How to assess the severity of SARS

Abstract

The present invention relates to a method for assessing the severity of Severe Acute Respiratory Syndrome (SARS) in a patient, the method being based on a severity score consisting of at least: a) a respiratory system score, b) a score determined by the level of pancreatic stone protein / regenerative protein (PSP / reg) in a body fluid sample from the patient. The present invention can be used in health management units to triage patients to determine treatment priorities.

Description

[Technical field]

[0001] The present invention relates to a method for assessing the severity of Severe Acute Respiratory Syndrome (SARS), in particular SARS-CoV-2 (Covid-19), which can be used in health care units to triage patients to determine treatment priorities. [Background technology]

[0002]

[0004] The rapid and global spread of SARS-CoV-2 and the associated Covid-19 outbreak has posed multiple challenges to public health systems. This is especially true in intensive care units (ICUs), where the sudden increase in the number of patients requiring invasive respiratory support has severely strained ICU medical personnel, infrastructure, materials, and treatment needs. An impressive amount of data has been published in the past few months defining the clinical characteristics of Covid-19 patients, including risk factors for severe disease and death. Different studies of Covid-19 ICU patients have reported different but consistently high mortality rates, ranging from 61 to 97% (F. Zhou et al., The Lancet 2020). Patients infected with SARS-CoV-2 who are generally defined as “at risk” (older age and / or those with comorbidities such as cardiovascular disease, diabetes, chronic respiratory disease, hypertension, and cancer (RE Jordan et al., BMJ 2020)) are more likely to suffer from Covid-19 complications, mainly severe pneumonia, septic shock, and multiple organ dysfunction. In a recent study, 11% of Covid-19 patients who developed acute respiratory distress syndrome (ARDS) deteriorated in a short period of time and later died of multiple organ failure (N. Chen et al., The Lancet 2020, 10223:507-513).

[0003]

[0005] Sepsis is currently defined as "life-threatening organ dysfunction caused by dysregulation of the host response to infection" (Sepsis-3) (M. Singer et al., JAMA 2016, 315:801-810). Clinically, organ dysfunction is defined as a sequential organ failure assessment (SOFA) score of ≥2. A subset of patients with sepsis progresses to septic shock. These patients with septic shock are clinically defined as having persistent hypotension requiring vascular compression medications to maintain a mean arterial pressure >65 mmHg and serum lactate >2 mmol / L (18 mg / dL) despite adequate resuscitation efforts. From these definitions, it is clear that all SARS-CoV-2-infected patients who have required invasive mechanical ventilation due to pulmonary failure shall be defined as "septic" because they have a SOFA respiratory score of ≥2.

[0004]

[0006] In this context, it is important to identify identifiers for the early onset of Covid-19 complications such as septic shock and multi-organ dysfunction. Apart from being cumbersome to measure due to the multiple parameters that make up the SOFA score, and the need for a central laboratory to collect all data, the SOFA score does not predict organ dysfunction at a given time point, but rather represents the extent of organ dysfunction. Therefore, early warning signal(s) of organ dysfunction and septic shock are needed to provide clinicians with timely data for patient management to mitigate the effects of these dysfunctions and promptly reset homeostasis. Septic shock and multi-organ dysfunction are major complications in critically ill Covid-19 patients admitted to the intensive care unit (ICU) and are associated with high mortality. Therefore, biomarkers predictive of these conditions are essential for early diagnosis in order to optimize patient management strategies.

[0005]

[0007] Currently, diagnosis can only be made by a combination of multiple clinical signs, the complex Sequential Organ Failure Assessment score (SOFA score), and the controversial Sepsis-3 definition (S. Sinha et al., J Anaesthesiol Clin Pharmacol. 2018, 34:4:542-543), and not by a simple blood test. Other biomarkers, procalcitonin (PCT) and C-reactive protein (CRP), have been extensively studied, but today none of them have demonstrated the ability to detect sepsis quickly enough and with a high enough diagnostic accuracy (C. Rhee et al., Critical care 2016, 6:20:89).

[0006]

[0008] Pancreatic stone protein / regenerating protein (PSP / reg) belongs to the family of lectin-binding proteins and allows for the diagnosis of sepsis, septic shock and organ dysfunction much earlier than all other current solutions, as proposed in the international guidelines of medical societies (C Scinger et al., JAMA 2016, 315:8:801-810).

[0007]

[0009] A literature review summarizing 13 PSP / reg studies (P. Eggimann et al., Biomarkers 2019, 13:02:135-145) was published in 2019, and a promising study from the Burn Center at University Hospital Zurich was published in January 2020 (H.J. Klein et al., Ann Surg. 2020).

[0008]

[0010] These numerous publications show that the PSP / reg assay is more specific and sensitive than other biomarkers for early diagnosis of sepsis, septic shock and multiple organ failure in ICU adult (M. Llewlyn et al., Crit. Care 2013, 17:2:R60), pediatric (Z. Jiri et al., Cytokine 2014, 66:2:106-111), neonatal (A. Rass et al., BioMed. Res. Int 2016, 1-8) and burn (HJ Klein et al., World Journal of Surgery 2020, 44:3000-3009) patients. PSP / reg allows the identification of sepsis in patients after cardiac surgery (H. Klein et al., PLoS ONE 2015, 10:3:e0120276), PSP / reg predicts the outcome of patients with peritonitis in the ICU (R. Gukasjan et al., Crit. Care Med 2013, 41:4:1027-1036), PSP / reg is a biomarker of organ failure in ventilator-associated pneumonia (VAP) (L. Boeck et al., Chest 2011, 140:4:925-932) and mortality in adults (Y.-A. Que et al., Crit. Care 2012, 16:4:R114) and children (Q. Wu et al., Med. Sci. Monit 2017, 23:1533-1539).

[0009]

[0011] The value of PSP / reg was determined in healthy individuals in 2015 (E. Schlapbach et al., BMC Anesthesiol 2015, 15:168). PSP / reg detects early infection and sepsis in trauma patients (M. Keel et al., Crit. Care Med 2009, 37:5:1642-1648), emergency departments (L. Garcia de Guardinia-Romualdo et al., Eur. J. Clin. Invest 2017, 47:4:297-304), pediatric acute osteomyelitis (C. Cui et al., Med. Sci. Monit 2017, 23:5211-5217), and cancer patients with febrile neutropenia (L. Garcia de Guardiana-Romualdo et al., Clin Chem Lab Med 2019, 57:4:540-548).

[0010]

[0012] Although the pathophysiological mechanism of PSP / reg has not yet been clearly defined (R. Graf, Pancreatology 2020, 20:3:301-304), rat studies suggest that serum PSP / reg in septic patients is derived mainly through the acute phase response of the pancreas (T. Reding et al., Oncotarget 2017, 8:30162-30174). In humans, PSP / REG activates granulocyte neutrophils (M. Keel et al., Crit. Care Med 2009, 37:51642-1648), which would confirm the possibility that PSP / reg functions as an acute phase protein.

[0011]

[0013] The association between changes in biomarker concentrations in the development of sepsis (bacterial and viral), septic shock and multiple organ dysfunction was evaluated in the present invention to identify new diagnostic strategies for early identification of complications in Covid-19 patients.

[0012]

[0014] Currently, it is very difficult to identify clinical deterioration in hospitalized SARS patients, especially in Covid-19 patients, because most of them have sepsis due to viral infection and respiratory distress. Moreover, cytokine storm creates a complex clinical picture, making it difficult for practitioners to assess the severity of the clinical situation.

[0013]

[0015] Furthermore, no scores currently exist to help clinicians triage and better direct patients for treatment. Summary of the Invention [Problem to be solved by the invention]

[0014]

[0016] Therefore, there is a great need for solutions to speed up and improve the assessment of the severity of SARS. [Means for solving the problem]

[0015]

[0017] The inventors believe that the severity assessment of SARS, and in particular SARS-CoV-2, is at least as follows: a. Respiratory system score, b. A score determined by the level of pancreatic stone protein / regeneration protein (PSP / reg) in a bodily fluid sample from said patient. We found that the use of a severity score composed of the following could facilitate and improve the quality of the study:

[0016]

[0018] According to a preferred embodiment of the present invention, the method comprises the following steps: a. providing a bodily fluid sample from said patient; b. determining the level of pancreatic stone protein / regeneration protein (PSP / reg) in said sample; c. determining a PSP / reg score; d. determining a respiratory score; e. Determining a severity score by adding the PSP / reg score and the respiratory score. Includes.

[0017]

[0019] The severity score may also conveniently include other biomarker scores, such as C-Reactive Protein (CRP).

[0018]

[0020] The severity score is indicative of the occurrence of clinical complications and / or deterioration, including multiple organ failure, bacterial sepsis and severe viral sepsis.

[0019]

[0021] The PSP / reg score correlates with the Sequential Organ Failure Assessment score (SOFA score). Effect of the Invention

[0020]

[0022] The present invention allows for the triage, selection, direction, location and / or stratification of patients according to severity level.

[0021]

[0023] The invention is explained in a more precise manner in this section with the aid of the following figures. [Brief description of the drawings]

[0022] [Figure 1] FIG. 1 shows how the severity score for Covid-19 patients is determined. The severity score, called the Covid-19 Sequential Organ Failure Assessment score (cSOFA), is composed of the sum of the Respiratory Score (RESPSCORE) and the PSP Score (PSPSCORE). The RESPSCORE is set by the physician as shown in the table and is directly related to the PaO2 / FiO2 measurement, known as the respiratory dysfunction component of the SOFA score. The PSPSCORE is derived from the measured PSP / reg levels as shown in the table. RESPSCORE+PSPSCORE=cSOFA (Covid-19 Sequential Organ Failure Assessment score). [Diagram 2] Figure 2a shows the correlation between the cSOFA score and the commonly known SOFA score. Each point represents the averaged cSOFA-SOFA comparison over the duration of each patient's ICU stay. This analysis includes 96 patients in the ICU. The white area represents a difference between the cSOFA score and the SOFA score of up to 2 classes. The light gray area represents a difference between the cSOFA score and the SOFA score of up to 3 classes, and the dark gray area represents a difference between the cSOFA score and the SOFA score of 4 classes or more. Figure 2b shows the distribution of patients included in the analysis and indicates the class difference between the cSOFA score and the SOFA score. [Diagram 3]FIG. 1 illustrates how cSOFA is interpreted according to its levels for determining the patient's clinical severity and its direction. A cSOFA score equal to zero indicates a low risk of clinical deterioration and therefore consideration should be given to sending the patient home. A cSOFA score of 1-3 indicates a moderate risk of clinical deterioration and therefore consideration should be given to hospitalization. A cSOFA score of >3 indicates a high risk of clinical deterioration and therefore consideration should be given to transferring the patient to an intermediate or intensive care unit. [Figure 4] FIG. 4 shows a decision tree for triage and direction of patients according to cSOFA score levels as shown in FIG. 3. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] [Definition]

[0002] As defined herein, a patient infected with SARS-CoV-2 refers to a patient who tests positive by any method that identifies the presence of SARS-CoV-2.

[0024]

[0003] "PSP / reg" refers to the human pancreatic stone protein, also called regenerative gene (REG) I protein or lithostatin or pancreatic thread protein (Gross et al., J. Clin. Invest. 1985, 76:2115-2126), which can be the isoform alpha (Uniprot SEQ ID NO: P05451, also identified herein as SEQ ID NO: 1) or beta (Uniprot SEQ ID NO: P48304, also identified herein as SEQ ID NO: 2).

[0025]

[0028] As defined in the illustrated example referring to SARS-CoV-2, the severity score is called the Covid-19 Sequential Organ Failure Assessment (cSOFA) and the Respiratory Score (RESP) SCORE ) and PSP score (PSP SCORE ) and RESP. SCORE is identical to the respiratory dysfunction component of the SOFA score.SCORE may be established by practitioner assessment, as shown in Figure 1, and / or PaO according to the SOFA scoring system, if available. 2 / FiO 2 It may be obtained directly from measurements. SCORE is established based on the measured patient levels of pancreatic stone protein / regeneration protein PSP / reg in body fluids according to the table shown in FIG. 1 .

[0026]

[0029] Useful body fluids for determining PSP / reg levels are, for example, whole blood, serum, plasma, urine, sputum, cerebrospinal fluid, tears, saliva, sweat, breast milk, or extracts from solid tissues or faeces.

[0027]

[0030] Any known method can be used to determine the level of PSP / reg in body fluids. Methods that come into consideration are, for example, ELISA, RIA, EIA, mass spectrometry or microarray analysis, as well as any fluid assay method.

[0028]

[0031] The obtained cSOFA score, which ranges from 0 to 10, correlates well with the well-established SOFA score, which ranges from 0 to 10, for Covid-19 patients, as shown in Figure 2. The SOFA score represents the degree of organ dysfunction at a given time and is widely used today to assess organ failure, sepsis and septic shock. This score is complex and based on multiple clinical parameters, and therefore cumbersome to establish, which is why it is mainly used in intensive care units. The cSOFA score is based on only two parameters that can be rapidly measured and calculated. The cSOFA score is an alternative to the SOFA score, since it can be easily determined by any medical professional. In particular, since the SOFA score is usually used in intensive care situations, the cSOFA score is a solution in all other situations where the SOFA score is not currently easily available or calculated (emergency departments, general wards, primary care, testing centers, etc.). As a result, the use of the cSOFA score in these other situations makes it possible to determine clinical complications, deterioration, triage and direction of Covid-19 patients.

[0029]

[0032] As described in Figure 3, a cSOFA score equal to 0 indicates a low risk of clinical deterioration and therefore consideration should be given to sending the patient home. A cSOFA score of 1 to 3 indicates a moderate risk of clinical deterioration and therefore hospitalization should be considered. A cSOFA score of >3 indicates a high risk of clinical deterioration, including risk of multiple organ failure, bacterial sepsis and severe viral sepsis (severe cytokine storm) and therefore transfer of the patient to an intermediate or intensive care unit should be considered.

[0030]

[0033] Based on the described classification of cSOFA scores (see Figure 3), a decision tree for triage, selection and direction of Covid-19 patients is established as shown in Figure 4. In emergency departments, primary care settings or triage centers, the cSOFA score is established once at the time of admission for the purpose of triage and identification of clinical severity. During hospitalization, the cSOFA score is established at least daily for the same purpose.

[0031]

[0034] The present invention is not limited to the evaluation of SARS-CoV-2, but can be advantageously used in patients infected with any type of SARS.

Claims

1. 1. A method for aiding in the assessment of severity of Severe Acute Respiratory Syndrome (SARS) in a patient, comprising: a) Respiratory score, b) a score determined by the level of pancreatic stone protein / regenerative protein (PSP / reg) in a body fluid sample from said patient; It is based on a severity score consisting of: A method wherein said respiratory score is based on PaO 2 / FiO 2 measurements.

2. The method of claim 1 for assisting in assessing the severity of SARS-CoV-2 (Covid-19).

3. Steps below: a) determining the level of pancreatic stone protein / regeneration protein (PSP / reg) in a body fluid sample from said patient; b) determining the PSP / reg score; c) determining a respiratory system score; d) Determining a severity score by adding the PSP / reg score and the respiratory score. The method of claim 1 or 2, comprising:

4. The method of any one of claims 1 to 3, wherein the severity score also includes other biomarker scores.

5. The method of claim 4, wherein the biomarker is C-reactive protein (CRP).

6. The method according to any one of claims 1 to 5, wherein the body fluid sample is serum, plasma, a whole blood sample, saliva, urine, sputum, cerebrospinal fluid, tears, sweat, breast milk, or an extract from a solid tissue or faeces.

7. The method of any one of claims 1 to 6, wherein a severity score of less than 1 indicates a low risk of clinical complications and / or deterioration.

8. The method according to any one of claims 1 to 6, wherein a severity score of >3 indicates an increased risk of developing severe viral sepsis (severe cytokine storm), bacterial sepsis, multiple organ failure and / or death.

9. The method of any one of claims 1 to 8, wherein the PSP / reg level is determined by ELISA, RIA, EIA, mass spectrometry, microarray analysis or any fluid assay method.

10. 10. Use of a severity score as defined in any one of claims 1 to 9 to aid in the triage, selection, orientation, location and / or stratification of patients in a healthcare unit.

Images