Whatever happened to the Shwartzman phenomenon?

Abstract

Ninety years ago, Gregory Shwartzman first reported an unusual discovery following the intradermal injection of sterile culture filtrates from principally Gram-negative strains from bacteria into normal rabbits. If this priming dose was followed in 24 h by a second intravenous challenge (the provocative dose) from same culture filtrate, dermal necrosis at the first injection site would regularly occur. This peculiar, but highly reproducible, event fascinated the microbiologists, hematologists, and immunologists of the time, who set out to determine the mechanisms that underlie the pathogenesis of this reaction. The speed of this reaction seemed to rule out an adaptive, humoral, immune response as its cause. Histopathologic material from within the necrotic center revealed fibrinoid, thrombo-hemorrhagic necrosis within small arterioles and capillaries in the micro-circulation. These pathologic features bore a striking resemblance to a more generalized coagulopathic phenomenon following two repeated endotoxin injections described 4 yr earlier by Sanarelli. This reaction came to be known as the generalized Shwartzman phenomenon, while the dermal reaction was named the localized or dermal Shwartzman reaction. A third category was later added, called the single organ or mono-visceral form of the Shwartzman phenomenon. The occasional occurrence of typical pathological features of the generalized Shwartzman reaction limited to a single organ is notable in many well-known clinical events (e.g., hyper-acute kidney transplant rejection, fulminant hepatic necrosis, or adrenal apoplexy in Waterhouse-Fredrickson syndrome). We will briefly review the history and the significant insights gained from understanding this phenomenon regarding the circuitry and control mechanisms responsible for disseminated intravascular coagulation, the vasculopathy and the immunopathy of sepsis.

Aggregatibacter, a Low Abundance Pathobiont That Influences Biogeography, Microbial Dysbiosis, and Host Defense Capabilities in Periodontitis: The History of a Bug, and Localization of Disease

“…In that capacity, the limulus lysate test has replaced Schwartzman reaction testing in rabbits as a means of detecting endotoxin to ensure that hospital instruments and supplies are free from low levels of endotoxin [101]. In the Schwartzman phenomenon, thrombosis is due to diffuse intravascular coagulation resulting in tissue necrosis [102]. As a replacement for Schwartzman testing, the horseshoe crab limulus lysate system was found to be significantly more sensitive and thus could serve as a replacement for animal testing.…”

“…x; doi: FOR PEER REVIEW www.mdpi.com/journal/pathogens phenomenon, thrombosis is due to diffuse intravascular coagulation resulting in tissue necrosis[102].810As a replacement for Schwartzman testing, the horseshoe crab limulus lysate system was found to be 811 significantly more sensitive and thus could serve as a replacement for animal testing. The process 812 required that scientists bleed the horseshow crab, collect their hemolymph, separate the hemocytes, 813 lyse them, and use the lysate for the assessment of nanogram to picogram levels of endotoxin.…”

Immune Mechanisms Underlying Susceptibility to Endotoxin Shock in Aged Hosts: Implication in Age-Augmented Generalized Shwartzman Reaction

“…We then considered that induction of a hypersensitive response to LPS was important for simulating/mimicking human endotoxin shock in mice. The generalized Shwartzman reaction is well recognized as a hypersensitive innate immune response in experimental animals [36].…”

“…If the provocative challenge was too short (less than 2 h) or too long (beyond 48 h), dermal necrosis did not occur. Shwartzman also performed the experiment using a similar preparation with sterile culture filtrate of Gram-positive streptococcal species but failed to duplicate dermal reactions, suggesting that the heat-stable component of Gram-negative bacteria (later identified as LPS) is important for inducing this reaction [36]. However, Shwartzman described only the localized dermal response and not the systemic response in this phenomenon.…”

“…However, Shwartzman described only the localized dermal response and not the systemic response in this phenomenon. According to the review of Chahin et al, the generalized Shwartzman reaction was actually discovered by Sanarelli four years earlier than the report by Shwartzman [36]. The generalized Shwartzman reaction is now considered a potentially lethal endotoxin shock reaction that can be induced by the administration of a sublethal dose of LPS into LPS-primed animals at an interval of 24 h (Figure 1A) [38].…”