comprises
(i) a container, and/or
(ii) a data carrier.
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