Page 2245 - Hematology_ Basic Principles and Practice ( PDFDrive )

1992 Part XII Hemostasis and Thrombosis

contaminated during processing. The organism has also been isolated [IL]-1, IL-1β, IL-6, and IL-8; MCP-1; and interferon-γ), which
from deer, sheep, goats, horses, dogs, birds, and flies. Large outbreaks exacerbate toxin- and leukocyte-induced endothelial dysfunction.
have been reported in association with ingestion of contaminated Changes in endothelial function include upregulation of expression
ground beef, although contamination of poultry, cheese, fruits, and of Stx receptors, which further sensitizes cells to Stx-induced injury,
vegetables has also been reported. Other cases have been attributed increased expression of P-selectin and tissue factor, increased release
to ingestion of contaminated water or unpasteurized apple cider or of vWF, and downregulation of thrombomodulin expression. Early
milk. The incidence of STEC-HUS may be increasing as a result of in the course of the disease, Stx also acts in concert with lipopolysac-
developments in food production methods. Industrial farming gener- charide to trigger a procoagulant state that involves platelet
ates large quantities of potentially contaminated manure that periodi- activation.
cally enters streams, where it can contaminate feed and uncooked It remains unclear why a minority of patients infected with STEC
vegetables. A 2011 outbreak of HUS in Northern Germany that bacteria develops STEC-HUS. Activation of complement may con-
affected more than 3000 individuals was caused by enteroaggressive tribute to the pathogenesis of Stx-HUS. Stx2 directly activates the
E. coli O104:H4; the infection vector was traced to bean sprouts with alternative pathway (AP) of complement and binds to short consensus
evidence of intrahousehold transmission. Carriage of STEC may be repeat (SCR) 6-8 and 19-20 of factor H, which mediate surface
asymptomatic, and fecal-oral transmission may contribute to epi- recognition, blocking its ability to inhibit complement activation on
demic spread in day care centers, nursing homes, and petting zoos. cell surfaces. It has been hypothesized that subtle allotypic variation
Aerosolization in barns has been implicated in outbreaks at fairs. in factor H (CFH) may modulate the sensitivity of CFH to Stx2-
STEC strains are also associated with sporadic, nonepidemic cases induced dysregulation in susceptible patients.
of HUS. The disease occurs more frequently during the summer and
autumn in temperate climates. Infection by Shiga toxin–producing
Shigella dysenteriae serotype 1 is associated with HUS in developing Laboratory Manifestations
countries and carries a higher mortality.
Like TTP, STEC-HUS is characterized by MAHA and thrombocy-
topenia. Thrombocytopenia tends to be less severe than that observed
Pathobiology in TTP, and renal disease is the major clinical manifestation.
Renal biopsy, although rarely required for diagnosis in endemic
STEC-HUS is caused by endothelial cell damage initiated by Shiga areas, illustrates the importance of endothelial damage. Involved
toxin and the inflammatory cytokines they induce. The type of Shiga glomeruli show widening of the subendothelial space, which is filled
toxin, as well as other virulence factors, contributes to risk. with cellular debris and fibrin. Glomerular capillary endothelial cells
After ingestion, the noninvasive enteropathic E. coli bacteria colo- are swollen and occasionally detached, leading to obliteration of the
nize the terminal ileum and follicle-associated epithelium of Peyer capillary lumens.
patches, after which they colonize the colon. Once colonization Though clinical features are often sufficient for the diagnosis of
occurs, STEC bacteria express numerous virulence factors by hori- STEC-HUS, bacteriologic confirmation should be sought through
zontally transmitted gene cassettes termed pathogenicity islands. One stool culture, testing for Stx (e.g., by enzyme-linked immunosorbent
pathogenicity island contains the locus of enterocyte effacement, assay), stool analysis for Stx structural genes, or acute and convales-
which contains genes for the adhesin intimin, as well as a type III cent serologies. Stool should be tested as soon as possible after the
(three) secretion system that mediates transfer of bacterial proteins onset of diarrhea. The recovery rate for STEC appears to be at least
directly into enterocytes. Their capacity to cause HUS is mediated 90% during the first 6 days but less than 33% thereafter. E. coli
by two 70-kDa bacterial exotoxins. The toxins are transported across O157:H7 ferments sorbitol slowly, appearing as colorless overnight
the intestinal epithelium through specific para- and intercellular colonies on sorbitol-MacConkey agar; sorbitol-negative cultures may
mechanisms and then circulate, most likely by low affinity binding be further characterized using commercially available O157:H7-
to the surface of neutrophils and platelets, before being transferred specific antisera. Methods to detect Stx or their structural genes
to higher affinity receptors expressed on glomerular endothelial cells improve diagnostic sensitivity.
that are upregulated by proinflammatory cytokines. Antibody titers against E. coli O157:H7 antigens and Stx rise after
The toxin produced by these strains of E. coli is identical to Shi- infection, persist for 8–12 weeks, and may be useful to confirm STEC
gella toxin and is therefore generally referred to as Shiga-like toxin 1 infection in selected cases; however, they are not widely available. In
(Stx1). Most strains of pathogenic E. coli produce a second homolo- some cases, further evaluation may be desired to differentiate STEC-
gous toxin, Stx2, which is associated with a higher risk for HUS. The HUS from the other TMAs, such as autoimmune disease, aHUS and
toxins are carried on a lysogenic bacteriophage capable of infecting TTP.
other strains of E. coli. Intact, 70-kDa Stx holotoxins consist of a
32-kDa A subunit and five 7.7-kDa B receptor-binding subunits. The
toxin binds to terminal Gala1-4Galb (galabiose) residues on globos- Prognosis
yltriaosylceramide (Gb 3 ; also known as CD77 and the human blood
k
group P antigen). Increased expression of Gb 3 on glomerular micro- The outcome of patients with STEC-HUS is generally favorable,
vascular and cerebral endothelium compared with other vascular beds although STEC-HUS remains the most common cause of acute renal
contributes to their heightened sensitivity to apoptosis, cytotoxicity, failure in children and up to 60% of children require dialysis during
upregulation of integrins, and procoagulant activity. The higher levels the acute phase. However, STEC-HUS is usually self-limited and as
of Gb 3 expression in children compared with adults may explain why a result of advances in supportive care, mortality has been reduced to
children are particularly prone to develop HUS. 3% to 5%, with death usually caused by severe involvement of the
Following binding to Gb 3 , Stx1 and Stx2 are internalized and central nervous system, intestine, or myocardium. Renal insufficiency
transported in a retrograde manner to the endoplasmic reticulum and generally resolves within 2–3 weeks, although some patients have
translocated into the cytosol. The A subunit is proteolyzed to a prolonged anuria, requiring several months before recovery. Despite
27-kDa A1 subunit that binds the 60S ribosomal subunit and cleaves a favorable short-term outcome, many children with STEC-HUS
adenine 4323 from the 28S ribosomal RNA. This prevents elonga- develop chronic renal insufficiency over time. In one report of 29
tion factor 1-dependent binding of aminoacyl tRNA, which inhibits patients with “typical” childhood HUS followed for 15–28 years, 7
protein synthesis and leads to ribotoxic stress response, changes in developed chronic renal failure and 12 developed hypertension,
cellular function, and apoptosis. Stx alters the usual balance between proteinuria, or reduced glomerular filtration rate, whereas only 10
intestinal absorption and secretion to a net excretory phenotype. E. showed no residual abnormalities. Therefore 50% to 60% of patients
coli lipopolysaccharide and Stx also stimulate leukocyte and intrarenal have complete recovery with long-term preservation of renal func-
expression of proinflammatory cytokines (including interleukin tion. Long-term outcomes are worse in older patients. Proteinuria