An Effective Treatment Strategy for Cytokine Storm in Severe Influenza

Despite the use of vaccines and antiviral therapies such as oseltamivir, severe influenza kills thousands to tens of thousands of Americans each year. Flu infection often leads to a vigorous immune response and body-wide inflammation, leading to the hallmark symptoms of high fever, cough, headache, muscle and joint pain, and severe fatigue. However, when the inflammation becomes excessive, driven by the overproduction of inflammatory mediators called cytokines, this “cytokine storm” can rapidly kill cells, causing severe tissue damage while precipitating organ dysfunction and failure, particularly of the lungs, kidneys, and circulatory system. It is life-threatening, even for already hospitalized patients. Immunomodulatory therapy has been proposed as a possible way to improve the outcome, with or without antiviral agents.

Anti-inflammatory and immunosuppressive drugs have not been successful in treating cytokine storm and improving survival. Nonsteroidal anti-inflammatory drugs (NSAIDS), such as ibuprofen, are used commonly to treat mild to moderate inflammation, but have not demonstrated the ability to control cytokine storm. Similarly, corticosteroids have also had mixed results, and their use for treating severe influenza is not recommended due to an increased risk of hospital-acquired infections and death.1-5 Other experimental approaches, such as the use of statins, have shown some success when used with other agents to alter the body’s immune response.1,2

Antioxidants such as N-acetylcysteine can inhibit viral replication, which in turn reduces production of inflammatory mediators.1 Peroxisome proliferator-activated receptors help regulate inflammation, and their agonist agents have been used to combat the inflammatory response.1 There has been evidence that sphingosine-1-phosphate receptor 1 ligands can suppress inflammation resulting from influenza infection.3 However, these treatments remain experimental, and more effective strategies are needed.

A nonpharmacologic treatment for cytokine storm currently used in Europe is based on a novel blood purification technology. CytoSorb therapy from CytoSorbents Corp. (Monmouth Junction, NJ) uses biocompatible, porous polymer beads in a hemoperfusion cartridge to adsorb mid-sized inflammatory mediators such as cytokines and toxins from the blood. Whole blood is repeatedly pumped out of the body and through the sorbent cartridge using standard dialysis machines, with purified blood recirculated back to the patient.

Case study

A 56-year-old man had severe H1N1 influenza and was receiving the antiviral drug oseltamivir. He developed multiple organ failure and septic shock and was treated with vasopressors. The patient had acute respiratory distress syndrome and was on mechanical ventilation. He also developed acute renal failure requiring hemodialysis. The classic antiviral cytokine IFN-γ was undetectable, but the patient had true cytokine storm with interleukin-6 levels greater than 8000 pg/mL. Because IFN-γ peaks relatively quickly in influenza infection, the patient may have been at the end of active viral infection but suffered from the consequences of cytokine storm.

Despite continued treatment with oseltamivir, vasopressors, and broad-spectrum antibiotics, including piperacillin/tazobactam and erythromycin, the patient did not improve. CytoSorb blood purification was started at 250 mL/min for six hours per day, for a total of seven days. Kidney function improved and dialysis was discontinued one day after CytoSorb treatment. Rapid improvements in hemodynamic stability were also observed, and the patient was weaned off all vasopressors within three days of treatment. The patient’s IL-6 levels were reduced from 8076 pg/mL before treatment to 94 pg/mL after treatment. The patient went on to fully recover.

Conclusion

CytoSorb blood purification technology has been used successfully in a number of conditions in which deadly inflammation can lead to organ injury and failure, and is a promising therapeutic approach to treating critically ill patients. For more information, visit http://cytosorbents.com/products/cyto-sorb/.

References

  1. D’Elia, R.V.; Harrison, K. et al. Targeting the “cytokine storm” for therapeutic benefit. Clin. Vaccine Immunol. 2013 Mar, 20(3), 319–27; doi: 10.1128/CVI.00636-12.
  2. Liu, Q.; Zhou, Y.H.; Yang, Z.Q. The cytokine storm of severe influenza and development of immunomodulatory therapy. Cell Mol. Immunol. 2016 Jan, 13(1), 3–10; doi: 10.1038/cmi.2015.74.
  3. Ramos, I. and Fernandez-Sesma, A. Modulating the innate immune response to influenza a virus: potential therapeutic use of anti-inflammatory drugs. Front Immunol. 2015 Jul 20, 6, 361; doi: 10.3389/ fimmu.2015.00361.
  4. Iwasaki, A. and Medzhitov, R. A new shield for a cytokine storm. Cell 2011 Sep 16, 146(6), 861–2; doi: 10.1016/j. cell.2011.08.02710.
  5. Rodrigo, C.; Leonardi-Bee, J. et al. Corticosteroids as adjunctive therapy in the treatment of influenza. Cochrane Database of Systematic Reviews. Mar 7, 2016; doi: 10.1002/14651858.CD010406.pub2.

Erin Murphy is a freelance medical writer; e-mail: emurphy@pascalecommunications

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