Hemolytic Uremic Syndrome and Streptococcus Pneumoniae: Improving our Understanding
Article Outline
Abbreviations: HUS, Hemolytic uremic syndrome
Hemolytic uremic syndrome (HUS) is associated with a variety of infectious agents and most commonly follows a diarrheal prodrome caused by enteric Escherichia coli or Shigella infection (D+ HUS). On the other hand, Streptococcus pneumoniae–associated HUS, which does not usually have a preceding diarrheal illness, has been grouped with a heterogeneous group of disorders as “atypical” or D− HUS. Although recognized since the early 1970s, the association of HUS with pneumococcal infection is underappreciated within the general pediatric community. The report by Waters et al1 in this issue of The Journal reviews the largest experience with this disease and is important to everyone who treats children because it (1) highlights awareness and the possible increasing incidence of HUS associated with invasive pneumococcal disease; (2) provides more comprehensive outcome data for these patients than heretofore available, and confirms that renal outcomes are better than for other forms of atypical/nondiarrheal HUS; and (3) reiterates an important concern related to treatment with plasma products, which may aggravate the disease.
See related article, p 140
Before the article by Waters et al,1 information about this disease was derived from small numbers of patients, with limited follow-up data. This report provides a sufficiently large number of patients (n = 43), albeit with median follow-up of only 9 months, to permit more accurate conclusions about renal sequelae of this disease. It is not surprising that patients with pneumococcal meningitis, irrespective of the severity of associated acute HUS, had a poor outcome. Also, as noted by others,2, 3 the severity of acute illness associated with pneumococcal HUS reported by Waters et al1 was worse than with D+ HUS; 36 (84%) required dialysis, and 40/41 required blood transfusion. However, the longer-term renal outcome of pneumococcal HUS reported in this study was, somewhat surprisingly, comparable with or better than that reported after typical D+ HUS.4, 5 Thus, if the acute effects of pneumococcal septicemia and meningitis are excluded, residual renal dysfunction reflected by proteinuria occurred in 28% of cases, and combined proteinuria and impairment of renal function in 22% of cases. This is similar to the experience of Brandt et al2 who reported a 25% rate of residual renal dysfunction in patients with pneumococcal HUS, but not as positive as the conclusion of Huang et al6 suggesting that long-term renal effects are rare. This report, however, is in sharp contrast to the outcomes reported by Nathanson et al,3 in which only 2 of 7 survivors of the acute illness had normal renal function at follow-up. This study, importantly, provides data on a much larger number of patients. The long-term follow-up of survivors of D+ HUS reported by Fitzpatrick et al5 and Seigler et al4 showed either albuminuria or reduced glomerular filtration rate in 49% and 51% of survivors, respectively. Overall therefore, once the acute illness is past, and barring neurologic damage related to meningitis, the outcome for children with pneumococcal HUS seems favorable compared with other forms of HUS.
The pathogenesis of HUS in children with pneumococcal disease was first enunciated in 1977 by Klein et al,7 who described exposure of the Thomsen-Freidenreich antigen (T antigen) on red blood cells, platelets, and glomeruli in 2 affected patients. The T antigen is exposed as a result of neuraminidase production by S. pneumoniae, which cleaves N-acetylneuraminic acid (also known as sialic acid) from glycoproteins on cell membrane surfaces. The exposed T antigen then interacts with an immunoglobulin M anti-T antibody, a normal constituent of plasma, resulting in polyagglutination and hemolysis. Detection of T-antigen has been proposed as a predictor of HUS, and it has been suggested that if the T activation test result is positive, plasma and unwashed blood products, which contain additional anti-T antibody, should be avoided. However, T antigen can be detected in approximately 50% of children with invasive pneumococcal disease without HUS and is not found in all children with HUS,6 suggesting that the role of neuraminidase may be an oversimplification of the pathogenesis of pneumococcal HUS. It is unfortunate that studies to date have provided little additional information about pathogenesis, and it is unclear why only a small portion of patients with invasive pneumococcal disease have developed HUS. Perhaps it is related to individual variation in the amount of circulating anti-T antibody, or the amount of neuraminidase produced by various S. pneumoniae strains or serotypes? Also, the possible role of complement dysregulation which is implicated in the pathogenesis of other forms of “atypical” HUS should be investigated. Until further information concerning the pathogenesis of pneumococcal HUS is available, avoidance of plasma or unwashed blood products, which contain anti-T antibodies, is suggested. This is of particular importance because many of these children are critically ill with multisystem disease and frequently require blood products as part of their general care.
Also, for many children with severe HUS that is unresponsive to treatment of the underlying disease, plasma exchange may be recommended. In such a situation, 5% albumin should be used as the preferred replacement solution, unless deficiency of clotting factors develops.
Currently, pneumococcal HUS is usually classified as “atypical” or D− HUS. However, this classification includes an increasing number of conditions resulting from inherited deficiencies or dysregulation of complement. Many of these conditions are persistent or relapsing and have a poor prognosis for long-term renal function. It is therefore inappropriate to classify pneumococcal HUS with this group.
It is disconcerting, on the basis of the findings of this study and the experience of others,6, 8 that the incidence of pneumococcal HUS seems to be increasing. The conjugate heptavalent pneumococcal vaccine (PCV7), which is universally used in infants in North America and increasingly elsewhere, provides protection against the serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F. Perusal of Table II in the article by Waters et al1 shows that of the 12 patients for whom serotyping of S. pneumoniae was available, only one was potentially preventable by the current North American vaccine. Therefore it is unlikely that the incidence of this condition will diminish as a result of PCV7 vaccination but will persist as a significant complication of invasive pneumococcal disease.
References
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PII: S0022-3476(07)00397-6
doi:10.1016/j.jpeds.2007.04.057
© 2007 Mosby, Inc. All rights reserved.
Refers to article:
- Hemolytic Uremic Syndrome Associated with Invasive Pneumococcal Disease: The United Kingdom Experience
