ASSEMBLY FOR EXTRACORPOREAL TREATMENT OF BODY FLUIDS

Abstract

A method for extracorporeal treatment of a body fluid of a patient suffering from sepsis, in an extracorporeal flow line, comprising removing at least one harmful substance from the body fluid of the patient. In a first injection step, a first mixture containing functionalized magnetic particles bound to at least a first binding agent at least directed against a first type of target molecules contained in the body fluid is added to the extracorporeal flow line comprising a sample of the body fluid extracted from a patient and containing at least the first type of target molecules. The first mixture is injected in a therapeutically effective dose necessary to reduce a concentration of the target molecules of at least the first type in the body fluid sample of the patient, followed by a mixing step and a separation step for reduction of the target molecule concentration.

Claims

1. A method for extracorporeal treatment of a body fluid of a patient suffering from a dysregulated immune response, in an extracorporeal flow line, comprising removing at least one harmful substance from the body fluid of the patient, comprising the following steps: at least a first injection step, in which, by means of a first injection device, a first mixture containing functionalized magnetic particles bound to at least a first binding agent at least directed against a first type of target molecules contained in the body fluid is added to the extracorporeal flow line comprising a sample of the body fluid extracted from a patient suffering from a dysregulated immune response, e.g. sepsis, and containing at least the first type of target molecules, in a therapeutically effective dose necessary to reduce a concentration of the target molecules of at least the first type in the sample of body fluid of the patient, subsequently, mixing the body fluid comprising the functionalized magnetic particles to ensure sufficient binding of the target molecules of at least the first type to the functionalized magnetic particles; and separating the functionalized magnetic particles bound to the target molecules of at least the first type from the sample of body fluid, such that a concentration of target molecules of at least the first type in the sample of body fluid is reduced, wherein the first injection step is controlled based on data obtained from the sample of the patient's body fluid providing information about the immunological status of the patient, and wherein the first injection step is controlled in terms of at least one of the following: injection rate, time of injection, injection dose, concentration, injection pressure.

2. The method according to claim 1, wherein the body fluid is blood.

3. The method according to claim 1, wherein the method further comprises, upstream of the first injection step, a diagnostic step, in which data providing information about the immunological status of the patient is obtained.

4. The method according to claim 1, wherein the data obtained in the diagnostic step from the patient's body fluid providing information about the immunological status of the patient is transmitted to a control unit which is arranged in an electrical or wireless communication with the extracorporeal circuit and wherein the control unit controls the first injection step.

5. The method according to claim 1, wherein the method further comprises at least a second injection step, in which, by means of a second injection device, a second mixture different from the first mixture and containing functionalized magnetic particles, is added to the extracorporeal flow line comprising the body fluid extracted from the patient, and wherein the second injection step is carried out upstream of, downstream of or simultaneously with the first injection step, wherein the first injection step and the second injection step are each individually controlled separate from each other based on data providing information about the immunological status of the patient.

6. The method according to claim 5, wherein in the second injection step, the functionalized magnetic particles contained in the second mixture are bound to at least a second binding agent different from the at least first binding agent and at least directed against a second type of target molecules contained in the body fluid and different from the first type of target molecules.

7. The method according to claim 5, wherein in the second injection step, the second mixture contains the at least first binding agent at a different concentration than in the first mixture.

8. The method according to claim 1, wherein the functionalized magnetic particles injected are nano-size magnetic adsorbants.

9. The method according to claim 1, wherein the functionalized magnetic particles each comprise a magnetic core and at least one functional layer.

10. The method according to claim 1, wherein the separation step is carried out by a magnetic filter.

11. The method according to claim 1, wherein the first binding agent is directed at least against a first type of target molecule selected from a group consisting of: pathogen-associated-pattern immune activators, pro-inflammatory mediators, anti-inflammatory mediators, complement factors, and cleavage products thereof.

12. The method according to claim 6, wherein the second binding agent is directed at least against a second type of target molecule selected from a group consisting of pathogen-associated-pattern immune activators, pro-inflammatory mediators, anti-inflammatory mediators, complement factors and cleavage products thereof.

13. The method according to claim 1, wherein in the first injection step and/or in the second injection step, the first binding agent and/or the second binding agent is selected from a group consisting of: antibodies, peptides, lectines, chemical chelating agents, and polymers.

14. The method according to claim 1, wherein in case the patient to be treated suffers from hyper-inflammation as a result of bacterial infection, the at least first binding agent and/or at least the second binding agent is directed at least against a first and/or second type of target molecule selected from a group consisting of: LPS, lipotechoic acid, bacterial toxins, flagellin, bacterial RNA/DNA, peptidoglycan, TNFα, IL-1, IL-6, IL-8, IL-15, IL-18, GM-CSF, IFNγ, and complement factors; and/or wherein in case the patient to be treated suffers from hyperinflammation as a result of viral infection, the at least first binding agent and/or at least the second binding agent is directed at least against a first and/or second type of target molecule selected from a group consisting of: viral RNA/DNA, peptidoglycan, TNFα, IL-1, IL-6, IL-8, IL-15, IL-18, GM-CSF, IFNγ, and complement factors; and/or wherein in case the patient to be treated suffers from hyperinflammation as a result of fungal infection, the at least first binding agent is directed at least against a first and/or second type of target molecule selected from a group consisting of: fungal toxins, chitin, fungal DNA/RNA, TNFα, IL-1, IL-6, IL-8, IL-15, IL-18, GM-CSF, IFNγ, and complement factors; and/or wherein in case the patient to be treated suffers from immunosuppression, the at least first binding agent and/or at least the second binding agent is directed at least against a first and/or second type of target molecule selected from a group consisting of: LPS, lipotechoic acid, bacterial toxins, flagellin, bacterial RNA/DNA, viral RNA/DNA, fungal toxins, chitin, fungal DNA/RNA peptidoglycan, HMGB1, histone, IL-6, IL-10, IL-33, TGFβ, and C5a.

15. An assembly for extracorporeal magnetic separation-based body fluid purification of a patient suffering from sepsis dysregulated immune response, comprising: an extracorporeal flow line interconnected between an inlet port and an outlet port; at least a first injection device for injecting a first mixture comprising functionalized magnetic particles bound to at least a first binding agent at least directed against a first type of target molecule contained in the body fluid into the extracorporeal flow line; a mixing unit, for mixing the functionalized magnetic particles in the body fluid after injection of the functionalized magnetic particles to allow a therapeutically effective level of complexation between the functionalized magnetic particles and the first type of target molecule; and a separation unit comprising a magnetic field region for magnetically separating the functionalized magnetic particles and the target molecules bound thereto from the body fluid; wherein the first injection device is controlled based on data obtained from the sample of the patient's body fluid providing information about the immunological status of the patient, and wherein the first injection step is controlled in terms of at least one of a group consisting of: injection rate, time of injection, injection dose, injection concentration, and injection pressure.

16. The assembly according to claim 15, wherein the assembly further comprises a diagnostic unit, in which data providing information about the immunological status of the patient is obtained, or a diagnostic sample port which enables the extraction of a test sample of the body fluid for obtaining data providing information about the immunological status of the patient, wherein the immunological status of the patient is obtained by measuring an expression of at least one marker molecule or a concentration of at least one marker molecule in the body fluid of the patient by means of an assay or by a sensor.

17. The assembly according to claim 15, wherein the assembly further comprises at least a second injection device, by which a second mixture, different from the first mixture, and containing functionalized magnetic particles, is added to the extracorporeal flow line comprising the body fluid extracted from the patient, wherein the second injection step is carried out upstream of, downstream of or simultaneously with the first injection step, and wherein the first injection step and the second injection step are each individually controlled separate from each other based on data providing information about the immunological status of the patient.

18. The assembly according to claim 15, wherein in the second injection device, the functionalized magnetic particles contained in the second mixture are bound to a second binding agent different from the first binding agent and directed against a second type of target molecule contained in the body fluid and different from the first target molecule, or wherein in the second injection device the functionalized magnetic particles contained in the second mixture are bound to the first binding agent, but are present in a different concentration in the second mixture than in the first mixture.

19. The assembly according to claim 15, wherein the assembly further comprises a control unit which is arranged in an electrical or wireless communication with the extracorporeal flow line, and which is arranged to receive the data providing information about the immunological status of the patient.

20. The assembly according to claim 15, wherein the assembly further comprises at least one of a group consisting of: a pump device for pumping the body fluid flow through the flow line, an incubation unit, a conditioning unit, a thrombus filter unit, a valve, a heat exchanger, a drip chamber, a pressure sensor, a flow sensor, a dispersion sensor, and a temperature sensor.

21. The assembly according to claim 15, wherein the assembly further comprises at least one reservoir associated with the first injection unit, and wherein the reservoir comprises the magnetic particles to be injected by at least the first injection unit.

22. The method according to claim 3, wherein an expression of at least one marker molecule or a concentration of at least one marker molecule in the body fluid of the patient is measured in an assay or by a sensor.

23. The method according to claim 3, wherein an expression of at least one marker molecule or a concentration of at least one marker molecule in the body fluid of the patient is measured in an endotoxin activity assay (EAA) or an enzyme-linked immunosorbent assay (ELISA).

24. The method according to claim 11, wherein the first binding agent is directed at least against a first type of target molecule selected from a group consisting of: cytokines, nitric oxide, thromboxanes, leukotrienes, phospholipids, prostaglandins, kinins, complement factors, coagulation factors, superantigens, monokines, chemokines, interferons, free radicals, proteases, arachidonic acid metabolites, prostacyclins, beta endorphins, myocardial depressant factors, anandamide, 2-arachidonoylglycerol, tetrahydrobiopterin, cell fragments and chemicals including histamine, bradykinin, and serotonin.

25. The method according to claim 11, wherein the at least first binding agent is directed at least against a first type of target molecule selected from a group consisting of: LPS, lipotechoic acid, TNFα, TGFβ, IL-1, IL-6, IL-8, IL-10, IL-15, IL-18, IL-33, GM-CSF, IFNγ, HMGB1, C5a, C3a, and adrenomedullin.

26. The method according to claim 12, wherein the second binding agent is directed at least against a second type of target molecule selected from a group consisting of: cytokines, nitric oxide, thromboxanes, leukotrienes, phospholipids, prostaglandins, kinins, complement factors, coagulation factors, superantigens, monokines, chemokines, interferons, free radicals, proteases, arachidonic acid metabolites, prostacyclins, beta endorphins, myocardial depressant factors, anandamide, 2-arachidonoylglycerol, tetrahydrobiopterin, cell fragments and chemicals including histamine, bradykinin, and serotonin.

27. The method according to claim 12, wherein the second binding agent is directed at least against a second type of target molecule selected from a group consisting of: LPS, lipotechoic acid, TNFα, TGFβ, IL-1, IL-6, IL-8, IL-10, IL-15, IL-18, IL-33, GM-CSF, IFNγ, HMGB1, C5a, C3a, and adrenomedullin.

28. The method according to claim 13, wherein the at least first binding agent and/or the at least second binding agent is an antibody or an aptamer, at least directed against the first type of target molecule and/or the second type of target molecule.

29. The method according to claim 13, wherein the at least first binding agent and/or the at least second binding agent is a monoclonal antibody.

30. The assembly according to claim 15, wherein the functionalized magnetic particles are nano-size magnetic absorbents.

31. The assembly according to claim 15, wherein the separation unit is a magnetic filter.

32. The assembly according to claim 16, wherein the diagnostic unit is arranged upstream of the first injection device.

33. The assembly according to claim 19, wherein the control unit is arranged to receive the data providing information about the immunological status of the patient from the diagnostic unit.

34. The assembly according to claim 19, wherein the control unit is arranged to control at least the first injection step.

35. The assembly according to claim 19 or claim 34, wherein the control unit is arranged to control any second or further second injection step.

36. The assembly according to claim 19, wherein the control unit comprises a user interface.

37. The assembly according to claim 20, wherein the assembly comprises a conditioning unit in the form of a dispersion unit.

38. The assembly according to claim 21, wherein the reservoir is disposable.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0081] Preferred embodiments of the invention are described in the following with reference to the drawings, which are for the purpose of illustrating the present preferred embodiments of the invention and not for the purpose of limiting the same. In the drawings,

[0082] FIG. 1 shows three possible different treatment methods; wherein FIG. 1A shows a fight against hyper-inflammation by removing hyper-inflammatory mediators; FIG. 1B shows a restoration of immune competence by removing immunosuppressant mediators; and FIG. 1C shows a balancing of hyper-inflammation and immunosuppression;

[0083] FIG. 2 shows a flow chart of the various diagnostic and phenotyping steps based on which the extracorporeal treatment is based;

[0084] FIG. 3 shows a simplified schematic representation of the assembly of extracorporeal treatment method.

DESCRIPTION OF PREFERRED EMBODIMENTS

[0085] In FIGS. 1A-1C, the immune response of three exemplary patients to an “injury”, i.e. pathogenic insult is shown, including the influence of the extracorporeal treatment in each case. As described above, each patient has an individual immune status, depending, among others, on his clinical symptoms, age, comorbidities, or time point of treatment.

Example A: Removal of Hyperinflammatory Mediators

[0086] In case of sepsis, the response according to a first model A rapidly sets in with both proinflammatory and anti-inflammatory reactions. Severe sepsis is characterized by an overwhelming hyperinflammatory phase, including fever and abnormally increased circulatory volume, resulting in septic shock. Cardiovascular collapse, metabolic derangements, and multiple organ dysfunction are the main causes of death in such severe cases of septic shock. Treatments include short acting therapies with anti-inflammatory or anticytokine agents.

[0087] In patient A, as shown in FIG. 1A, following a pathogenic insult, hyperinflammation is suspected after standard examination and following “surviving sepsis campaign”. The primary infection is identified as a gram-negative infection. Based on this diagnosis, LPS and pro-inflammatory cytokines (the early pro-inflammatory cytokines IL-1, TNFα, and IL-18) are removed from the blood in the extracorporeal treatment according to the invention. For this purpose, injecting functionalized magnetic particles bound to a first binding agent directed against LPS, e.g. selected from polymyxin B or a derivative thereof, a monoclonal antibody directed against LPS, mannose-binding lectin, or polyethyleneimine (PEI), is added to the extracorporeal flow line comprising blood extracted from patient A. Then, a second injection of functionalized magnetic particles bound to a second binding agent against IL-1, e.g. a monoclonal antibody, is carried out, followed by a third injection of functionalized magnetic particles bound to a third binding agent against TNFα, e.g. a monoclonal antibody, and a fourth injection of functionalized particles bound to a fourth binding agent against IL-18, e.g. a monoclonal antibody. Alternatively, one or more pre-mixed injection mixtures, e.g. a special, “hyperinflammatory mix”, containing multiple functionalized magnetic particles with the multiple necessary binding agents directed against various target molecules is used. The treated blood is returned into the circulatory system of patient A. After 6 hours, measurement of the concentration of TNFα and IL-1 show a decreased level of these targets with a short circulation time. Therefore, the dosing of TNF alpha and IL-1 sorbents (binding agents) are reduced.

[0088] After 8 hours, the pathogen strain is identified and the most potent appropriate antibiotic is administered. An antibiotic-induced LPS-release is foreseen, which is why the dosing of LPS-removal (sorbents/binding agents against LPS) is increased. As LPS has various sources, the efficiency of LPS removal can be increased by applying a mixture of different binding agents directed against LPS, e.g. consisting of a monoclonal antibody against LPS and polymyxin B or a derivative thereof.

[0089] After the hyperinflammatory phase, patient A goes through a short counterbalancing phase of immunosuppression and recovers.

[0090] Therefore, if a hyper-inflammation is detected, hyper-inflammatory mediators are removed.

Example B: Removal of Immunosuppressant Mediators

[0091] Comorbidities, especially in elderly patients, can impair the immune response. In patients responding according to this second model B, the development of sepsis can result in a blunted or absent hyperinflammatory phase, and a rapid development of an anti-inflammatory state. In this case, immunoadjuvant therapy serves as the treatment of choice.

[0092] In patient B, the primary infection is identified as a gram-positive infection. Following the pathogenic insult, it is possible that patient B reacts with a normal inflammatory phase, followed by a phase of immunosuppression (as shown). However, it is also possible, that, analogous to patient A, the patient first displays a phase of hyperinflammation (not shown in Figure B). Based on the diagnosis of a gram-positive infection, in case a hyperinflammation is suspected after standard examination and following “Surviving Sepsis Campaign”, lipotechoic acid and pro-inflammatory cytokines (the early pro-inflammatory cytokines IL-1, TNFα, and IL-18) are removed from the blood in the extracorporeal treatment according to the invention. For this purpose, injecting functionalized magnetic particles bound to a first binding agent directed against lipotechoic acid, e.g. a monoclonal antibody, is added to the extracorporeal flow line comprising blood extracted from patient B. Then, a second injection of functionalized magnetic particles bound to a second binding agent against IL-1, e.g. a monoclonal antibody, is carried out, followed by a third injection of functionalized magnetic particles bound to a third binding agent against TNFα, e.g. a monoclonal antibody, and a fourth injection of functionalized particles bound to a fourth binding agent against IL-18, e.g. a monoclonal antibody. Alternatively, one or more pre-mixed injection mixtures, containing multiple functionalized magnetic particles with the multiple necessary binding agents directed against various target molecules is used, e.g. a special, “immunosuppression mix”.

[0093] The treated blood is returned into the circulatory system of patient B. After 6 hours, measurement of the concentration of TNFα and IL-1 show a decreased level of these targets with a short circulation time. Therefore, the dosing of TNF alpha and IL-1 sorbents (binding agents) is reduced.

[0094] After 2 days of a possible hyper-inflammatory phase (analogous to patient A) or a normal inflammatory phase (contrary to patient A), as shown in FIG. 1B, patient B falls into a persistent immunosuppression as confirmed by mHLA-DR measurement, which increases the risk of secondary infections and of death. Despite the insult being from a gram-positive pathogen, high levels of LPS are measured due to translocation from the gut, as the membrane of the gut often becomes damaged and thus, permeable. Therefore, a removal of LPS is initiated. Furthermore, the removal of IL-10, IL-6 and C5a is initiated, as their overexpression (high concentrations) leads to an impaired immune response. The removal of IL-10, IL-6, C5a, and LPS lead to a restored immune function as confirmed by mHLA-DR. Patient B survives.

[0095] Therefore, if immune competence is impaired, immune competence is restored by removing immunosuppressant mediators.

Example C: Restoration of Balance of Immune Response

[0096] A third model C of a possible immunological response to sepsis shows a cycling between hyperinflammatory and hypoinflammatory or immunosuppressive states. If such patients develop sepsis, they display an initial hyperinflammatory response, followed by a hypoinflammatory state/or phase of immunosuppression. In case of a secondary infection, such patients can develop a repeated hyperinflammatory response, leading either to recovery or to a re-entry of the hypoinflammatory phase, with the danger of a severe immunosuppression.

[0097] In Patient C, as shown in FIG. 1C, hyper-inflammation is detected after standard examination and following “Surviving Sepsis Campaign”. The primary infection is identified as a gram-negative infection. Based on this diagnosis, LPS and pro-inflammatory cytokines (the early pro-inflammatory cytokines IL-1, TNFα, and IL-18, which have a short circulation time) are removed from the blood in the extracorporeal treatment according to the invention. For this purpose, injecting functionalized magnetic particles bound to a first binding agent directed against LPS, e.g. selected from polymyxin B or a derivative thereof, a monoclonal antibody directed against LPS, mannose-binding lectin, or polyethyleneimine (PEI) (as in patient A), is added to the extracorporeal flow line comprising blood extracted from patient C. Then, a second injection of functionalized magnetic particles bound to a second binding agent against IL-1, e.g. a monoclonal antibody, is carried out, followed by a third injection of functionalized magnetic particles bound to a third binding agent against TNFα, e.g. a monoclonal antibody, and a fourth injection of functionalized particles bound to a fourth binding agent against IL-18, e.g. a monoclonal antibody. Here too, it is possible, to use pre-mixed injection mixtures, e.g. “hyper-/hypo-mixtures” containing multiple functionalized magnetic particles with the multiple necessary binding agents directed against various target molecules.

[0098] The treated blood is then returned into the circulatory system of patient C. After 2 days of hyper-inflammatory phase, patient C falls into a persistent immunosuppression as confirmed by mHLA-DR measurement, which increases the risk of secondary infection and death. High levels of LPS are measured due to translocation from the gut. Therefore, a removal of LPS is initiated. Furthermore, the removal of IL-10, IL-6, TGFβ and C5a is initiated from day 3-5, as their overexpression (high concentrations) leads to an impaired immune response.

[0099] A hyper-inflammatory phase is treated on day 6 with the removal of proinflammatory cytokines (see above). Immunosuppression is then treated on day 7-8, leading to recovery of patient C.

[0100] Therefore, if an imbalance of hyper-inflammation and immunosuppression is detected, the balance is restored by treatment of each phase separately and subsequently.

[0101] FIG. 2 shows a flow chart of the steps leading to the control of the extracorporeal treatment according to the invention:

[0102] Based on clinical symptoms, the emergency physician or intensive care physician suspects either a hyper-inflammation or an immunosuppression (or persistent, inflammation, immunosuppression and catabolic syndrome (PICS)). Based on this suspicion, the immune status or function is first evaluated by checking general clinical criteria, i.e. general markers, such as body temperature, heart rate, respiratory rate, and general organ function.

[0103] General criteria for SIRS are the following: [0104] body temperature: Temp >38° C. (100.4° F.) or <36° C. (96.8° F.) [0105] heart rate: >90 [0106] respiratory rate: >20 or PaCO.sub.2<32 mm Hg (PaCO.sub.2=arterial carbon dioxide tension) [0107] leukocyte count (WBC): >12,000/mm.sup.3, <4,000/mm.sup.3, or >10% bands

[0108] When a patient presents with two or more SIRS criteria but with hemodynamic stability (i.e. blood pressure at baseline), a more detailed clinical assessment must be made to determine the possibility of an infectious etiology.

[0109] Furthermore, the procalcitonin (PCT) test is used by emergency and intensive care physicians for the diagnosis of sepsis. Procalcitonin is a considered the most significant biomarker for severe inflammations and infections. Normally, PCT only occurs in the blood in very low concentrations. Its production and release can be stimulated by almost every organ by inflammatory cytokines and bacterial endotoxins. Therefore, the higher the concentration of PCT, the more likely is a systemic infection and a sepsis.

[0110] If an infection is suspected or confirmed based on standard monitoring, the patient is diagnosed with sepsis and a lactate level is obtained to determine the degree of hypoperfusion and inflammation. Severe sepsis is diagnosed in case of organ dysfunction, hypotension or hypoperfusion, for which a lactic acidosis can be an indicator, if the systolic blood pressure is <90 or drops ≥40 mm Hg of normal. A lactate level ≥4 mmol/L is considered an indicator for Severe Sepsis, and aggressive management with broad spectrum antibiotics, intravenous fluids, and vasopressors should be initiated (aka EGDT). Severe sepsis with hypotension, despite adequate fluid resuscitation, is an indicator for septic shock. Patients that present with a suspected or confirmed infection and hemodynamic instability should immediately be treated for septic shock. While SIRS criteria will likely be present in these patients, aggressive management should not be delayed while waiting for laboratory values such as the WBC or lactate. In case of evidence of two or more organs failing, multiple organ dysfunction syndrome is diagnosed. Early recognition of sepsis, severe sepsis, and septic shock, and early administration of broad spectrum and organism specific antibiotic are the most critical actions.

[0111] In case the patient is in a phase of hyper-inflammation, the infection source is then identified as being either bacterial, viral or fungal. In case of bacterial infections, the infection source can further be specified as the bacteria being gram-negative or gram-positive. After the active infection source has been identified, the treatment is selected, depending on the infection source.

[0112] If the patient is found to be in a state of immunosuppression, especially if the patient is found to belong to a high-risk subgroup, an immune status phenotyping is carried out.

[0113] After a sepsis has been clinically diagnosed, treatment following the “Surviving Sepsis Campaign” is immediately induced. Meanwhile, the phenotype of the immune status is further specified by phenotyping, i.e. by assaying the concentration of various target substances/markers. The measurement of target substances/markers is carried out preferably by an endotoxin activity assay (EAA test) in case of lipopolysaccharides, and by an enzyme-linked immunosorbent assay (ELISA) in case of cytokines/complement factors. Further characterizing of the immune status and a more precise etiology is possible by assaying the genomics and metabolomics of the patient.

[0114] The proposed treatment, which can be adapted based on the results of phenotyping, comprises an adaptive treatment for inflammation patients, wherein the therapeutic assembly includes one or several defined sorbents, preferably magnetic nanosorbents, equipped with specific affinity binders, e.g. antibodies towards inflammation targets, e.g. for LPS, TNF, IL6, IL8, IL10, and preferably also C3a, C5a. One or several of these sorbents are dosed according to the immunological status of the patient, i.e. based on the results of the above described diagnostic step, preferably including immune status phenotyping. Over the duration of treatment, the injection mixture(s), i.e. the sorbent-/binding agent mixtures can be adapted to the actual immune status of the patient over time. Repeated diagnostic tests of the body fluid before and after one or more cycles of treatment, allow the adjustment of the type and/or concentration and/or amount of injected functionalized magnetic nanosorbents.

[0115] Proposed Treatment Options:

[0116] Target Molecules to be Removed in Case of Hyper-Inflammation as a Result of Gram-Negative Bacterial Infection: [0117] Primary infection pathogen, i.e. whole bacteria [0118] Primary infection PAMPS (pathogen-associated molecular patterns): LPS, bacterial toxins, flagellin, bacterial RNA/DNA, peptidoglycan [0119] Pro-inflammatory immune mediators: TNFα, IL-1, IL-6, IL-8, IL-15, IL-18, GM-CSF, IFNγ [0120] Complement factors: C5a, C3a

[0121] Target Molecules to be Removed in Case of Hyper-Inflammation as a Result of Gram Positive Bacterial Infection: [0122] Primary infection pathogen, i.e. whole bacteria [0123] Primary infection PAMPS: lipotechoic acid, bacterial toxins, flagellin, bacterial RNA/DNA, peptidoglycan [0124] Pro-inflammatory immune mediators: TNFα, IL-1, IL-6, IL-8, IL-15, IL-18, GM-CSF, IFNγ [0125] Complement factors: C5a, C3a

[0126] Target Molecules to be Removed in Case of Hyper-Inflammation as a Result of Gram Indefinite Bacterial Infection: [0127] Primary infection pathogen, i.e. whole bacteria [0128] Primary infection PAMPS: bacterial toxins, flagellin, bacterial RNA/DNA, peptidoglycan [0129] Pro-inflammatory immune mediators: TNFα, IL-1, IL-6, IL-8, IL-15, IL-18, GM-CSF, IFNγ [0130] Complement factors: C5a, C3a

[0131] Target Molecules to be Removed in Case of Hyper-Inflammation as a Result of Viral Infection: [0132] Virus [0133] Primary infection PAMPS: viral RNA/DNA, peptidoglycan [0134] Pro-inflammatory immune mediators: TNFα, IL-1, IL-6, IL-8, IL-15, IL-18, GM-CSF, IFNγ [0135] Complement factors: C5a, C3a

[0136] Target Molecules to be Removed in Case of Hyper-Inflammation as a Result of Fungal Infection: [0137] Fungal cells [0138] Primary infection PAMPS: fungal toxins, chitin, fungal DNA/RNA [0139] Pro-inflammatory immune mediators: TNFα, IL-1, IL-6, IL-8, IL-15, IL-18, GM-CSF, IFNγ [0140] Complement factors: C5a, C3a

[0141] Target Molecules to be Removed in Case of Hyper-Inflammation, Despite an Already Resolved Primary Infection, when the Main Problem is a Secondary Infection or an Imbalance of the Immune System: [0142] Primary infection PAMPS: LPS (e.g. entered the vascular system through a perforated membrane of the intestines); [0143] DAMPS (damage-associated molecular patterns): HMGB1, histone, cell DNA/RNA [0144] Pro-inflammatory immune mediators: TNFα, IL-1, IL-6, IL-8, IL-15, IL-18, GM-CSF, IFNγ [0145] Complement factors: C5a, C3a

[0146] Target Molecules to be Removed in Case of Immunosuppression with a Still Active Infection Source: [0147] Primary infection PAMPS: according to infection type, see above; [0148] DAMPS: HMGB1, histone, cell DNA/RNA [0149] Cytokines with immunosuppressive effect: IL-6, IL-10, IL-33, TGFβ [0150] Complement factors: C5a, C3a

[0151] Target Molecules to be Removed in Case of Immunosuppression Despite a Resolved Primary Infection, when the Main Problem is a Secondary Infection or an Imbalance of the Immune System: [0152] Primary infection PAMPS: LPS (e.g. entered the vascular system through a perforated membrane of the intestines); [0153] DAMPS: HMGB1, histone, cell DNA/RNA [0154] Cytokines with immunosuppressive effect: IL-6, IL-10, IL-33, TGFβ [0155] Complement factors: C5a, C3a

[0156] The treatment steps shown in FIG. 2 do not have to be applied in a linear fashion, as the treatment steps can also be part of a feedback loop, wherein one or more steps is/are controlled based on the diagnostic data collected at different points in time and thus based on a possible algorithm implemented in a computer program or translated into instructions for medical personnel.

[0157] A schematic overview of the assembly according to the present invention is shown in FIG. 3. In this specific embodiment, the assembly comprises an extracorporeal circuit, i.e. an extracorporeal flow line. This extracorporeal flow line can be connected to a body of a patient suffering from a dysregulated immune response, for continuous treatment or purification of the body fluid, which in this case is blood. However, the extracorporeal circuit can be disconnected from the patient's body and samples of the untreated blood previously extracted from the patient's body can be injected into an inlet port of the extracorporeal flow line. The untreated blood is diagnosed in a diagnostic unit connected to or associated with the extracorporeal flow line. In the embodiment shown in FIG. 3, the diagnostic results are interpreted by a controller that acutates the injection units and doses the suitable nanosorbents. The blood is driven through the extracorporeal flow line by a blood pump. The depicted assembly further can contain at least one sorbent reservoir and/or at least one conditioning unit (not shown). Four injection units/devices are shown in form of injection ports into which separate pre-mixed injections mixtures, containing functionalized nanomagnets are attached for injection of the respective injection mixtures into the untreated blood flowing in the extracorporeal flow line. Following the injection step, the blood is mixed and incubated for sufficient complexation of the target molecules to the binding agents, i.e. nanosorbents. In the embodiment shown, the mixing- and incubation steps are carried out in a segment of the extracorporeal flow line. After a sufficient, possibly pre-defined level of complexation is reached, the blood is directed through a separation unit, in which the magnetic particles are separated from their binding agents, which now are bound to toxic substances or target molecules, the removal, i.e. total removal or reduction of concentration, of which is the result of the treatment. The end product of such a single “cycle” or pass of the extracorporeal treatment is purified blood, which can either be continuously directed back into the patient's body or extracted at the outlet port of the extracorporeal flow line for storage, further treatment cycles (possibly with other binding agents) or return to the body of the patient at a later point in time.