Research into TRALI therapies generates results that are a TAD interesting!

What is this research about?

TRALI stands for Transfusion-Related Acute Lung Injury. As its name suggests, TRALI is lung damage that occurs in reaction to a blood transfusion. It is uncommon, but potentially fatal, and symptoms range from mild to life-threatening breathing difficulties. TRALI occurs when antibodies in the donor’s blood react with incompatible proteins in the recipient. This reaction may cause immune cells (called neutrophils) in the recipient’s lung to produce substances that damage the lung. However, why a patient develops TRALI is often not clear, and much remains to be understood about how this reaction happens. If a patient shows symptoms of TRALI, the transfusion is stopped and supportive care (e.g. oxygen to help breathing) is given. Unfortunately, there is no effective treatment for this potentially fatal reaction.

In brief...

Laboratory-based research shows that IVIg - a drug currently used to treat other disorders - may be a potential therapy to reduce the severity of TRALI reactions.

Intravenous immunoglobulin (IVIg) is a plasma-derived drug that is used to treat many diseases, particularly those involving antibody deficiencies. There have been very rare reports of patients developing TRALI after treatment with IVIg. However, given how often IVIg is used, and how rare these reports have been, the link between IVIg and TRALI is unclear. Interestingly, exactly how IVIg works is not known, but it is helpful in disorders that involve antibody reactions and inflammation. Since TRALI involves antibodies, the researchers hypothesized that IVIg might actually be an effective treatment to prevent or reverse TRALI. They developed a laboratory-based approach to test this hunch, with surprising results.

What did the researchers do?

The researchers tested their theory using laboratory mice. Injection of mice with an antibody called 34-1-2s causes symptoms that closely mirror a TRALI reaction in a patient. These include symptoms of shock (measured as a drop in body temperature), lung damage (indicated by excess water in the lung) and sometimes death. Two different types of mice were used; one with a healthy immune system, and one with a weak immune system. After injection with 34-1-2s, both types of mice showed a drop in body temperature and other symptoms. Symptoms were less severe in mice with a healthy immune system and their body temperature recovered after a few hours. These milder symptoms more closely resemble a condition in humans similar to TRALI called Transfusion Associated Dyspnea (TAD). In mice with a weak immune system, symptoms were more severe and closely resembled TRALI. To determine the effect of IVIg treatment in these mice, the researchers used two approaches. Firstly, they investigated whether IVIg could prevent TRALI by giving IVIg to the mice 18 hours before TRALI was induced by 34-1-2s injection. Secondly, they investigated whether IVIg treatment could protect mice already undergoing a TRALI reaction. To do this, IVIg was given just after the first symptoms of TRALI were observed.

What did the researchers find?

  • Pre-treatment with IVIg completely prevented both TAD- and TRALI-like symptoms in the mice, including shock, lung damage and mortality.
  • When IVIg was given after the first symptoms of TRALI were observed, symptoms of shock were still seen. However, IVIg treatment reduced lung damage, and reduced mortality in the mice with a weak immune system.
  • The reason why IVIg reduces the severity of TRALI reactions was also investigated. The results indicated that IVIg may prevent the release of damaging substances (called reactive oxygen species or ROS) from neutrophils in the lung. In that way, IVIg treatment limits the amount of lung damage.

How can you use this research?

The results of this study support the researchers’ hunch that IVIg may be a potential treatment for TRALI. This research has several implications for real-life situations that occur with patients undergoing transfusion. A major finding was that pre-treatment with IVIg completely prevents both TAD- and TRALI-like symptoms in mice. In general, pre-treatment of patients with IVIg is not feasible in the clinic, as we do not always know in advance when a patient may need a transfusion or who will develop a TRALI reaction. However, the results suggest that some groups of at-risk patients may benefit from IVIg treatment before undergoing elective surgery.

Perhaps more importantly, this study also found that once a TRALI reaction is underway and a patient has symptoms, IVIg treatment may help to stop it progressing to a more severe or life-threatening reaction. The prospect that IVIg treatment may reduce the severity of TRALI reactions is an exciting one, as we currently have no treatment for patients who display TRALI reaction symptoms. However, this study was done in mice, so more evidence is needed to see if the effect would be the same in humans. Until then, this therapy remains an experimental treatment. However, for all those physicians of patients with suspected TRALI who are in desperate need of therapy, this paper is certainly worth a close look.

About the research team

Dr. John Semple is an adjunct scientist with Canadian Blood Services. Dr. Semple is also a scientist at the Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, and a professor of pharmacology, medicine, and laboratory medicine and pathobiology at the University of Toronto. Dr. Alan Lazarus is a scientist with Canadian Blood Services Centre for Innovation, based on Toronto, ON. Dr. Lazarus is also a professor in medicine, and laboratory medicine and pathobiology at the University of Toronto and a scientist in the Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael's Hospital. Michael Kim, Jing Hou, Mark McVey and Young Jin Lee work in Dr. Semple’s laboratory and Zhong-Wei Chai worked in Dr. Lazarus’s laboratory. Arata Tabuchi works in Dr. Wolfgang M. Kuebler's laboratory at the Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael's Hospital.

This research unit is derived from the following publication(s)

[1] Semple JW, Kim M, Hou J, McVey M, Young JL, Tabuchi A, Kuebler WM, Chai A, Lazarus AH. Intravenous Immunoglobulin Prevents Murine Antibody-mediated Acute Lung Injury at the Level of Neutrophil Reactive Oxygen Species (ROS) Production. PLoS One 2012; 7(2): e31357. doi:10.1371/journal.pone.0031357

Acknowledgements: This research received financial support from the Canadian Institutes for Health Research and Canadian Blood Services (funded by the provincial and territorial Ministries of Health).

Keywords: Transfusion reactions, transfusion-related acute lung injury (TRALI), intravenous immunoglobulins (IVIg), transfusion associated dyspnea (TAD)

Want to know more? Contact Dr. John Semple at semplej@smh.ca or Dr. Alan Lazarus at lazarusA@smh.ca

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