In one embodiment, the sample is selected from the group consisting of a blood sample, such as a whole blood sample, a serum sample or a plasma sample, and/or a urine sample.

In one embodiment, the level of proADM or fragment(s) thereof is determined in a sample obtained by the first medical personnel to consult with the patient after occurrence of the symptoms of SARS or of infection with a SARS-virus.

In one embodiment, the patient is infected with a SARS-coronavirus and shows mild or no symptoms of SARS or of infection with a SARS-virus.

For example, the method may be employed in combination with testing for the presence of a SARS-virus, such as a coronavirus, independent of whether symptoms are evident.

In one embodiment, the method comprises:

- providing a sample from said patient, and
- determining a level of proADM or fragment(s) thereof in said sample,
- wherein a low risk level of proADM level or fragment(s) thereof in said sample indicates that the patient is not at risk of disease progression to a condition that requires intensified treatment and/or disease monitoring, and/or
- wherein a high risk level of proADM level or fragment(s) thereof in said sample indicates that the patient is at risk of disease progression to a condition that requires intensified treatment and/or disease monitoring.

In one embodiment, a low risk level of proADM level or fragment(s) thereof in said sample indicates that the patient is not at risk of a disease progression to a condition that requires hospitalization, and/or wherein a high risk level of proADM level or fragment(s) thereof in said sample indicates that the patient is at risk of a disease progression to a condition that requires hospitalization.

In one embodiment, a low risk level of proADM level or fragment(s) thereof in said sample indicates that the patient is not at risk of a disease progression to a condition that requires treatment and/or disease monitoring on an ICU, and/or wherein a high risk level of proADM level or fragment(s) thereof in said sample indicates that the patient is at risk of a disease progression to a condition that requires treatment and/or disease monitoring on an ICU.

In one embodiment, a low risk level of proADM level or fragment(s) thereof in said sample indicates that the patient is not at risk of a disease progression to a condition that requires oxygen support, invasive mechanical ventilation, or non-invasive mechanical ventilation, and/or wherein a high risk level of proADM level or fragment(s) thereof in said sample indicates that the patient is at risk of a disease progression to a condition that requires oxygen support, invasive mechanical ventilation, or non-invasive mechanical ventilation.

In embodiments, a low risk level of proADM level or fragment(s) thereof in said sample indicates that the patient is not at risk of a disease progression to a condition that requires oxygen support, invasive mechanical ventilation, or non-invasive mechanical ventilation immediately after determining the level of proADM or fragment(s) thereof, or within 30 minutes, 1 hour, 2, 3, 4, 5, 6, 8, 12, 16, 20, 24 hours or within 2, 3, 4, 5, 6, 7, 10, 14, 17, 21, 24, or 28 days, or during the hospital stay; and/or wherein a high risk level of proADM level or fragment(s) thereof in said sample indicates that the patient is at risk of a disease progression to a condition that requires oxygen support, invasive mechanical ventilation, or non-invasive mechanical ventilation immediately after determining the level of proADM or fragment(s) thereof, or within 30 minutes, 1 hour, 2, 3, 4, 5, 6, 8, 12, 16, 20, 24 hours or within 2, 3, 4, 5, 6, 7, 10, 14, 17, 21, 24, or 28 days or during the hospital stay

In one embodiment, the low risk level is equal or below 0.87 nmol/l±20%, and/or wherein said high risk level is above 0.87 nmol/l±20%.

It represents a surprising finding that a cut-off value of proADM of or above 0.87 nmol/l±20% (preferably using an immunoassay for MR-proADM) enables a reliable indication that a patient is likely to experience worsening of their condition (such as a SARS-coronavirus infection), such that intensifying treatment and/or disease monitoring and/or hospitalization is necessary.

As such, the prognostic statements described herein appear to represent a surprising and beneficial finding in the field of SARS prognosis and patient management in a primary care and/or hospital setting.

In one embodiment, the low risk level is equal or below 0.93 nmol/l±20%, and/or wherein said high risk level is above 0.93 nmol/l±20%.

It represents a surprising finding that a cut-off value of proADM of or above 0.93 nmol/l±20% (preferably using an immunoassay for MR-proADM) enables a reliable indication that a patient is likely to experience worsening of their condition (such as a SARS-coronavirus infection), such that intensifying treatment and/or disease monitoring and/or hospitalization is necessary. In some embodiments, a cut-off value of proADM of or above 0.93 nmol/l±20% enables assessment of disease severity, disease progression, risk for in-hospital mortality and also for decisions regarding patient disposition, as patients with values above this cut-off showed increased risk of one or more of disease progression to a serious state, indicating a risk for in-hospital mortality.

In a further embodiment, the low risk level is equal or below 0.75 nmol/l±20%, and/or wherein said high risk level is above 0.75 nmol/l±20%.

In a further embodiment, the low risk level is equal or below 1.5 nmol/l±20%, and/or wherein said high risk level is above 1.5 nmol/l±20%.

In a further embodiment, the low risk level is equal or below 0.75 nmol/l±20%, and/or wherein said high risk level is above 2.5 nmol/l±20%.

In a further embodiment, the low risk level is equal or below 0.75 nmol/l±20%, and/or wherein said high risk level is above 2.5 nmol/l±20%.

Further cut-off values of the present invention, which can be associated with specific time points of sample isolation after occurrence of symptoms, presentation of the patient to medical personnel and/or hospitalization, are disclosed in the examples.

The term “indicates that the patient is, or is not, at risk of disease progression to a condition that requires hospitalization” relates in some embodiments to the prognosis of a worsening of patient condition. In some embodiments, this term relates to a prognosis of whether certain treatments, which are only or primarily available in hospital, are necessary. In some embodiments, this term relates to prognosis of disease outcome.

Although proADM is known to predict disease outcome for some medical conditions, the present invention presents particular cut-off values applicable to a patient that has or is at risk of developing a severe acute respiratory syndrome (SARS) in primary care scenarios in particular patient groups, which would not have been derived from the prior art or suggested previously in the context of predicting potential hospitalization.

In some embodiments, treatments commonly received in hospital relate to treatments excluding topical and/or oral antibiotic administration.

Examples of treatments commonly received in hospital relate further to intravenous administration of antiviral therapies, administration experimental therapies, off-label use of medication and treatments approved for other indications, administration of antibiotics, or other fluid therapy, such as fluid management, fluid resuscitation, fluid replacement and/or fluid redistribution, such as of colloids and/or crystalloids, or blood transfusions.

Other treatments primarily available in hospital are, but are not limited to, renal replacement therapy (RRT), artificial and mechanical ventilation, surgery or cleaning procedures, such as focus cleaning.

The term “hospitalization” refers preferably, in some embodiments, to hospital admission. This differs from being referred to hospital, being assessed, and subsequently released (sent home). Hospital admission refers preferably to maintained control and/or assessment of the medical condition of a patient in the hospital, whether it be in an emergency room, ward, intensive care station, or other area of a hospital or clinic. Admission preferably, in some embodiments, relate to overnight admission of the patient for monitoring.

In embodiments, the method of the invention includes a step of hospitalizing the patient in case a high risk level of proADM has been determined. In embodiments of the invention, hospitalizing the patient refers to admission of the patient to a hospital or clinic or similar medical institution for a maintained control and/or assessment of the medical condition or the health status and/or monitoring of changes of the health state of the patient and/or medical treatment, preferably for several hours, such as more than 5, 6, 7, 8, 9, 10, 11, 12, 15, 18 or 24 hours or longer.

The method of the invention represents a significant and surprising advancement in comparison to known methods of the state of the art. Although determining the level of proADM as a biomarker in sepsis patients has been described, there has been no prior disclosure regarding the use of proADM as a marker in a method for therapy guidance, stratification and/or control in a patient that has or is at risk of developing a severe acute respiratory syndrome (SARS), such as a coronavirus infection or preferably COVID-19 (infection with SARS-CoV2), for deciding whether such a patient requires intensifying treatment and/or disease monitoring and/or hospitalization or not.

In particular, the method of the invention defines a high risk level of proADM or fragment(s) thereof, which is decisive for indicating whether the patient should be hospitalized or not, and which has not been previously disclosed in the context of this decision making process. The present invention is particularly useful for patients with symptoms of SARS or of an infection with a SARS-virus and/or that may not exhibit symptoms of viral pneumonia, pneumonia, sepsis, acute respiratory distress syndrome (ARDS) and/or respiratory failure. The method of the invention is also particularly useful for patients that do not suffer from hematological disorders or other disorders that may affect the immune system and/or the defense of the patients against infections, wherein these patients may for example only display mild symptoms of SARS or of infection with a SARS-virus.

In embodiments, the patient has already been diagnosed with SARS, such as COVID-19.

In embodiments, the patient shows no symptoms of SARS or of an infection with a SARS-virus. In embodiments, the patient is at risk of developing SARS and shows no symptoms of SARS or of an infection with a SARS-virus.

In one embodiment, the level of proADM or fragment(s) thereof is determined in a sample obtained by the first medical personnel to consult with the patient after occurrence of the symptoms of SARS or of infection with a SARS-virus.

In embodiments of the invention the term “first medical personnel to consult with the patient after occurrence of the symptoms of SARS or of infection with a SARS-virus” relates to, but is not limited to, general practitioners (GP), home health care workers or care givers, nurses in residences for retirees, ambulance drivers, or workers, paramedics, doctors making home visits, nurses in community clinics, and the like. The first medical personnel is preferably construed to encompass and medical staff, whether a doctor or other care giver, who first encounters a patient who has developed symptoms of infectious disease, but who has preferably not been diagnosed with a sever illness. In some embodiments, the first medical personnel to encounter a subject is in a hospital, in the admissions area, in the emergency room or emergency department (ED), who are receiving subjects presenting with symptoms of SARS or of infection with a SARS-virus.

It is entirely surprising that based on a single proADM measurement an accurate and reliable conclusion can be made as to whether the patient will go on to develop a SARS of such severity that hospitalization is required, such as viral pneumonia. This prognostic ability of proADM is, to the knowledge of the inventors, novel and surprising.

In one embodiment, the patient is presented in a primary care unit and a high risk level of proADM or fragment(s) thereof indicates that hospitalization of the patient is required, and wherein a low risk level of proADM or fragment(s) indicates that hospitalization of the patient is not required.

In preferred embodiments of the present invention the method is defined by the prognosis of potential hospitalization in a patient group, for whom it was previously difficult, if not impossible, to determine by routine clinical and/or molecular diagnostic means, whether a serious risk existed of serious deterioration of medical conditions, thereby requiring hospitalization. This patient group may be considered patients with mild symptoms of SARS or of infection with a SARS-virus, or patients at risk of developing a SARS.

In one embodiment, at the time of sample provision the patient shows mild symptoms of SARS or infection with a SARS-virus corresponding to a qSOFA score of 0 or 1.

In one embodiment, at the time of sample provision, the patient shows mild symptoms of SARS or infection with a SARS-virus corresponding to a PSI score of ≤90.

In one embodiment, at the time of sample provision the patient shows no clinical symptoms for a blood stream infection, a sepsis, a severe sepsis and/or septic shock in the patient.

In one embodiment, at the time of sample provision the patient shows no clinical symptoms for a bacterial infection of the respiratory tract, pneumonia, respiratory failure, multi-organ failure and/or acute respiratory distress syndrome (ARDS).

It was entirely surprising that patients that only show mild symptoms of SARS or infection with a SARS-virus, such as patients corresponding to a qSOFA score of 0 or 1, and patients that show symptoms of SARS or infection with a SARS-virus that however do not indicate the presence of a blood stream infection, sepsis, bacterial infection of the respiratory tract, pneumonia, respiratory failure, multi-organ failure and/or acute respiratory distress syndrome (ARDS), can be categorized as requiring hospitalization on the basis of determining a high risk level of proADM or fragment(s) according to the present invention.

It was entirely surprising that patients that only show mild symptoms of SARS or infection with a SARS-virus, such as patients corresponding to a PSI score of ≤90, and patients that show symptoms of SARS or infection with a SARS-virus that however do not indicate the presence of a blood stream infection, sepsis, bacterial infection of the respiratory tract, pneumonia, respiratory failure, multi-organ failure and/or acute respiratory distress syndrome (ARDS), can be categorized as requiring hospitalization on the basis of determining a high risk level of proADM or fragment(s) according to the present invention.

This represents a great advantage of the method of the invention, since a specialized physician would not expect that patients with mild symptoms of SARS or of infection with a SARS-virus and/or symptoms that do not hint towards blood stream infection, sepsis, additional bacterial infection of the respiratory tract, pneumonia, respiratory failure, multi-organ failure and/or acute respiratory distress syndrome (ARDS), would require hospitalization, for example to monitor progression of the symptoms of the SARS or of infection with a SARS-virus and perform treatment. Such patients may usually be examined by medical personnel and subsequently released from continuous medical observation, for example with treatment instructions that can be carried out without professional medical supervision. However, the method of the present invention can identify patients, by objective means, who do not exhibit severe symptoms of a SARS or of infection with a SARS-virus and that still do require hospitalization.

On the other hand, for reasons of caution there is a tendency of medical personnel, in particular personnel that is not specialized in the field of SARS or of infection with a SARS-virus, to send patients with symptoms of a SARS or of infection with a SARS-virus and even with mild symptoms that do not indicate blood stream infection, sepsis, additional bacterial infection of the respiratory tract, pneumonia, respiratory failure, multi-organ failure and/or ARDS to the hospital or emergency department, although this may not be required. The method of the invention represents a great advantage since it can provide objective criteria even to unexperienced medical personnel that may not be specialized in SARS or of infection with a SARS-virus to decide whether a patient has to be hospitalized or not. So the rate of unnecessary hospital admissions that are due to overly cautious decision making of the medical personnel observing the patient could be lowered by the aid of the method of the invention. On the other hand, the rate of patients with mild symptoms that are not admitted to the hospital although they would require constant medical observation may be increased.

A preferred cut-off value of 0.87 nmol/L±20% is completely unexpected and surprising and has not been reported in the state of the art for the patient group described herein and for the decision making process of hospitalizing a patient or not. This cut-off is particularly beneficial for deciding to hospitalize patients with mild symptom and patients that are not suspected of progressing to a severe disease state, such as a state requiring mechanical ventilation, since these patients may in many cases be wrongly released from constant medical supervision due to the lack of suitable diagnostic and prognostic tests that support the decision making process.

In one embodiment, the level of proADM or fragment(s) thereof in said sample in between 0.5 nm/L±20% and 0.87 nmol/L±20% indicates the presence of the disease and that the patient is not at risk of a disease progression to a condition that requires a hospitalization.

The range of proADM values from 0.5 nm/L±20% and 0.87 nmol/L±20% is of particular benefit, as healthy patients often have proADM levels from 0.0 to 0.5 nmol/L. In some embodiments, patients with over 1.5 nmol/L also require serious treatment. Therefore, there previously existed a “gray zone” of uncertainty for medical professionals, when ADM values from 0.5 nm/L±20% to 0.87 nmol/L±20% were measured. The present invention however now enables reliable prognostic statement for such patients. In some embodiments, these patients are ruled out from hospitalization, as they do not exhibit a significant risk of progressing to a serious condition requiring hospitalization.

A preferred cut-off value of 0.93 nmol/L±20% is completely unexpected and surprising and has not been reported in the state of the art for the patient group described herein and for the decision making process of hospitalizing a patient or not. This cut-off is particularly beneficial for deciding to hospitalize patients with mild symptom and patients that are not suspected of progressing to a severe disease state, such as a state requiring mechanical ventilation, since these patients may in many cases be wrongly released from constant medical supervision due to the lack of suitable diagnostic and prognostic tests that support the decision making process.

In one embodiment, the level of proADM or fragment(s) thereof in said sample in between 0.5 nm/L±20% and 0.93 nmol/L±20% indicates the presence of the disease and that the patient is not at risk of a disease progression to a condition that requires a hospitalization.

The range of proADM values from 0.5 nm/L±20% and 0.93 nmol/L±20% is of particular benefit, as healthy patients often have proADM levels from 0.0 to 0.5 nmol/L. In some embodiments, patients with over 1.5 nmol/L also require serious treatment. Therefore, there previously existed a “gray zone” of uncertainty for medical professionals, when ADM values from 0.5 nm/L±20% to 0.93 nmol/L±20% were measured. The present invention however now enables reliable prognostic statement for such patients. In some embodiments, these patients are ruled out from hospitalization, as they do not exhibit a significant risk of progressing to a serious condition requiring hospitalization.

In one embodiment, a high risk level of proADM or fragments thereof indicates that the patient is at risk of disease progression to a life-threatening condition within 28 days, 72 hours, 48 hours, 24 hours, preferably 12 hours and wherein a low risk level of proADM indicates that the patient is not at risk of disease progression to a life-threating condition within 28 days 72 hours, 48 hours, 24 hours, preferably 12 hours.

In one embodiment, a high risk level of proADM or fragments thereof indicates that the patient is at risk of disease progression to a life-threatening condition within 21 days, 14 days, 7 days, 5 days, or 4 days, and a low risk level of proADM indicates that the patient is not at risk of disease progression to a life-threating condition within 21 days, 14 days, 7 days, 5 days, or 4 days.

In a preferred embodiment, a high risk level of proADM or fragments thereof indicates that the patient is at risk of disease progression to a life-threatening condition within 7 days, and a low risk level of proADM indicates that the patient is not at risk of disease progression to a life-threating condition within 7 days.

In embodiments, a high risk level of proADM or fragment(s) thereof in said sample, preferably a high risk level of over 1.5 nmol/L, indicates that the patient is at risk of a disease progression to a condition that requires hospitalization and/or treatment and/or disease monitoring on an ICU and/or of an adverse event. In embodiments, a high risk level of proADM or fragment(s) thereof in said sample, preferably a high risk level of over 1.5 nmol/L, indicates the occurrence of an adverse event, such as death, in particular death within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 21, 24, or 28 days, preferably 7 or 28 days. In embodiments, a low risk level of proADM or fragment(s) thereof in said sample, preferably a low risk level of 1.5 nmol/L or below, indicates the absence of an adverse event, such as death, in particular death within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 21, 24, or 28 days, preferably 7 or 28 days.

In one embodiment, the level of proADM or fragment(s) thereof in said sample is indicative of the risk of a development of a systemic inflammatory response (SIRS), coagulation disorders, blood stream infection, sepsis, severe sepsis and/or septic shock in the patient that requires hospitalization.

In one embodiment, the level of proADM or fragment(s) thereof in said sample is indicative of the risk of a development of a bacterial infection of the respiratory tract, pneumonia, respiratory failure, multi-organ failure and/or ARDS.

In one embodiment, a high risk level of proADM thereof indicates that the patient is at risk to develop a systemic inflammatory response (SIRS), coagulation disorders, blood stream infection, sepsis, severe sepsis and/or septic shock that requires hospitalization within 72 hours, 48 hours, 24 hours, preferably 12 hours and wherein a low risk level of proADM indicates that the patient is not at risk to develop blood stream infection, a sepsis, a severe sepsis and/or a septic shock within 48 hours, 24 hours, preferably 12 hours.

In one embodiment, a high risk level of proADM thereof indicates that the patient is at risk to develop a pathogenesis of a viral infection of the respiratory tract comprising pneumonia, respiratory failure, multi-organ failure and/or ARDS that requires hospitalization within 72 hours, 48 hours, 24 hours, 12 hours or immediate and wherein a low risk level of proADM indicates that the patient is not at risk to develop a bacterial infection of the respiratory tract, pneumonia, respiratory failure, multi-organ failure and/or ARDS within 72 hours, 48 hours, 24 hours, preferably 12 hours or immediate.

In one embodiment, the level of proADM or fragment(s) thereof in said sample is indicative of the patient requiring frequent monitoring and/or critical care treatment. In one embodiment, the patient with a high risk level will require a medical treatment provided in a hospital setting. Examples of these treatments include but are not limited to fluid therapy, intravenous antibiotics, mechanical ventilation, experimental therapy, off-label administration of pharmaceutical compositions, antiviral therapy, in some embodiments essentially any treatment beyond oral antibiotics, which may be self-administered at home.

In one embodiment, the method additionally comprises:

- determining at least one clinical score, such as NEWS, SOFA, qSOFA, CRB-65, PSI and/or APACHE II score, for the patient suspected of having an infectious disease,
- wherein the at least one clinical score and the level of proADM or fragment(s) thereof is indicative of the presence of the SARS or of infection with a SARS-virus, such as virus-induced pneumonia, and whether the patient is at risk of a disease progression to a condition that requires a hospitalization.

In one embodiment, determining a level of proADM or fragment(s) thereof comprises determining a level of MR-proADM in the sample. As demonstrated in the examples below, MR-proADM, preferably determined using established immunoassay products of B.R.A.H.M.S (Hennigsdorf, Germany), shows a reliable and effective prognosis according to the methods described herein. Alternative ADM molecules, including precursors or fragments, may also be employed.

In one embodiment, the sample is selected from the group consisting of a blood sample, such as a whole blood sample, a serum sample or a plasma sample, and/or a urine sample.

In one embodiment, the sample is isolated from the patients within 24 hours, 6 hours, 2 hours, 1 hour, more preferably within 30 minutes or 15 minutes after the symptoms have been determined.

In embodiments, the sample is isolated from the patient within 24 h (1 day), 2 days, 3, days, 4 days, 5 days, 6 days, 7 days, 8 days 9 days or 10 days after the symptoms have been determined and/or the time point of presentation to medical personnel and/or the time point of hospitalization.

Surprisingly, the preferred cut-off levels of 0.75, 0.87, 1.5, 2.25 and 2.5 nmol/l can be used at different time points after occurrence of symptoms and/or presentation to medical personnel and/or hospitalization for the prognosis of disease progression. These preferred cut-of levels are associated with advantageous sensitivity and specificity, depending on the specific application of the method of the invention.

In one embodiment, the method additionally comprises determining a level of at least one additional biomarker or fragment(s) thereof in a sample from said patient. Preferably, the level of the at least one additional biomarker is indicative of an initiation of treatment with an anti-infective agent, preferably an anti-viral agent and/or an antibiotic or antimitotic agent.

In one embodiment, the method additionally comprises:

- a. determining a level of at least one additional biomarker or fragment(s) thereof in a sample from said patient, wherein the at least one additional biomarker preferably is PCT or fragment(s) thereof, and
- b. wherein the level of the at least one additional biomarker is indicative of an initiation of treatment with an anti-infective agent, preferably an anti-viral agent and/or an antibiotic or antimitotic agent.

In one embodiment, at least one additional biomarker is PCT or fragment(s) thereof and a level of PCT or fragment(s) thereof above 0.25 ng/ml, preferably above 0.5 ng/ml is indicative of an bacterial infection or sepsis and indicates an initiation of a treatment with an anti-infective agent, preferably an antibiotic or antimitotic agent.

In one embodiment, at least one additional biomarker is PCT or fragment(s) thereof and a level of PCT or fragment(s) thereof below 0.25 ng/ml is indicative of a bacterial infection or sepsis and indicates an initiation of a treatment with an anti-infective agent, preferably an antibiotic or antimitotic agent, is not needed.

In one embodiment, at least one additional biomarker is PCT or fragment(s) thereof and a level of PCT or fragment(s) thereof below 0.1 ng/ml is indicative of the absence of a bacterial infection.

As demonstrated in more detail below, the combined measurement of additional biomarkers, in particular PCT, or other or additional acute care biomarkers such as D-Dimer, Troponin or Copeptin enables improved prognosis and/or further SARS related indications on the extent, severity or type of infection, myocardial infarction or coagulation disorders present in the subject. The combined measurement of PCT and proADM may, in some embodiments, lead to the decision regarding hospitalization in addition to the antibiotic dose and means of administration to the patient. The combination of these biomarkers therefore provides a beneficial and—in the particular patient group and practitioner group of the present invention—surprising effect.

In embodiments, the at least one additional biomarker additional biomarker is arginine vasopressin (AVP), pro-arginine vasopressin (proAVP) and/or Copeptin (CT-proAVP).

In embodiments, the additional biomarker includes Endothelin-1 (ET-1), such as CT-proET-1.

Surprisingly, it could be shown that the combined measurement of ET-1 (including CT-proET-1) and/or AVP (including proAVP and/or CT-proAVP) as additional biomarkers with proADM enables improved prognosis of disease progression. This improved prognosis can include an indication or prediction of the occurrence of an adverse event, such as death, preferably within a certain time frame after diagnosis and treatment initiation, such as within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 21, 24, or 28 days.

The invention further relates to a method for therapy guidance, stratification and/or control in a patient with symptoms of a SARS or of infection with a SARS-virus, comprising a prognosis of disease progression, the method comprising:

- providing a sample from said patient,
- determining a level of proADM or fragment(s) thereof in said sample, and
- comparing the level of proADM or fragment(s) thereof in said sample to a cut-off value,
- wherein said cut-off value is 0.87 nmol/l±20%,
- wherein a (low risk) level of proADM or fragment(s) thereof in said sample below said cut-off value indicates that the patient is not at risk of a disease progression to a condition that requires hospitalization, and wherein a high risk level of proADM or fragment(s) thereof in said sample above said cut-off value indicates that the patient is at risk of a disease progression to a condition that requires hospitalization.

The method therefore relates to a method of treating a SARS or of infection with a SARS-virus in a patient, including electing the patient for treatment employing a method for therapy guidance, stratification and/or control in a patient with symptoms of a SARS or of infection with a SARS-virus, comprising a prognosis of disease progression, the method comprising:

- providing a sample from said patient,
- determining a level of proADM or fragment(s) thereof in said sample, and
- comparing the level of proADM or fragment(s) thereof in said sample to a cut-off value,
- wherein said cut-off value is 0.87 nmol/l±20%,
- wherein a (low risk) level of proADM or fragment(s) thereof in said sample below said cut-off value indicates that the patient is not at risk of a disease progression to a condition that requires hospitalization, and wherein a high risk level of proADM or fragment(s) thereof in said sample above said cut-off value indicates that the patient is at risk of a disease progression to a condition that requires hospitalization.

The method of treatment preferably includes the administration of suitable therapeutic measures to said patient using preferably one or more of the particular therapies described herein.

In one embodiment, the invention relates to or comprises a method for treating a patient with symptoms of a SARS or of infection with a SARS-virus, the method comprising the steps of:

- determining whether the patient has a high or low risk level of proADM, by:
- obtaining or having obtained a biological sample from the patient;
- performing or having performed an assay that determines a level of proADM or fragment(s) thereof in said sample;
- wherein a low risk level of proADM level or fragment(s) thereof in said sample is equal or below 0.87 nmol/l±20%, and/or
- wherein a high risk level of proADM level or fragment(s) thereof in said sample is above 0.87 nmol/l±20%,
- wherein when a high risk level of proADM level or fragment(s) thereof in said sample is determined, the patient is treated, said treatment preferably including hospitalization, or a medical treatment available only or primarily at a hospital.

The invention further relates to a method for therapy guidance, stratification and/or control in a patient with symptoms of a SARS or of infection with a SARS-virus, comprising a prognosis of disease progression, the method comprising:

- providing a sample from said patient,
- determining a level of proADM or fragment(s) thereof in said sample, and
- comparing the level of proADM or fragment(s) thereof in said sample to a cut-off value,
- wherein said cut-off value is 0.93 nmol/l±20%,
- wherein a (low risk) level of proADM or fragment(s) thereof in said sample below said cut-off value indicates that the patient is not at risk of a disease progression to a condition that requires hospitalization, and wherein a high risk level of proADM or fragment(s) thereof in said sample above said cut-off value indicates that the patient is at risk of a disease progression to a condition that requires hospitalization.

The method therefore relates to a method of treating a SARS or of infection with a SARS-virus in a patient, including electing the patient for treatment employing a method for therapy guidance, stratification and/or control in a patient with symptoms of a SARS or of infection with a SARS-virus, comprising a prognosis of disease progression, the method comprising:

- providing a sample from said patient,
- determining a level of proADM or fragment(s) thereof in said sample, and
- comparing the level of proADM or fragment(s) thereof in said sample to a cut-off value,
- wherein said cut-off value is 0.93 nmol/l±20%,
- wherein a (low risk) level of proADM or fragment(s) thereof in said sample below said cut-off value indicates that the patient is not at risk of a disease progression to a condition that requires hospitalization, and wherein a high risk level of proADM or fragment(s) thereof in said sample above said cut-off value indicates that the patient is at risk of a disease progression to a condition that requires hospitalization.
- wherein preferably when a high risk level of proADM level or fragment(s) thereof in said sample is determined, the patient is treated, said treatment preferably including hospitalization, or a medical treatment available only or primarily at a hospital.

In embodiments of the method for therapy guidance, stratification and/or control in a patient with symptoms of a SARS or of infection with a SARS-virus of the invention, in addition or alternatively to the cut-off value of 0.87 nmol/l, other cut-off values, such as 0.93 nmol/l, can be used. As shown in the examples, cut-off values of 0.75, 1.5, 2.25 and 2.5 nmol/l are useful and therefore represent suitable cut-off values to be used in the context of this aspect of the invention. The examples disclose further cut-off values that can be employed, and that are associated with specific advantageous when used in conjunction with specific time points of sample isolation. Events determining time points of sample isolation, such as the initial occurrence of symptoms in a patient, hospitalization of a patient or diagnosis of SARS infection, for example by a positive laboratory test result, are disclosed herein.

The present invention therefore provides a new, quick and reliable test for primary healthcare practitioners, such as doctors, nurses, etc., to quickly assess the risk of patient with symptoms of a SARS or of infection with a SARS-virus to develop a condition requiring hospitalization, such as sepsis.

In certain embodiments of the method of the invention, the condition requiring hospitalization is a viral infection-related complication, such as an infection, a nosocomial infection, sepsis and/or septic shock. In certain embodiments of the method of the invention, the condition comprises an infection, a nosocomial infection, sepsis and/or septic shock, preferably based on a respiratory infectious disease, urinary tract infectious disease, a skin infectious disease or an abdominal infectious disease.

It is particular advantage that the cut-off of proADM or fragment(s) thereof to be used in the context of the method of the invention can be used to rule-out hospitalization. Accordingly, the method enables a more accurate assessment of the prognosis/risk of a patient, depending on the situation of sample isolation and the further information available at that time, for example an increased risk of developing severe condition.

Depending on the result of the method of the present invention, embodiments of the method may comprise subsequent therapeutic decisions and/or therapeutic actions. Such therapeutic decisions may include the initiation, change or modification of medical treatment. Preferably, if the method of the present invention is indicative of development to a condition requiring treatment in hospital, suitable therapeutic measures, such as initiation or change of a certain medication, mechanical ventilation, surgery or fluid therapy may be initiated.

Any therapy, medical treatment or therapeutic action disclosed herein can be employed in the context of the method of the invention as a subsequent therapeutic decision or therapeutic action, in particular if the therapeutic measure is specifically administered in hospital, including but not limited to mechanical ventilation, intravenous fluid therapy, dialysis, management of electrolyte abnormalities (in particular potassium, calcium and phosphorus). Furthermore, a maintained intensive observation and care of the patient may be indicated potentially over extended periods of time, such as several day, weeks or even months. This may involve keeping or moving the patient to an ICU and/or prolonging the stay of the patient in an ICU.

On the other hand, if the result of the method of the present invention is indicative of the absence of risk of developing a condition requiring hospitalization, no specific treatment measures with respect to such complication may be required, or less serious, self-administrable treatments may be prescribed.

Embodiments of the Invention Relating to Patients that have been Diagnosed with SARS and that May be Critically Ill

In a further aspect disclosed herein, the present invention relates to the provision of means for the prognosis, risk assessment and/or risk stratification of a subsequent adverse event in the health of a patient that has been diagnosed with SARS and that may be critically ill, in particular within a short time frame after initiating treatment.

The present invention therefore seeks to provide a method, kit and further means for therapy monitoring of a patient that has been diagnosed with SARS and that may be critically ill, as well as means for the prognosis, risk assessment and/or risk stratification of a subsequent adverse event in the health of a patient that has been diagnosed with SARS and that may be critically ill on the basis of proadrenomedullin (proADM) levels determined in a sample from a patient. One object of the invention is therefore the use of a biomarker or combination of biomarkers to distinguish a patient that has been diagnosed with SARS and that may be critically ill who has undergone or are undergoing treatment, who has a high risk of an adverse event, from a patient that has been diagnosed with SARS and that may be critically ill who has a low risk of a subsequent adverse event.

In embodiments, the invention therefore relates to a method for prognosing disease progression, wherein the method comprises prognosing a subsequent adverse event in the health of a patient that has been diagnosed with SARS, comprising

- providing a sample of said patient, wherein the sample is isolated from the patient after diagnosis and treatment initiation,
- determining a level of proadrenomedullin (proADM) or fragment(s) thereof in said sample,
- wherein said level of proADM or fragment(s) thereof indicates the likelihood of a subsequent adverse event in the health of said patient.

In embodiments, the present invention therefore relates to a method for therapy monitoring, comprising the prognosis, risk assessment and/or risk stratification of a subsequent adverse event in the health of a patient that has been diagnosed with SARS, comprising

- providing a sample of said patient, wherein the sample is isolated from the patient after diagnosis and preferably treatment initiation,
- determining a level of proADM or fragment(s) thereof in said sample,
- wherein said level of proADM or fragment(s) thereof correlates with the likelihood of a subsequent adverse event in the health of said patient.

In this aspect of the invention, the patients of the method of the present invention have already been diagnosed with SARS and are preferably already receiving treatment. The method of the present invention can therefore be used for monitoring the success of the treatment or therapy that has been initiated, on the basis of determining the likelihood of a subsequent adverse event. The therapy monitoring preferably involves the prognosis of an adverse event and/or the risk stratification or risk assessment of the patient with respect to a future adverse event, wherein this risk assessment and the determination of said risk is to be considered as a means of monitoring the initiated therapy.

Physicians or medical personnel who are treating patients that have been diagnosed with SARS can employ the method of the present invention in different clinical settings, such as primary care setting or, preferably, in a hospital setting, such as in an emergency department, or in an intensive care unit (ICU). The method is very useful to monitor the effect of a therapy that has been initiated on a patient that have been diagnosed with SARS and can be used to judge whether a patient under treatment is a high risk patient that should be under intense medical observation and should potentially receive additional therapeutic measures, or whether the patient is a low risk patient with an improving health state that might not require as intense observation and further treatment measures, possibly because the initiated treatment is successfully improving the state of the patient. Initial treatments of a patient that have been diagnosed with SARS may have a direct effect on the likelihood of adverse events in the health of the patient. As such, the assessment of risk/prognosis of a future adverse event provides feedback on or monitoring of the therapy instigated.

In the context of this method of the invention, the viral infection comprises preferably a coronavirus infection, such as an infection with a SARS-coronavirus. Preferably, the SARS-coronavirus comprises SARS-CoV2. In embodiments, the viral infection is not an influenza virus infection.

Furthermore, the patient may belong to a patient group with an increased risk of an adverse event in case of a SARS or an infection with a SARS-virus, such as patients with an age of 60 years or more, preferably 70 years or more, patients with long-term respiratory or lung disease, such as asthma, cystic fibrosis or chronic obstructive pulmonary disease (COPD), patients with long-term heart disease, such as heart failure, patients with long-term kidney disease, patients with long-term liver disease, such as hepatitis, patients with diabetes, patients with long-term neurological conditions, such as Parkinson's disease, motor neuron disease, multiple sclerosis (MS), cerebral palsy, or a learning disability, patients with splenic disease, such as sickle cell anemia or splenectomy, patients with a weakened immune system, such as patients with HIV or AIDS, or patients receiving immunosuppressive medication, patients with a body mass index (BMI) of 40 or above (severely obese patients), pregnant women, patients that had an organ transplantation taking immunosuppressive medication, cancer patients and in particular cancer patients receiving chemotherapy or radiotherapy.

The likelihood of the occurrence of a subsequent adverse event can be assessed on the comparison of the level of proADM or fragments thereof in the sample in comparison to a reference level (such as a threshold or cut-off value and/or a population average), wherein the reference level may correspond to proADM or fragments thereof in healthy patients, or in patients who have been diagnosed with SARS.

Accordingly, the method of the present invention can help to predict the likelihood of a subsequent adverse event in the health of the patient. This means, that the method of the invention can discriminate high risk patients, who are more likely to suffer from complications, or whose state will become more critical in the future, from low risk patients, whose health state is stable or even improving, so that it is not expected that they will suffer from an adverse event, such as death of the patient or a deterioration of the patient's clinical symptoms or signs, which might require certain therapeutic measures.

A particular advantage of the method of the present invention is that a patient who has been identified as a low risk patient by means of the method of the present invention could be more rapidly discharged from an ICU. Also, for low risk patients, the intensity and/or frequency of the observation of the health status of the patient could be decreased. Accordingly, the hospital or other medical institution in charge of the patient could more efficiently decide which patients require intensive medical care and observation. Consequently, the respective hospital or institution could, for example, more efficiently occupy ICU beds with high-risk patients. This would lead to an improved medical care for the high-risk patients, since the medical personnel could focus on such patients, while low risk patients could be discharged from the ICU. This would also lead to significant benefits from avoided costs for unnecessary measures that would otherwise be applied to low risk patients.

The time point when the patients have been diagnosed with SARS and the first treatment measures are initiated is defined as “time point 0”, which may be the reference for the time point of isolation of the sample used for determining proADM or fragments thereof. If diagnosis of the patient and treatment initiation do not occur at the same time, time point 0 is the time point when the later of the two events of diagnosis and initiation of medical treatment occurs. Typically, diagnosis of patients suffering from SARS or from infection with a SARS-virus is immediately followed by or concomitant to initiation of therapy.

It was entirely surprising that the level of proADM or fragments thereof in a sample from the patient can provide critical information about the likelihood of the occurrence of a subsequent adverse event in the health of said patients. There has been no indication that a single measurement of proADM or fragments thereof after diagnosis and treatment initiation of a patient that has been diagnosed with SARS could provide such important information with respect to success of the ongoing treatment and prognosis of the health status of the patient.

The use of proADM or fragments thereof as a single parameter in embodiments of the present invention is advantageous over the use of clinical scores, since proADM levels can be determined fast and objectively, while determining clinical scores such as SOFA, SAPS II, APACHE II, PSI, CRB-65 and qSOFA requires more time for collecting several parameters that also involve patient examination and interrogation and subsequent analysis.

According to a preferred embodiment, the sample is isolated from said patient within 30 minutes after said diagnosis and treatment initiation, or at least 30 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 24 hours, 4 days, 7 days or 10 days after said diagnosis and treatment initiation. Further possible time points of sample isolation include 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days or 9 days after said diagnosis and treatment initiation. In other embodiments the sample is isolated from said patient 12-36 hours and/or 3-5 days after treatment initiation.

The fact that the level of proADM or fragments thereof at a time point as short as about 30 minutes after diagnosis and treatment initiation can provide such information was completely unexpected.

In embodiments, the sample is isolated from the patient within 30 minutes after said diagnosis and treatment initiation, or 30 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 24 hours, 4 days, 7 days or 10 days after said diagnosis and treatment initiation.

In preferred embodiments of the method of the present invention said sample is isolated from said patient about 30 minutes, 1 hour, 2 hours, 3 hours, 4, hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours 22 hours, 24 hours, 30 hours, 36 hours, 42 hours, 48 hours, 60 hours, 72 hours, 84 hours, 4 days, 5 days, 6 days, 7 days, 8 days 9 days or 10 days after said diagnosis and treatment initiation.

In other embodiments, the sample is isolated at time points after said diagnosis and initiating treatment of 30 minutes to 12 hours, 12-36 hours, 3-5 days, 7-14 days, 8-12 days, or 9-11 days.

Ranges between any given of the above values may be employed to define the time point of obtaining the sample.

In another preferred embodiment of the present invention, the patient has been diagnosed using at least one additional biomarker or a clinical score. It is particularly advantageous in the context of the present invention, if the initial diagnosis of SARS or of infection with a SARS-virus of the patient at time point 0 was based at least partially on the level of at least one biomarker or a determined clinical score.

In certain embodiments the present invention comprises the determination of additional parameters, such as markers, biomarkers, clinical scores or the like.

In preferred embodiments of the present invention, the adverse event in the health of said patient is death, preferably death within 2-30 days after diagnosis and treatment initiation, a new infection, such as a bacterial infection, respiratory failure, organ failure and/or a deterioration of clinical symptoms requiring a focus cleaning procedure, transfusion of blood products, infusion of colloids, emergency surgery, invasive mechanical ventilation and/or renal or liver replacement.

In preferred embodiments of the invention, said level of proADM or fragment(s) thereof correlates with the likelihood of a subsequent adverse event in the health of said patient within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or up to 30 days after diagnosis and treatment initiation.

In certain embodiments of the invention, the treatment received by the patient comprises one or more of symptomatic treatment, treatment to reduce fever and/or pain, anti-inflammatory treatment, antiviral treatment, antibiotic treatment, oxygen support, invasive mechanical ventilation, non-invasive mechanical ventilation, renal replacement therapy, vasopressor use, fluid therapy, extracorporeal blood purification and/or organ protection.

In preferred embodiments of the invention, the sample is selected from the group consisting of a blood sample, a serum sample, a plasma sample and/or a urine sample.

Preferably, the method is carried out in some embodiments by determining a level of proADM or fragment(s) thereof, wherein said determining of proADM comprises determining a level of MR-proADM in the sample. The employment of determining MR-proADM is preferred for any given embodiment described herein and may be considered in the context of each embodiment, accordingly. In preferred embodiments the “ADM fragment” may be considered to be MR-proADM.

In further embodiments of the invention the level of proADM or fragment(s) thereof correlates with the likelihood of a subsequent adverse event in the health of said patient. In a preferred embodiment the level of proADM or fragment(s) thereof positively correlates with the likelihood of a subsequent adverse event in the health of said patient. In other words, the higher the level of proADM determined, the greater the likelihood of a subsequent adverse event.