Specific Treatments

(a) D+ HUS. The benefit of any treatment in this form of HUS must be measured against the natural history

of the disease. The claims of a beneficial effect of anticoagulants, antiplatelet agents, fresh plasma, plasma exchange, and fibrinolytic therapy have been difficult to interpret because of the spontaneous improvement seen in the majority of patients. Rizzoni et al (164) conducted a prospective randomized controlled trial on the use of FFP in D+ HUS and concluded that infusions of plasma did not influence the short or medium term clinical outcome. In a second similar study, Loirat et al (163) also showed no apparent long-term benefits but seven patients in the control group, and none in the FFP group, had extensive cortical necrosis diagnosed by renal biopsy. The results of controlled trials with antithrombotic agents (153,154) have been disappointing. In view of the complications of haemorrhage and the lack of any clear benefits, there s e e m s to be no i n d i c a t i o n for a n t i c o a g u l a t i o n or fibrinolytic agents in this disease.

Chapter 1: Introduction

(b) D- HUSm In contrast to D+ HUS, patients with idiopathic or familial D- HUS have a poor prognosis unless

specific treatment is used. Anecdotal impressions of beneficial effects of fresh blood, fresh plasma or plasma exchange have been reported. Patients with deficient PGlg s t i m u l a t i n g factors and some of tho s e w i t h p l a t e l e t aggregating factors respond to fresh plasma infusions (170). Patients with inhibitors of PGI2 production or

platelet aggregating factors have not responded to plasma but have improved after plasma exchange (171,172). Plasma exchange now has an established position in the management of adults with TTP; a controlled trial by the Canadian Apheresis Group comparing plasma exchange with plasma infusion found plasma exchange to be more effective than plasma infusion in reducing both mortality and morbidity

(173) .

(b) C o n s e n s u s o n T r e a t m e n t . In t y p i c a l , uncomplicated D+ HUS it is generally agreed that careful

supportive management, without specific treatment, should be carried out until the results of prospective trials to assess the usefulness of other specific treatments are available. In D- HUS, which has a poor prognosis, a more a g g r e s s i v e a p p r o a c h to t r e a t m e n t is justified; this involves infusions of FFP and PGlg followed by a programme of plasma exchange.

Chapter 1: Introduction

1.5 Outcome 1.5.1 Prognostic Indicators

The prognosis for HUS is known to depend on several factors, most significantly the subtype and predominant histopathological lesion (11,46,174). Children with D+ HUS who have a predominant glomerular injury have a much better outcome than those with D- HUS who have arteriolar injury or cortical necrosis. Other factors suggesting a poor prognosis include older age at onset (60,175,176), a family history of HUS, recurrence, anuria for more than 14 days, intestinal gangrene and pneumococcal infection

(177) .

1.5.2 D+ HUS

(a.)Mortality^ Before the introduction of dialysis, a high proportion of children with any form of HUS died of f l u i d o v e r l o a d , m e t a b o l i c d e r a n g e m e n t , and u r a e m i a (1,27,21,178,179). Once short-term dialysis became a widely available form of treatment, the prognosis for HUS generally improved, and most recent series from Europe and North America report an acute fatality rate between 4 and 12% (60,143,144,180,181). High mortality rates, up to 60%, have been reported in post-dysenteric D+ HUS (182-185). The poor outcome in this form of HUS appears to be because

Chapter 1: Introduction

of more profound renal injury. In a recent series from Northern India (185), the mortality rate was higher in those with prolonged anuria and total cortical necrosis.

(b) Morbidity, The long-term prognosis following D+ HUS remains incompletely documented. Follow-up studies

published over the years, from different countries, have produced variable results for renal outcome ranging from 15-40% of survivors with renal sequelae (21,143,144,186). This subject will be discussed in more detail in Chapter 5.

1.5.3 D- HUS

The p r o g n o s i s for D- HUS is p o o r w i t h a h i g h mortality (25-30%) and morbidity (31,45,60,174). This subject will be discussed in more detail in Chapter 3.

Chapter 2: HUS Clinical Review

CHAPTER 2 RETROSPECTIVE REVIEW OF HUS 1966-1992

2.1 Introduction

This chapter provides an overall summary of the p r i n c i p a l e p i d e m i o l o g i c a l and c l i n i c a l f e a t u r e s of children presenting to the Hospital for Sick Children, Great Ormond Street (HSC,GOS), between 1966 and 1992 with a diagnosis of HUS. It is from these patients that the c l i n i c a l and l a b o r a t o r y studies e l a b o r a t e d in later chapters in this thesis emanate.