What triggers the fevers?

posted: by: Linda Tintle DVM Tags: "Clinic Specials" "News" 

Shar-Pei have a heritable autoinflammatory episodic fever disorder which may or may not lead to amyloidosis.

I believe that the carriers have a partially defective innate immune system and that the dogs that have inherited two defective genes (one from each parent) are the ones most likely to develop amyloidosis. The DNA testing is to be done through the NIH this month on the samples we submitted and I hope that we find more concrete answers. The defective innate immune system puts them at risk for two things 1) periodic fevers 2) reactive systemic AA amyloidosis if the chronic background inflammation is severe. I'd like to present some recent information I have been reviewing about the underlying trigger for the fever episodes.

One nagging mystery is what triggers the fevers?

In some dogs they seem completely random, in others there is evidence that stress can bring on a fever, for example: a visit to the vet with or without vaccination, dog shows, grandchildren, etc. Dogs can develop amyloidosis without ever having a single fever or getting their first classic episode after the onset of signs of amyloidosis. The severity and frequency of fevers are unrelated to whether they develop amyloidosis.  Dogs that have never had a single vaccination in their lives and been raised holistically have succumbed to amyloidosis young.  It is the silent chronic background inflammation from their defective innate immune system mediators that is the real killer.

A fascinating article was published earlier this year about humans with Familial Mediterranean Fever, endotoxin tolerance and the underlying immunopathology for the periodic fevers:

Davtyan TK, Hakopyan GS, Avetisyan SA, Mkrtchyan NR. Impaired endotoxin tolerance induction in patients with familial Mediterranean fever.
Pathobiology. 2006;73(1):26-39.

OBJECTIVE: To investigate periodic disturbances in proinflammatory activation of neutrophils and monocytes in patients with familial Mediterranean fever (FMF) both during an attack and in remission. METHODS: 20 FMF patients, who were naive to colchicine treatment and did not have amyloidosis, and 10 patients with Behcet's disease (BD) were enrolled in this study. Phagocytosis, respiratory burst, CD11a/CD18 expression and intracellular cytokine synthesis were determined by flow cytometry. Endotoxin tolerance induction was defined by a reduced capacity of monocytes to respond to lipopolysaccharide (LPS) activation following a first exposure to LPS. RESULTS: In FMF patients, we observed upregulation of neutrophil and monocyte phagocytic activity and oxidative burst during remission and downregulation of phagocytic activity and stimulus-dependent oxidative burst during an attack. A comparative analysis of oxidative burst has revealed that while the neutrophil population shows a certain periodicity in the increase (during remission) and decrease (during attacks) in the spontaneous and inducible respiratory burst, periodicity in the monocyte population is very poor. In addition, LPS-induced oxidative burst and CD11a/CD18 integrin surface expression is higher in patients during an attack compared to patients in remission. The induction of homologous tolerance of monocytes to the repeated action of LPS is observed in FMF patients during an attack, normal donors and patients with BD, whereas monocytes from patients in remission failed to induce LPS homologous tolerance and exhibited heightened sensitivity to bacterial endotoxin. We found that colchicine is able to restore impaired LPS homologous tolerance induction in FMF patients in remission upon increased synthesis of IL-4 in FMF patient monocytes. CONCLUSION: Chronic inflammation during FMF is characterized by periodic changes in monocyte and neutrophil activation and heightened sensitivity to endotoxin, which is associated with the episodic nature of FMF. Increased endotoxin sensitivity in the period of remission could result from a shift in the monocyte activation program from 'alternatively' into 'classically' activated monocytes, which may have important implications for the treatment of FMF.

It may be that Shar-Pei with FSF are unable to properly respond to exposure to bacterial endotoxin with normal "tolerance" during quiescent periods and over-react with a high fever.  An analogy would be that the car is sitting at the traffic light with the engine revved high, and when the light changes - it is off with rapid acceleration but it's got really bad brakes.  A formula for a nasty crash.

I'd be delighted to discuss the implications of this with anyone. It makes the most sense of anything I've seen and helps to elucidate how colchicine may decrease the severity and frequency of fever events.  It may also explain the occasional case of "Baytril-responsive" episodic fevers that have been reported.  Look closely for sources of endotoxin producing bacteria in the dog with frequent refractory fevers - Klebsiella, Strep, (does not release endotoxin but shows endotoxin-like effects), Pseudomonas, etc in ears, kidneys, skin, respiratory tract?

Linda Tintle DVM
Wurtsboro NY

November 2006

endotoxin (en·do·tox·in) (en´do-tok”sin) [endo- + toxin]  a heat-stable toxin associated with the outer membranes of certain gram-negative bacteria, including the brucellae, the enterobacteria, neisseriae, and vibrios. Endotoxins are not secreted but are released only when the cells are disrupted; they are less potent and less specific than the exotoxins; and they do not form toxoids. They are composed of complex lipopolysaccharide molecules, of which the polysaccharide unit (somatic O antigen) is responsible for antigenicity, occurring in hundreds of variations, and the phospholipid moiety (lipid A) is the source of toxicity. When injected in large quantities the endotoxins produce hemorrhagic shock and severe diarrhea; smaller amounts cause fever, altered resistance to bacterial infection, leukopenia followed by leukocytosis, and numerous other biologic effects. Called also bacterial pyrogen. See also toxin.
Dorlands Medical Dictionary: http://www.mercksource.com/pp/us/cns/cns_hl_dorlands.jspzQzpgzEzzSzppdocszSzuszSzcommonzSzdorlandszSzdorlandzSzdmd_e_09zPzhtm