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Study suggests that Intravenous Immunoglobulin (IVIG) Increases Survival in Critically Ill COVID-19 Patients requiring Intubation with Mechanical Ventilation
Overall survival was 60.8% in the treatment group which received IVIG (octagam® 5%), versus 38.1% in the control group which did not receive IVIG, corresponding to a trend of 2.2 times reduced risk of death when receiving IVIG treatment
The Effects of IVIG in COVID-19 May Be Related to its Known Immunomodulatory Activities in Various Auto-immune Diseases
Topline results from a retrospective study in 93 critically ill COVID-19 patients have become available. The data shows that IVIG treatment reduces inflammation, which is associated with poor clinical outcomes and death, and points to an increase in survival, in critically ill COVID-19 patients, when compared to a control group. The study was conducted at the Istanbul University Hospital, Turkey, under the lead of Prof. Dr. Figen Esen.
In critically ill COVID-19 patients, the cause of death often implicates an abnormal pulmonary immune response. This abnormal immune response is characterized by high levels of inflammatory markers, which are associated with poor clinical outcomes.1, 2 Acute respiratory distress syndrome (ARDS) and multiorgan failure are major causes of mortality in COVID-19 patients3. High levels of pro-inflammatory cytokines and chemokines are part of a severe inflammatory response known as a “cytokine storm” which may cause multiple organ dysfunction and ARDS in critically ill COVID-19 patients.4
There is no known effective treatment for patients infected with COVID-19, except for remdesivir and dexamethasone.
Early treatment of COVID-19 patients with systemic immune modulators such as IVIG may reduce aberrant immune responses and the subsequent inflammatory responses, which are observed in the severe stages of ARDS and may cause lasting lung damage and death.5, 6
IVIG has been proven to protect from infections in immunodeficient patients and has also been increasingly recognized for its immunomodulatory and anti-inflammatory effects. Although the mechanisms of action of IVIG are not completely understood, it may modulate the immune response via multiple mechanisms, including blocking a wide array of pro-inflammatory cytokines that potentially lead to severe inflammatory responses, including cytokine storm, as well as Fc-gamma receptor binding of activated macrophages)4.
Octagam® (5% and 10%) is a polyvalent IVIG preparation that is approved in over 80 countries worldwide for the treatment of immunodeficiency and other immune disorders.
It is hypothesized that octagam® can treat critically ill COVID-19 patients by reducing and/or preventing hyperinflammation as it has been observed in severe disease.4
In the Istanbul University Hospital study, octagam® 5% was administered at approx. 0.4g/kg body weight for 5 consecutive days (2g/kg body weight total dose) to 51 critically ill COVID-19 patients, all requiring intensive care with intubation and mechanical ventilation. Biomarkers and clinical outcomes were compared with those of 42 critically ill COVID-19 patients who did not receive IVIG. Other treatments used in both treatment groups included favipiravir, hydroxychloroquine, azithromycin, oseltamivir, tocilizumab, and anakinra.
A higher survival rate was observed in the octagam® treatment group. At the end of the study, overall survival was 60.8% in the treatment group which received octagam®, versus 38.1% in the control group which did not receive IVIG (p=0.0906 after controlling for baseline factors), corresponding to a trend of 2.2 times reduced risk of death when receiving IVIG.
At six days after start of treatment, the inflammatory marker C-reactive protein (CRP) was significantly reduced by 46% versus baseline in the IVIG group, whereas there was no reduction compared to baseline in the control group (p=0.0488).
Prof. Dr. Figen Esen, Head of the Intensive Care Department, Istanbul University Hospital, commented: “In the critical care setting, the management of sepsis includes modulation of the immune system and the host response. Whilst IVIG treatment in sepsis has shown positive beneficial effects in terms of infection and lowering inflammation and mortality, the relatively small amount of data generated from high quality clinical trials has prevented its widespread incorporation into clinical guidelines.
The clinical picture of severe COVID-19 in the critical care setting includes many of the same features as sepsis, however with a much more severe inflammatory chaos induced by cytokine storm. There is one other difference; here we do not have any proven effective treatments, apart from manipulating the patient’s immune system, either by augmenting or suppressing.
IVIG therapy presents a perfect choice to modulate the patient’s immune system and calm down the situation. Although our results have certain limitations, we have observed in routine clinical use of IVIG in severely ill COVID-19 patients, a significant reduction in inflammation in the group receiving IVIG treatment, leading to an improved clinical outcome in terms of a much higher survival rate.
We are happy to see the results of our data leading to further prospective randomized multicenter trials in severely ill COVID-19 patients, and we are really very excited to see the results”.
“These positive results from Istanbul University Hospital appear to demonstrate the immune-modulating properties of IVIG in severely-ill COVID-19 patients, in reducing hyperinflammation and the associated cytokine storm syndrome and improving clinical outcomes”, said Wolfgang Frenzel, M.D., Head of Research & Development at Octapharma. “We are hopeful of further positive results in our ongoing Phase 3, multicenter clinical trial on the efficacy and safety of octagam® 10% therapy in COVID-19 patients with severe disease progression, currently being conducted at a number of study sites in the USA”.
These results from Istanbul University Hospital contribute to a growing body of clinical evidence suggesting the role IVIG plays in increasing survival and improving clinical outcomes in critically ill COVID-19 patients, by preventing and/or reducing hyperinflammation and the associated cytokine storm syndrome.
Following on from this positive data from Istanbul University Hospital and also a prospective investigator-initiated study conducted by Dr George Sakoulas of Sharp Memorial Hospital in San Diego, USA, Octapharma has started a Phase 3, multicenter clinical trial on the efficacy and safety of octagam® 10% therapy in COVID-19 patients with severe disease progression.
This study is currently being conducted in various centers in the United States and compares the efficacy and safety of IVIG plus standard of care (SOC) versus placebo in the treatment of COVID-19 patients at risk of requiring mechanical ventilation.
Octagam® 5% is a ready to use, liquid preparation of highly purified immunoglobulin for intravenous administration (IVIG). It was originally approved in Europe in 1995, and is now approved in over 80 countries worldwide for the treatment of primary and secondary immunodeficiencies and a variety of other immune disorders. It is approved as immunomodulation therapy in immune thrombocytopenia (ITP), Guillain-Barré syndrome (GBS) and Kawasaki disease, chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) in selected geographical areas.
Headquartered in Lachen, Switzerland, Octapharma is one of the largest human protein manufacturers in the world, developing and producing human proteins from human plasma and human cell lines. Octapharma employs more than 10,000 people worldwide to support the treatment of patients in 118 countries with products across three therapeutic areas: Hematology, Immunotherapy, and Critical Care.
Octapharma has seven R&D sites and six state-of-the-art manufacturing facilities in Austria, France, Germany, Mexico and Sweden, with a combined capacity of approximately 8 million litres of plasma per annum. In addition, Octapharma operates more than 140 plasma donation centres across Europe and the US.
For further information on the action of Octapharma in the fight against COVID-19 see this article.
1. Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. Into the eye of the cytokine storm. Microbiology and molecular biology reviews : MMBR 2012; 76(1) 16-32. https://www.ncbi.nlm.nih.gov/pubmed/22390970
2. Lee KY. Pneumonia, Acute Respiratory Distress Syndrome, and Early Immune-Modulator Therapy. International journal of molecular sciences 2017; 18(2). https://www.ncbi.nlm.nih.gov/pubmed/28208675
3. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020; 46: 846-848. https://pubmed.ncbi.nlm.nih.gov/32125452/
4. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 28;395(10229):1033-1034. https://pubmed.ncbi.nlm.nih.gov/32192578/
5. Calabrese LH. Cytokine storm and the prospects for immunotherapy with COVID-19. Cleveland Clinic journal of medicine 2020. https://www.ncbi.nlm.nih.gov/pubmed/32393592
6. Wright DJM. Prevention of the cytokine storm in COVID-19. The Lancet Infectious diseases 2020. https://www.ncbi.nlm.nih.gov/pubmed/32386610
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