Abstract
Threats of pyrogenicity were discovered more than a century ago. Measures to determine the safety of parenterals and, more recently, medical devices and cell therapies for human use have been in place for 70 years. Currently, there are three testing possibilities available: the Rabbit Pyrogen Test, the Limulus Amebocyte Lysate test (Bacterial Endotoxin Test), and test systems using human whole blood or human monocytes, called Monocyte Activation Test (MAT). The MAT is based on the human fever reaction and thus most closely reflects the human situation. Unfortunately, regulations and testing guidelines are not fully harmonized, despite formal international validation. Furthermore, data showing that the MAT is capable of covering the totality of possible pyrogens relevant to humans were not included in the MAT validations of the last decade. For this review we collate evidence from published literature, unpublished data of our own, and results from the international validation study to show that there is overwhelming scientific evidence to conclude that the whole blood MAT reliably detects non-endotoxin pyrogens. Therefore, further validation exercises do not seem warranted.
Highlights
Introduction and backgroundFever is one of the cardinal signs of inflammation and very often is related to bacterial or viral invasion of the human body (Dinarello, 1996)
Conclusions of the validation study The six different methods included in the validation study share a common methodical core consisting of an incubation of monocytoid cells with the sample and an ELISA read-out
The study proved that all four endpoints, IL-1β, IL-6, TNF-α, and neopterin, correlate with LPS in a way that is suitable for detecting pyrogens
Summary
Introduction and backgroundFever is one of the cardinal signs of inflammation and very often is related to bacterial or viral invasion of the human body (Dinarello, 1996). These substances were termed pyrogens, i.e., feverinducing substances (Kluger, 1991; Moltz, 1993) Whenever they enter the human body or come into contact with the human blood stream, the host’s innate defense mechanisms, carried by macrophages, monocytes, dendritic cells, and neutrophils, spring into action (Derijk et al, 1993). This can lead to severe signs of inflammation, shock, multi-organ failure, and sometimes even death (Hartung et al, 1997; Dinarello, 2000; Beutler et al, 2003).
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