Chapter 136. Meningococcal Infections (Part 4)

Chia sẻ: Colgate Colgate | Ngày: | Loại File: PDF | Số trang:6

Thêm vào BST

Báo xấu

78
lượt xem 5
download

Download Vui lòng tải xuống để xem tài liệu đầy đủ

Association of Virulence Mechanisms with Specific Meningococcal Infections Specific disease manifestations of meningococcal infections have specific virulence and pathogenic mechanisms, as described below for fulminant meningococcemia and meningitis. Fulminant Meningococcemia Purpura Fulminans Fulminant meningococcemia is perhaps the most rapidly lethal form of septic shock experienced by humans. It differs from most other forms of septic shock by the prominence of hemorrhagic skin lesions (petechiae, purpura; see Fig. 52-5) and the consistent development of DIC. The dominant proinflammatory molecule in the meningococcal cell wall is the endotoxin or LOS, and the outer membrane that contains it is poorly tethered to the underlying peptidoglycan....

Chủ đề:

Bình luận(0) Đăng nhập để gửi bình luận!

Lưu

Nội dung Text: Chapter 136. Meningococcal Infections (Part 4)

Chapter 136. Meningococcal Infections (Part 4) Association of Virulence Mechanisms with Specific Meningococcal Infections Specific disease manifestations of meningococcal infections have specific virulence and pathogenic mechanisms, as described below for fulminant meningococcemia and meningitis. Fulminant Meningococcemia Purpura Fulminans Fulminant meningococcemia is perhaps the most rapidly lethal form of septic shock experienced by humans. It differs from most other forms of septic shock by the prominence of hemorrhagic skin lesions (petechiae, purpura; see Fig. 52-5) and the consistent development of DIC.
The dominant proinflammatory molecule in the meningococcal cell wall is the endotoxin or LOS, and the outer membrane that contains it is poorly tethered to the underlying peptidoglycan. This structural peculiarity seems to account for the fact that meningococci shed LOS-containing membrane blebs as they grow. The bacteria can multiply to very high concentrations in the blood. The concentrations of endotoxin detected in the blood of patients with fulminant meningococcemia are 10- to 1000-fold higher than those found in the blood of patients with bacteremia due to other gram-negative bacteria. The bacteria and endotoxin-containing blebs stimulate monocytes, neutrophils, and endothelial cells, which then release cytokines and other mediators that can activate many distant targets, including other leukocytes, platelets, and endothelial cells. In addition, meningococci can invade the vascular endothelium. When activated, the endothelium produces molecules that can be procoagulant as well as adhesive for leukocytes. Patients with fulminant meningococcemia usually have extremely high blood levels of both proinflammatory mediators—i.e., TNF-α, IL-1, interferon γ (IFN-γ), and IL-8—and anti-inflammatory mediators—i.e., IL-1 receptor antagonist (IL-1Ra), soluble IL-1 receptors, soluble TNF-α receptors, and IL-10. The plasma of patients with meningococcal shock can decrease the responses of normal leukocytes to stimuli such as LOS; the implication is that anti- inflammatory mediators predominate in the blood late in infection.
Procoagulant, antifibrinolytic forces are also active in the blood of patients with fulminant meningococcemia (Fig. 136-2). Monocytes express large amounts of tissue factor. Fibrinopeptide A and thrombin-antithrombin levels are high, reflecting active clotting, while antithrombin and fibrinogen levels are low. Although the tissue factor–regulated ("extrinsic") arm of coagulation predominates, the contact system (factors XII and XI, prekallikrein, high- molecular-weight kininogen) is also activated. Striking deficiencies of antithrombin and proteins C and S can occur; studies have found a strong negative correlation between protein C activity and both the size of purpuric skin lesions and the mortality rate. Plasminogen levels are decreased, while plasmin- antiplasmin complexes and plasminogen activator inhibitor 1 (PAI-1) levels in the blood are very high. PAI-1 levels have been correlated with mortality risk. Figure 136-2
The pathogenesis of fibrin deposition in patients with fulminant meningococcemia. PAI-1, plasminogen activator inhibitor 1. (Adapted from M Levi et al: Eur J Clin Invest 27:3, 1997.) Fibrin deposition is therefore favored both by the procoagulant tendency (promoted through activation of tissue factor and deficiencies of proteins C and S and antithrombin) and by an antifibrinolytic tendency (favored by excessive PAI- 1). Both platelets and leukocytes doubtless contribute to the formation of microthrombi and to the vascular injury that ensues. Thrombosis of small to mid- sized arteries can produce peripheral necrosis and gangrene, necessitating limb or digit amputation. Meningitis
Meningococcal bacteremia can result in the seeding of the meninges, pericardium, and large joints. Up to one-third of patients with meningococcal disease present with meningitis or other closed-space infections without signs of sepsis. How meningococci traverse the blood-brain barrier and enter the CSF or reach other closed sites is unclear. Meningococci have been shown to invade endothelial cells both experimentally and in vivo. The choroid plexus is also a potential site of meningococcal entry into the CSF. Meningococcal pili may bind CD46, a complement-regulatory protein that is expressed by the choroid plexus and meningeal epithelia. Upon meningococcal entry into the CSF, a vigorous local inflammatory response ensues, probably triggered by endotoxin-containing meningococcal membranes. Both bacterial growth and the inflammatory response occur within the CSF, where levels of endotoxin, IL-6, TNF-α, IL-1β, IL-1Ra, and IL-10 exceed the concentrations found in plasma by 100- to 1000-fold. The inflammatory response is largely confined to the subarachnoid space and contiguous structures. The inflammatory cytokines TNF-α and IL-1 released in meningococcal bacteremia may also enhance the permeability of the blood-brain barrier. Meningitis and other closed-space infections (e.g., arthritis, pericarditis) are the result of bacterial survival and multiplication at these sites. For example, meningitis and its sequelae are due to the induction of local inflammatory cytokines and other mediators (e.g., nitric oxide), leukocyte infiltration across the blood-brain barrier, breakdown of the blood-brain barrier with edema, release of
metalloproteases, induction of cellular apoptosis, coagulation of vessels, and ischemia. Patients who develop meningitis without meningococcemia may be individuals in whom meningococci do not grow rapidly in or have been cleared from the blood; may have antibodies or phagocytes that slow meningococcal growth; or may lack the (unknown) factors that allow N. meningitidis to multiply rapidly in vivo. If disease is recognized early, the prognosis of patients with meningococcal meningitis is substantially better than that of patients with fulminant meningococcemia.