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• Meningococcal Sepsis: an alternative hypothesis
  Philip C Holland
  Published on: 22 July 2003

• Published on: 22 July 2003

  Meningococcal Sepsis: an alternative hypothesis

  • Philip C Holland, Consultant Paediatrician

  Dear Editor

  In their article on the pathophysiology of meningococcal sepsis Pathan et al. highlight their view that thrombosis is the principal etiology of the purpuric rash that is so characteristic of meningococcal sepsis.[1] As the explanation for this they cite the well-described procoagulant state found in the severe form of the disease and the impairment in the thrombolytic pathway.

  Evans [2]...

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  Dear Editor

  In their article on the pathophysiology of meningococcal sepsis Pathan et al. highlight their view that thrombosis is the principal etiology of the purpuric rash that is so characteristic of meningococcal sepsis.[1] As the explanation for this they cite the well-described procoagulant state found in the severe form of the disease and the impairment in the thrombolytic pathway.

  Evans [2] who studied five patients with severe meningococcal sepsis originally suggested the association between the rash and procoagulant state. He described disseminated intravascular coagulation with a histological picture of acute vasculitis, intracapillary thrombus and fibrin deposition. Thus the procoagulant state was associated with the rash of severe meningococcal sepsis. However in a recent consensus statement, in which one of the present authors was on the panel, it was not only noted that it was surprising that so little thrombosis was seen histologically but also that histologists had difficulty showing clot occlusion.[3] Later in the same statement they argue that this lack of thrombus is misleading, suggesting that the thrombus may have been lysed and thus not seen at the time of autopsy. Yet in this present review article they comment that thrombolysis is impaired. It was this impairment in thrombolysis, which led to the use (albeit unsuccessfully) of tissue plasminogen activator in severe meningococcal disease.

  In a recent article Kaptchuk discusses interpretative bias on research evidence, in particular plausibility and mechanism bias.[4] The assumption that the procoagulant state and purpura, in occurring together in meningococcal disease, are thus linked by thrombosis could be an example of mechanism bias, particularly as this is not confirmed histologically. There is also a danger in that all other data is interpreted assuming that thrombosis is the mechanism resulting in purpura. It is important to step back occasionally and examine the original hypothesis and reassess whether it is sound. We have previously argued for an alternative mechanism to thrombosis as a cause of the necrotic skin lesions. This hypothesis has the advantage in providing an explanation for the rapid onset of shock, the rash and hypocalcaemia found in meningococcal septicaemia.[5,6] The loss of calcium into the subcutaneous tissue (acute calcifylaxis or acute tissue necrosis) is classically associated with the same histological picture as seen in meningococcal disease. The intracapillary thrombosis as first described by Evans is more compatible with that seen in calcifylaxis and is unlikely to be severe enough to result in severe necrotic lesions. We have suggested that those children with severe meningococcal sepsis and rash have an excess of protease activity, which overwhelms the antiprotease response resulting in albumin cleavage and calcium release into the tissues.

  It is difficult to question long held ideas and what we have published is only a hypothesis and may be incorrect. However we feel that it does warrant examination and may advance understanding of the disease if shown to have some validity.

  References

  (1) Pathan N Faust SN Levin. Pathophysiology of meningococcal meningitis and septicaemia. Arch Dis Child 2003;88:601-607

  (2) Bernard G Artigas A Dellinger P et al. Clinical expert round table discussion (session 3) at the Margaux Conference on critical illness: The role of activated protein C in severe sepsis. Critical Care Medicine 2001 ;29:S75-S77.

  (3) Evans RW Glick B Kimball F et al. Fatal intravascular consumption coagulopathy in meningococcal sepsis. Am J Med 1969;46:910-918

  (4) Kaptchuk TJEffect of interpretive bias on research evidence. BMJ 2003;326:1453-1455.

  (5) Holland PC, Thompson D, Hancock SW, Evans SW, Hodge D, Shires S. Degradation of albumin in meningococcal sepsis. Lancet 2001;357:2102-2104.

  (6) Holland PC, Thompson D, Hancock SW, Hodge D. Calciphylaxis, proteases and purpura-an alternative hypothesis for the severe shock, rash and hypocalcaemia associated with meningococcal sepsis. Critical Care Med 2002;30(12):2757-2761.

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  Conflict of Interest:
  None declared.

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