MODIFIED HUMAN SERUM ALBUMIN AS A THERAPEUTIC IN COVID-19 PATIENTS

Dr. William Norberg, MD, Dr. P. Yaft, Pharm.D, and Dr. J. Norberg, MD

SUMMARY:

The authors feel that there is a role for a modified albumin solution, one that more closely represents the native endogenous albumin protein found in the plasma, without sacrificing the need for purification, as a potential therapy for SARS-CoV-2. Based on the above evidence we can conclude the following:

1. ACE and Albumin

a. The receptor critical for SARS-CoV-2 entry into host cells is the angiotensin-converting enzyme 2 ACE2.

b. This enzyme (ACE2) is present in the circulation, in addition to the organs.

c. Increasing the soluble ACE2 (that lacks the membrane anchor) in the blood that may act as a competitive interceptor of SARS-CoV by preventing binding of the viral particle to the surface-bound, full-length ACE2.

d. ACE2 is not a readily available therapeutic agent. Albumin downregulates the expression of the ACE2 receptors.

e. Insulin increases ACE2 gene and protein expression. Albumin can decrease ACE2 enzymatic activity.

2. Albumin as an independent risk factor at presentation

Covid-19 patients have lower serum albumin levels associated with increased risk of death, independent of other risk factors.

3. Cytokine Storm

a. SARS-CoV-2 can lead to acute respiratory distress syndrome (ARDS) resulting from an immunological cascade of responses (inflammatory cytokine storm). Albumin is the most prominent endogenous free radical scavenger and antioxidant. Albumin infusions result in a negative correlation with levels of IL6, TNF-α

b. Current SARS-CoV-2 therapies such as corticosteroids and antivirals attempting to calm the cytokine storm can further cause hepatic damage, limiting the creation of albumin.

4. Renal

SARS-CoV-2 patients have a high rate of renal abnormalities, including elevated albumin in the urine.

5. Liver

SARS-CoV-2 patients have a high rate of liver injury, and bile duct cells express ACE2. Liver injury further worsens the inflammatory response, albumin may be hepatoprotective and provides an exogenous source of albumin.

In vivo (unprocessed) and in vitro (processed) albumin behave differently. The author’s associated 24 case reports of a modified commercially available albumin within an amino-acid solution shows improved clinical outcomes and no untoward effects. We have been able to measure a 17% increase in the size of the albumin molecule when combined with amino acids. We attribute the improved clinical outcomes to the albumin protein expanding in size and more closely mirroring albumin’s endogenous properties, in addition to a proposed reduction in protein catabolism.

ARTICLE:

A new coronavirus, referred to as SARS-CoV-2, is responsible for the recent outbreak of severe respiratory disease. It has been known since the 2003 SARS epidemic that the receptor critical for SARS-CoV entry into host cells is the angiotensin-converting enzyme 2 ACE2.

Surface expression of ACE2 receptors on lung alveolar epithelial cells (type 2 pneumocytes) are a binding site for SARS-CoV-2, the virus that causes COVID-19. (1)

1. Hamming I., Timens W., Bulthuis M.L., Lely A.T., Navis G. and van Goor H. (2004) Tissue distribution of ace2 protein, the functional receptor for sars coronavirus. A first step in understanding sars pathogenesis. J. Pathol. 203, 631–637 https://doi.org/10.1002/path.1570

The angiotensin-converting enzyme 2 ACE2 is a monocarboxypeptidase best known for cleaving several peptides within the renin–angiotensin system. This enzyme in present in the circulation in small amounts, but widely expressed in organs, such as the kidneys and the gastrointestinal tract, with relatively low level of expression in lungs.(2)

2. Serfozo P., Wysocki J., Gulua G., Schulze A., Ye M., Liu P. et al. (2020) Ang ii (angiotensin ii) conversion to angiotensin-(1-7) in the circulation is pop (prolyloligopeptidase)-dependent and ace2 (angiotensin-converting enzyme 2)-independent. Hypertension 75, 173–182 https://doi.org/10.1161/HYPERTENSIONAHA.119.14071[PubMed]

Functionally, there are two forms of ACE2. The full-length ACE2 contains a structural transmembrane domain, which anchors its extracellular domain to the plasma membrane. The extracellular domain has been demonstrated as a receptor for the spike (S) protein of SARS-CoV. (3) and recently, for the SARS-CoV-2. (4)

3. Du L., He Y., Zhou Y., Liu S., Zheng B.J. and Jiang S. (2009) The spike protein of sars-cov–a target for vaccine and therapeutic development. Nat. Rev. Microbiol . 7, 226–236 https://doi.org/10.1038/nrmicro2090[PubMed]

4. Lu R., Zhao X., Li J., Niu P., Yang B., Wu H. et al. (2020) Genomic characterization and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet 395, 565–574 https://doi.org/10.1016/S0140-6736(20)30251-8[PubMed]

The soluble form of ACE2 lacks the membrane anchor and circulates in small amounts in the blood. (5)

5. Wysocki J., Ye M., Rodriguez E., Gonzalez-Pacheco F.R., Barrios C., Evora K. et al. (2010) Targeting the degradation of angiotensin ii with recombinant angiotensin-converting enzyme 2: Prevention of angiotensin ii-dependent hypertension. Hypertension 55, 90–98 https://doi.org/10.1161/HYPERTENSIONAHA.109.138420[PubMed]

Its proposed by (Batlle, et al) that this soluble form may act as a competitive interceptor of SARS-CoV and other coronaviruses by preventing binding of the viral particle to the surface-bound, full-length ACE2. (6) Indeed, in vitro studies showed that SARS-CoV replication was blocked by a soluble form of ACE2 in the monkey kidney cell line, Vero-E6. (7),(8)

6. Daniel Batlle, Jan Wysocki, Karla Satchell; Soluble angiotensin-converting enzyme 2: a potential approach for coronavirus infection therapy?. Clin Sci (Lond) 13 March 2020; 134 (5): 543–545. doi: https://doi.org/10.1042/CS20200163

7. Li W., Moore M.J., Vasilieva N., Sui J., Wong S.K., Berne M.A. et al. (2003) Angiotensin-converting enzyme 2 is a functional receptor for the sars coronavirus. Nature 426, 450–454 https://doi.org/10.1038/nature02145[PubMed]

8. Ksiazek T.G., Erdman D., Goldsmith C.S., Zaki S.R., Peret T., Emery S. et al. (2003) A novel coronavirus associated with severe acute respiratory syndrome. N. Engl. J. Med. 348, 1953–1966 https://doi.org/10.1056/NEJMoa030781[PubMed]

PCR analysis revealed that ACE-2 is also expressed in the lung, kidney, and gastrointestinal tract, tissues shown to harbor SARS-CoV. (9-11)

9. Ksiazek, T.G. et al. (2003) N. Engl. J. Med. 348:1953.

10. Harmer, D. et al. (2002) FEBS Lett. 532:107.

11. Leung, W.K. et al. (2003) Gastroenterology 125:1011

Moreover, ACE2 fused to the Fc portion of immunoglobulin has just been reported to neutralize SARS-CoV-2 in vitro (9) and the SARS-CoV-2 binds ACE2 with higher affinity than SARS-CoV (10). In this context, provision of soluble recombinant human ACE2 protein could actually be beneficial as a novel biologic therapeutic to combat or limit infection progression caused by coronaviruses that utilize ACE2 as a receptor [Figure 1].

[Figure 1]a

The authors propose that because ACE2 is not a readily available therapeutic agent, other readily available therapeutic agents should be explored. So how else can soluble endogenous ACE2 be produced? Albumin downregulates the expression of the ACE2 receptors (14) and has been shown to improve the ratio of arterial partial pressure of oxygen/fraction of inspired oxygen in patients with acute respiratory distress syndrome as soon as 24 hours after treatment and with an effect that persisted for at least seven days. (15)

14. Liu BC, Gao J, Li Q, Xu LM. Albumin caused the increasing production of angiotensin II due to the dysregulation of ACE/ACE2 expression in HK2 cells. Clin Chim Acta. 2009 May 1;403(1–2):23–30.

15. Uhlig C, Silva PL, Deckert S, Schmitt J, De Abreu MG. Albumin versus crystalloid solutions in patients with the acute respiratory distress syndrome: A systematic review and meta-analysis. Crit Care [Internet]. 2014 Jan 9 [cited 2020 Mar 30];18(1):R10. Available from: http://ccforum.biomedcentral.com/articles/10.1186/cc13187

Márquez E et al, found that insulin increases ACE2 gene and protein expression, by real-time PCR and Western blotting, respectively. Additionally in concordance with protein expression, insulin incubation in the presence of albumin resulted in a 35% decrease in ACE2 enzymatic activity that was statistically significant compared with insulin alone (PODins vs. PODai, P = 0.001) (16)

16. Márquez E, Riera M, Pascual J, Soler MJ. Albumin inhibits the insulin-mediated ACE2 increase in cultured podocytes. 01 JUN 2014. https://doi.org/10.1152/ajprenal.00594.2013

Moreover, researchers who have studied the clinical characteristics of Covid-19 patients have reported again and again that lower serum albumin levels were associated with an increased risk of death, even to suggest that “albumin therapy might be a potential remedy”. (17)

17. Liu Y, Yang Y, Zhang C, Huang F, Wang F, Yuan J, et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci. 2020;63(3):364–74.

It is known that SARS-CoV-2 can cause respiratory, intestinal, hepatic and neuronal diseases, and may lead to acute respiratory distress syndrome (ARDS), multiple organ failure (MOF) and even death in severe cases. (18-20)

18. Peiris J, Lai ST, Poon L, et al. Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet. 2003;361(9366):1319-1325.

19. Kupferschmidt K. Researchers scramble to understand camel connection to MERS. Science. 2013;341(6147):702. 4.

20. Zhu NA, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382(8): 727-733.

Reactive oxygen species (ROS) are the primary pathogenic molecules produced in viral lung infections and ARDS.

Alveolar macrophages will release reactive oxygen spices (TNF-α), (IL-8), and activated neutrophils will release (proteases, oxidants, and PAF). Eventually these will destroy the virus, and damage the Type 1 pneumocytes (gas exchange) and Type 2 pneumocytes (↓ surfactant), (↑ surface tension) and result in alveolar collapse.

In sepsis patients the infusion of albumin positively correlated with increased levels of serum albumin and a negative correlation with the levels of IL6, TNF-α and SOFA score. It also found a correlation between changes in levels of albumin with changing levels of IL6 (p <0:01) and changes in SOFA score (p <0.05). (21)

TNF-α, IL-1 and IL-6 is are cytokines that have a crucial role in the inflammatory process caused by infection. From research Hamishekar et al showed that IL-6 and APACHE-2 is useful in predicting mortality and clinical evaluation in patients with severe sepsis. (22)

21. Arie Utariani, Budi Prasetyo, Jusak Nugraha. CORRELATION BETWEEN THE USE OF ALBUMIN INFUSION AND CONCENTRATIONS OF SERUM ALBUMIN, PROINFLAMMATORY CYTOKINES (TNF-α, IL6) AND SOFA SCORE IN SEPTIC PATIENTS. Department of Anesthesiology & Reanimation, Department of Clinical Pathology, Dr Soetomo Hospital, Faculty of Medicine, Universitas Airlangga, Surabaya

22. Hamishehkar H, Beigmohammadi MT, Abdollahi M, et al. Identification of enhanced cytokine generation following sepsis. Dream of magic bullet for mortality prediction and therapeutic evaluation. Daru. 2010;18(3):155–162.

Examination of the SARS-CoV-2 on the Kidney

New data on coronavirus disease include some startling revelations: Kidney involvement seems to be frequent in people who have been tested positive and have developed symptoms.

Two studies (23) (24) showed a high rate of renal abnormalities in corona-positive patients: Admitted to hospital, 34% of the 59 patients (23) developed massively elevated levels of albumin in urine (=proteinuria), a symptom of kidney damage 63% of the study patients developed proteinuria while in hospital, and many of them also had blood loss in their urine (hematuria). Kidney function was impaired in 27% of the study population and in 66% of the patients who died from the coronavirus infection. These findings are supported by a second study involving 710 hospitalized patients (23): On admission, 44% had hematuria and proteinuria (26.7% had hematuria only), and kidney function decreased in nearly 15%.

23. Li Z, Wu M, Guo J et al. Caution on Kidney Dysfunctions of 2019-nCoV Patients. medRxiv preprint doi: https://doi.org/10.1101/2020.02.08.20021212

24. Cheng Y, Luo R, Wang K, et al. Kidney impairment is associated with in-hospital death of COVID-19 patients. doi: https://doi.org/10.1101/2020.02.18.20023242

The authors argue that it is logical to assume that if a patients with SARS-CoV-2 will experience elevated proteinuria, then serum albumin would be depleted or result in some deficit.

Examination of the impact of the SARS-CoV-2 on the Liver

Table 1: Characteristics of liver injury during COVID-19

Table 1 - Characteristics of Liver Injury Covid-19.PNG

Recent studies on COVID-19 have shown that the incidence of liver injury ranged from 14.8% to 53%, mainly indicated by abnormal ALT/AST levels accompanied by slightly elevated bilirubin levels. (25-36)

25. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of 2019 novel coronavirus infection in China. medRxiv. 2020; in press. https://doi. org/10.1101/2020.02.06.20020974.

26. Cai Q, Huang D, Ou P, et al. COVID-19 in a Designated Infectious Diseases HospitalOutside Hubei Province, China. medRxiv. 2020; in press. https://doi.org/10.1101/2020.02.17.20024018

27. Fan Z, Chen L, Jun LI, et al. Clinical features of COVID-19- related liver damage. medRxiv. 2020; in press. https://doi. org/10.1101/2020.02.26.20026971

28. Wang D, Hu BO, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020.

29. Cao W. Clinical features and laboratory inspection of novel coronavirus pneumonia (COVID-19) in Xiangyang, Hubei. medRxiv. 2020; in press. https://doi.org/10.1101/2020.02.23.20026963

30. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507-513.

31. Shi H, Han X, Jiang N, et al. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis, 2020. https://doi.org/10.1016/S1473 -3099(20)30086-4

32. Xu X-W, Wu X-X, Jiang X-G, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ. 2020;m606.

33. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020. https://doi.org/10.1016/S2213-2600(20)30079-5

34. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.

35. Zhang B, Zhou X, Qiu Y, et al. Clinical characteristics of 82 death cases with COVID-19. medRxiv. 2020; in press. https://doi. org/10.1101/2020.02.26.20028191

36. Huang Y, Zhou H, Yang R, et al. Clinical characteristics of 36 non-survivors with COVID-19 in Wuhan, China. medRxiv;2020; in press. https://doi.org/10.1101/2020.02.27.20029009

One study reported that serum ALT and AST levels increased up to 7590 U/L and 1445 U/L, respectively, in a severe COVID-19 patient.24 Also it is very noteworthy that in this same study the albumin level was decreased in severe cases and the level of albumin was around 26.3-30.9 g/L. (37)

37. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507-513.

It has also been shown by Saad et al that the low level of albumin was a predictor of disease severity. (38) In addition to Albumin being observed a an independent risk factor for the development of severe MERS-CoV infection

38. Saad M, Omrani AS, Baig K, et al. Clinical aspects and outcomes of 70 patients with Middle East respiratory syndrome coronavirus infection: a single-center experience in Saudi Arabia. Int J Infect Dis. 2014;29:301-306

Chai et al. (39) found that both liver cells and bile duct cells express ACE2. However, the ACE2 expression of bile duct cells is much higher than that of liver cells, but to a comparable level of alveolar type 2 cells in the lung. Bile duct epithelial cells are known to play important roles in liver regeneration and immune response. (40)

39. Chai X, Hu L, Zhang Y, et al. Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection. bioRxiv;2020. https://doi.org/10.1101/2020.02.03.931766

40. Banales JM, Huebert RC, Karlsen T, Strazzabosco M, LaRusso NF, Gores GJ. Cholangiocyte pathobiology. Nat Rev Gastroenterol Hepatol. 2019;16(5):269-281

Significant pro-inflammatory cytokine responses were observed in the acute phase of MERS-CoV infection in patients, and the concentrations of serum IFN-γ, TNF-α, IL-15 and IL-17 were significantly increased. (41)

41. Mahallawi WH, Khabour OF, Zhang Q, Makhdoum HM, Suliman BA. MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile. Cytokine. 2018;104:8-13.

Additionally, the inflammatory cytokine storm was observed in severe COVID-19 cases. (42)

42. Liu J, Li S, Liu J, et al. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARSCoV-2 infected patients. medRxiv,2020, in press. https://doi. org/10.1101/2020.02.16.20023671

Similar to the situation in SARS, antibiotics, antivirals and steroids are widely used for the treatment of COVID-19. (43) These drugs are all potential causes of liver injury during COVID-19, but not yet being evident. (33) Actually, a recent study reported that the liver injury observed in COVID-19 patients might be caused by lopinavir/litonavir, which is used as antivirals for the treatment of SARS-CoV-2 infection. (27)

43. National Health Commission of the People's Republic of China. Diagnosis and Treatment of Coronavirus disease 2019 (Trial Version 7). http://www.nhc.gov.cn/yzygj/s7652m/202003/a31191442e 29474b98bfed5579d5af95.shtml. Accessed March 6, 2020

33. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020. https://doi.org/10.1016/S2213-2600(20)30079-5

27. Fan Z, Chen L, Jun LI, et al. Clinical features of COVID-19- related liver damage. medRxiv. 2020; in press. https://doi. org/10.1101/2020.02.26.20026971

Hepatic albumin synthesis is not of high priority, and synthesis takes place when the body is nourished adequately. A poor nutritional state, inflammation, exposure to hepatotoxins, and exposure to high colloid osmotic pressure inhibit synthesis. The authors would further argue that it is logical to assume that some patients with SARS-CoV-2 will experience hepatic dysfunction, either as a result of the disease progression or as a result of attempted therapies, and that in turn would result in reduced albumin production and serum albumin.

Albumin, the major serum protein, has multiple important physiological functions including maintenance of colloidal osmotic pressure, binding of a wide variety of compounds, and provision of the bulk of plasma antioxidant activity. Thus, a correlation between serum albumin concentration (CP) and health might be expected.

In fact, there is an astonishingly strong correlation between CP and mortality risk. For example, post-surgical mortality in 54,000 Veterans Administration (VA) Hospital patients increased quasi-logarithmically from <1% to 29% as the patients’ preoperative CP declined from 4.6 g/dL to < 2.1 g/dL. (44) (45)

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Albumin is the most abundant circulating protein found in plasma. It represents half of the total protein content (3.5 g/dL to 5 g/dL) of plasma in healthy human patients. Albumin is synthesized by liver hepatocytes and rapidly excreted into the bloodstream at the rate of about 10 gm to 15 gm per day. Very little albumin is stored in the liver, and most of it rapidly excretes into the bloodstream.

Human albumin is a small globular protein with a molecular weight of 66.5 kilodaltons (KDA). It consists of 585 amino acids which are organized into three repeated homologous domains and is made up of two separate sub-domains, A and B

Once albumin enters the circulation, about 30% to 40% stays in the bloodstream, and the remainder enters the interstitial space. The majority of protein that leaves the circulation then returns to circulation via the lymphatic system. The circulatory half-life of albumin is 16 hours. The majority of albumin’s osmotic effect is attributed to its large molecular weight, while the rest is thought to stem from its negative charge. The latter allows albumin to attract positively charged molecules and, ultimately, water into the intravascular compartment.

Serum albumin concentration (CP) is a remarkably strong prognostic indicator of morbidity and mortality in both sick and seemingly healthy subjects. Surprisingly, the specifics of the pathophysiology underlying the relationship between CP and ill-health are poorly understood. The acute development of hypoalbuminemia with sepsis or trauma results from increased albumin capillary permeability leading to redistribution of albumin from the vascular to interstitial space.

Albumin products fall into two categories. The plasma protein fraction (PPF) 38 is broadly similar to human albumin solution (HAS) and is derived (Fig. 1) by a higher‐yielding process but has a lower minimum albumin purity (>85% for PPF vs ≥95% for HAS). Its main disadvantage is the presence of hypotensive contaminants, particularly PKA. (46-48)

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The traditional method for the purification of albumin for therapeutic use has been cold ethanol fractionation, as described by Cohn and colleagues in 1946 (49) and its later variants.

49. John EJ, Strong LE, Hughes WL Jr, Mulford DJ, Ashworth JN, Melin M, et al. Preparation and properties of serum and plasma proteins. IV. A system for the separation into fractions of the protein and lipoprotein components of biological tissues and fluids. J Am Chem Soc1946; 68: 459–75

Albumin provides >50% of the total antioxidant of normal plasma. (50) This activity has been attributed to the abundant reduced sulfhydryl groups of albumin that have been shown to scavenge a variety of oxygen-free radicals including hypochlorous acid and nitric oxide. In addition to this inherent antioxidant activity, albumin also binds unconjugated bilirubin, a potent antioxidant. This antioxidant activity is commonly assumed to be the mechanism responsible for the strong inverse correlation between plasma unconjugated bilirubin concentration and the morbidity and mortality of many disease states.

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Although the purity and sterility of albumin solutions are standard quality control measures in manufacturing, the screening for posttranscriptional modifications (possibly manufacturing-induced) is not. (51) These modifications may result from nonenzymatic glycation reactions, leading to irreversible formation of advanced glycation end products (AGEs). Whether these pro-inflammatory modifications result in clinically relevant consequences in humans remains unknown. (52)

51. Humpert PM, Lukic IK, Thorpe SR, et al. AGE-modified albumin containing infusion solutions boosts septicaemia and inflammation in experimental peritonitis. J Leukoc Biol. 2009;86(3):589–597. doi:10.1189/jlb.1008646

52. Bar-Or, David MD; Bar-Or, Raphael BS; Rael, Leonard T. MS; Gardner, David K. PhD; Slone, Denetta S. MD; Craun, Michael L. MD. Heterogeneity and oxidation status of commercial human albumin preparations in clinical use. Swedish Medical Center, Trauma Research Laboratory (DB-O, RB-O, LTR), Center for Reproductive Medicine (DG), and Trauma Services (DSS, MLC), Englewood, CO; and DMI BioSciences (DB-O, RB-O, LTR), Englewood, CO.

Commercially available albumin solutions have posttranscriptional modifications that differ markedly from albumin from healthy volunteers and have up to a 10-fold difference in AGE content between batches and manufacturers. (51) (52) It remains unknown if these modifications affect the effectiveness, increase the safety risks, or have deleterious consequences.