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A number of histopathologic observations have cast doubt on the concept that all extracardiac lesions in IE are related to septic embolization from the infected cardiac valve. For example, the report of Alpert et al of four patients with acute IE showed that histologic and bacteriologic data implicated bacterial or fungal microemboli in the pathogenesis of the Osiers node; the authors theorized that the tender nature of the lesion was related to embolic lodgement in the dermal glomus apparatus of the densely packed tissue of the finger tip. In contrast, three reports from the French literature and one from the US stressed that Osiers nodes were often histologically characterized by an intense perivasculitis in the absence of bacterial organisms, and suggested a “hypersensitivity phenom­enon” as the basis for this lesion in IE. The major difference between the Alpert study and those in the French literature appears to relate to the timing of the lesion biopsy; the patients described by Alpert et al had their Osiers nodes sampled early in their evolu­tionary course (within 48 h of development), while those reported by French investigators were often sampled later in the course (eg, ten days post-devel­opment). Thus, it seems likely that as the lesion ages, localized host defenses are able to sterilize the Osiers node, leaving an intense inflammatory response.

Similar controversy has arisen over the etiology of other extracardiac manifestations of IE such as the chorioretinal Roth spot and the polyarthritis syn­drome, since bacterial or fungal organisms rarely have been documented within these lesions.
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The most convincing evidence concerning the pos­sible immunologic nature of the peripheral stigmata of IE have emanated from histopathologic analysis of renal tissue from patients with IE-related glomerluo- nephritis (GN). It has been recognized for many years that there are two main histologic forms of renal involvement in IE, “focal embolic” and “diffuse pro­liferative” GN. The former is a relatively trivial form of renal disease and is usually unassociated with functional impairment; the latter is universally associated with an “active” renal sediment and is often accompanied by moderate to severe depression of creatinine clearances. The diffuse GN of IE has often been seen in concert with detectable antiglob­ulins (rheumatoid factors), cryoglobulins, and hypo- complementemia, suggesting an immune-mediated lesion. It had previously been thought that the “focal embolic” lesion was related to bland and/or septic emboli to the renal cortex. This theory became untenable with recognition that this renal lesion could be seen in cases of pure right-sided IE in which the “pulmonary artery-pulmonary alveolus barrier” serves as an efficient filter for micro- and macro-embolization. It now appears certain from immunopathologic inves­tigations that these two forms of renal disease are on the same continuum of immune complex-mediated, extracardiac tissue injury in IE.

Prevalence figures on these two forms of IE-related GN are very variable depending upon the clinical- diagnostic criteria utilized. Studies employing hema­turia, pyuria and proteinuria as markers of diffuse GN tend to overestimate the prevalence, since cases of focal embolic and frank embolic renal infarction surely will be included. Conversely, studies that utilize only clinically-manifest renal functional impairment prob­ably underestimate the prevalence of the disease, as autopsy studies of IE patients confirm that “silent” GN may exist in the absence of such perturbations. The best data on IE-related GN prevalence have come from autopsy studies such as that of Spain and King in 1952. Of 52 untreated patients dying of subacute IE, 33 percent had diffuse GN and 48 percent had focal GN. Of interest, in 25 additional patients dying of subacute IE despite penicillin treatment, no cases of diffuse GN were observed, suggesting that this renal lesion in IE was amenable to cure by antimicrobial therapy. Most cases in this latter study were associated with viridans streptococci in patients with longstand­ing infection; these findings implied a relationship between duration of infection in streptococcal IE and development of diffuse GN. More recent autopsy studies in the antibiotic era by Neugarten et al have shown a somewhat different spectrum of GN in IE cases. These investigators found focal GN in 8 percent and diffuse GN in 14 percent of their cases dying of IE despite antibiotic therapy. Of note, their patient population was strikingly different from that reported by Spain and King in that: 1) S aureus was dispropor­tionately represented as a cause of both death and GN; 2) parenteral drug abuse was a common risk factor for IE, while underlying valvular heart disease was less frequently seen; and 3) long duration of antecedent illness was less frequently observed in association with development of GN. Supporting their findings were two other reports which documented the prevalence of clinically manifest GN in S aureus IE to be as high as 40-78 percent despite a mean duration of illness of seven-ten days.
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The markedly different prevalence of GN in streptococcal vs staph­ylococcal IE, as well as the distinct differences in durations of underlying symptoms and nature of the underlying valvular disease raised the question as to whether IE-related renal lesions might have a different pathogenetic basis depending on the valvular patho­gen. This concept has, in fact, been supported by study of complement activation and utilization in IE- associated GN. In series of patients with S aureus IE- related GN, levels of C₃ and factor В were low, while early complement cascade components tended to be normal or high, suggesting activation of the alternate complement pathway. In contrast, studies of comple­ment activation in streptococcal IE-associated GN tended to show utilization of early complement com­ponents (Cjq, C₄), as well as C₃ and factor B, suggesting classic complement pathway activation with perhaps secondary activation of the alternate complement pathway via the “amplification loop.”