Abstract
The whole blood pyrogen test was first described in this journal exactly twenty years ago. It employs the cytokine response of blood monocytes for the detection of microbiological contaminants with the potential to finally replace the still broadly used rabbit pyrogen test. The article reviews its development process, the current status of the test as well as the challenges and missed opportunities. The article highlights the enormous efforts of many people to get the test to where it is today. But it also shows the incredible missed opportunities for implementation and thus sparing about 400,000 rabbits still used for this purpose per year worldwide; in the EU, since the official acceptance of the test, the number of animals used for pyrogen testing did not fall but increased by about 10,000 to 170,000. The test is the first solution enabling adequate pyrogen testing of cell therapies, including blood transfusions, and medical devices, but has not been implemented for either application by authorities. As the test can quantitatively assess human-relevant airborne pyrogens, the contribution of pyrogens to chronic obstructive lung diseases and childhood asthma can for the first time be defined and home and workplace safety improved in the future.
Highlights
The term “pyrogen” was coined by Burdon-Sanderson in 1875 for a hypothetical substance in bacteria-free extracts of putrid meat, which caused fever upon injection into animals
We observed the same when we developed a rabbit blood pyrogen test to compare the responsiveness of rabbit and human blood to pyrogens (Schindler et al, 2003), i.e., rabbit blood, like human blood, showed a high responsiveness to LPS but a lower responsiveness to Gram-positive pyrogens than human blood
In late 1994, I was aware of the rabbit pyrogen test (RPT) and its most successful replacement, the Limulus amebocyte lysate assay (LAL) called bacterial endotoxin test (BET), but not of any need for further alternative methods
Summary
The term “pyrogen” was coined by Burdon-Sanderson in 1875 for a hypothetical substance in bacteria-free extracts of putrid meat, which caused fever upon injection into animals (for review see Clough, 1951). We observed the same when we developed a rabbit blood pyrogen test to compare the responsiveness of rabbit and human blood to pyrogens (Schindler et al, 2003), i.e., rabbit blood, like human blood, showed a high responsiveness to LPS but a lower responsiveness to Gram-positive pyrogens than human blood. Since the author receives license fees from sales of the kit version of the test by Merck-Millipore – the reader is advised to take these thoughts with a “grain of salt.”
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