Hemolytic-uremic syndrome in Switzerland: a nationwide surveillance 1997-2003

Hemolytic-uremic syndrome (HUS) is a leading cause of acute renal failure in childhood. In its typical presentation, it is preceded by an episode of diarrhea mostly due to Shiga-toxin-producing Escherichia coli. There is important geographical variation of many aspects of this syndrome. Nationwide data on childhood HUS in Switzerland have not been available so far. In a prospective national study through the Swiss Pediatric Surveillance Unit 114 cases (median age 21 months, 50% boys) were reported between April 1997 and March 2003 by 38 pediatric units (annual incidence 1.42 per 10(5) children < or =16 years). Shiga-toxin-producing E. coli were isolated in 32 (60%) of tested stool samples, serotype O157:H7 in eight. Sixteen children presented with only minimal renal involvement, including three with underlying urinary tract infection. Six patients presented with atypical hemolytic-uremic syndrome, and six with HUS due to invasive Streptococcus pneumoniae infection. Mortality was 5.3%, including two out of six children with S. pneumoniae infection. The severity of thrombocytopenia and the presence of central nervous system involvement significantly correlated with mortality. In conclusion, childhood HUS is not rare in Switzerland. Contrasting other countries, E. coli O157:H7 play only a minor role in the etiology. Incomplete manifestation is not uncommon.

Eculizumab in atypical hemolytic uremic syndrome: long-term clinical course and histological findings

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy associated with defective regulation of the alternative complement pathway. The prognosis for patients with aHUS is poor, and plasma exchange represents the first-line therapy. Eculizumab is a humanized monoclonal anti-C5 antibody that prevents the activation of the terminal complement pathway. Here, we report the case of a 9-year-old girl with frequent relapsing aHUS due to heterozygous factor H mutation who was initially treated with plasma exchange three times per week with 150% plasma exchange volume. This treatment frequently caused allergic reactions and school absences. Because any reduction in the frequency of plasma exchange immediately induced relapses of the aHUS, treatment with eculizumab, 600 mg every 2 weeks, was started and plasma exchange completely stopped. On this drug regimen the patient showed no evidence of disease activity during a period of more than 24 months. Renal function improved, proteinuria disappeared, the number of antihypertensive medications could be decreased, and the quality of life increased substantially. The inhibition of the terminal complement pathway by eculizumab was also confirmed by renal biopsy, which showed the absence of thrombotic microangiopathy 2 months after the initiation of eculizumab therapy. This case illustrates the long-term favorable outcome of aHUS with eculizumab treatment.

Decreasing frequency of plasma exchange complications in patients treated for thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, 1996 to 2011

Plasma exchange (PEX) treatment for patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) has risk for major complications.

Neonatal hemolytic uremic syndrome after mother-to-child transmission of a low-pathogenic stx2b harboring shiga toxin-producing Escherichia coli

This case describes evidence for a Shiga toxin-producing Escherichia coli (STEC) O146:H28 infection leading to hemolytic uremic syndrome in a neonate. STEC O146:H28 was linked hitherto with asymptomatic carriage in humans. Based on strain characteristics and genotyping data, the mother is a healthy carrier who transmitted the STEC during delivery. STEC strains belonging to the low-pathogenic STEC group must also be considered in the workup of neonatal hemolytic uremic syndrome.

The incidence of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: all patients, idiopathic patients, and patients with severe ADAMTS-13 deficiency

Summary. Background: Accurate estimates of the incidence of thrombotic thrombocytopenic purpura (TTP) are important to assess the resources required for current treatments as well as to anticipate the need to develop new treatments. Previous estimates have been indirect and have not reported data on patients with ADAMTS-13 deficiency. Objective: To determine the incidence of patients with TTP-hemolytic uremic syndrome (HUS) in three categories: all patients with clinically suspected TTP-HUS, patients with idiopathic TTP-HUS, and patients with severe ADAMTS-13 deficiency. Methods: Incidence rates were estimated from the Oklahoma TTP-HUS Registry, analyzing all 206 consecutive patients from January 1, 1996 to June 30, 2004 who were treated with plasma exchange for their initial episode of clinically suspected TTP-HUS. ADAMTS-13 activity was measured in 186 (90%) of the 206 patients. Results: The age–sex–race standardized annual incidence rates were 11.29 × 106 (95% CI: 9.70–12.88) for all patients with clinically suspected TTP-HUS; 4.46 × 106 (95% CI: 3.43–5.50) for patients with idiopathic TTP-HUS; and 1.74 × 106 (95% CI: 1.06–2.41) for patients with severe ADAMTS-13 deficiency (<5% activity). In all three categories, the incidence rates were greater for women and for blacks. For patients with severe ADAMTS-13 deficiency, the age–sex standardized incidence rate ratio of blacks to non-blacks was 9.29 (95% CI: 4.33–19.93). Conclusions: Accurate incidence rate estimates for all patients with clinically suspected TTP-HUS, idiopathic TTP-HUS, and TTP associated with severe ADAMTS-13 deficiency have been determined. The greater incidence among women and blacks is comparable with their increased risk for other autoimmune disorders.

Pancreatitis preceding acute episodes of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: report of five patients with a systematic review of published reports

BACKGROUND AND OBJECTIVES: The thrombotic thrombocytopenic purpura-hemolytic uremic syndromes (TTP-HUS) have diverse etiologies, clinical manifestations, and risk factors, but the events that may trigger acute episodes are often unclear. We describe the occurrence of TTP-HUS following pancreatitis and consider whether pancreatitis may be a triggering event for acute episodes of TTP-HUS. DESIGN AND METHODS: We report on three patients from the Oklahoma Registry and two patients from Northwestern University who had an acute episode of TTP-HUS following pancreatitis. A systematic review of published case reports was performed to identify additional patients who had TTP-HUS following pancreatitis. RESULTS. In each of our five patients there was an apparent etiology of alcoholism or common bile duct obstruction for the pancreatitis and no evidence of TTP-HUS when the pancreatitis was diagnosed. Two patients had severe ADAMTS13 deficiency with an inhibitor; in one of these patients TTP-HUS recurred following a subsequent recurrent episode of pancreatitis. The systematic review identified 16 additional patients who had TTP-HUS following pancreatitis; recurrent TTP-HUS occurred in three of these patients following a subsequent episode of recurrent pancreatitis. In all 21 patients, the interval between the diagnosis of pancreatitis and TTP-HUS was short (1-13 days; median, 3 days). The three Oklahoma patients represent approximately 1% of the 356 patients in the Registry. INTERPRETATION AND CONCLUSIONS: These observations suggest that in some patients pancreatitis, a disorder that results in an intense systemic inflammatory response, may be a triggering event for acute episodes of TTP-HUS.

The Oklahoma Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome Registry: the Swiss connection

OBJECTIVES: Thrombotic thrombocytopenic purpura (TTP) was initially described as an uncommon and usually fatal disorder. With effective treatment it is more frequently diagnosed, the clinical presentations are more diverse, and long-term sequelae are becoming recognized. METHODS: Patient data are from The Oklahoma TTP-hemolytic uremic syndrome (HUS) Registry, an inception cohort of 348 consecutive patients with their first episode of clinically diagnosed TTP or HUS, 1989-2006. The Registry enrolls all patients in a defined region who are diagnosed with TTP or HUS and for whom plasma exchange treatment is requested. ADAMTS13 activity has been analyzed on 235 (93%) of 254 patients since 1995 at the University of Berne, Switzerland. Patients are described by clinical categories, related to their associated conditions and clinically apparent etiologies, and by the presence of severe ADAMTS13 deficiency. RESULTS AND CONCLUSIONS: The clinical spectrum of syndromes described as TTP is variable with multiple etiologies. Advances in clinical and laboratory investigation have provided better understanding of the pathogenesis of these syndromes, their clinical evaluation and management, and their long-term outcomes. In addition to new information about TTP, these studies provide a model for translational research to define the complete community spectrum of uncommon disorders.

Different disparities of gender and race among the thrombotic thrombocytopenic purpura and hemolytic-uremic syndromes

Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) represent multiple disorders with diverse etiologies. We compared the gender and race of 335 patients enrolled in the Oklahoma TTP-HUS Registry across 21 years for their first episode of TTP or HUS to appropriate control groups. The relative frequency of women and white race among patients with TTP-HUS-associated with a bloody diarrhea prodrome and the relative frequency of women with quinine-associated TTP-HUS were significantly greater than their control populations. The relative frequency of women and black race among patients with idiopathic TTP and TTP-associated with severe ADAMTS13 deficiency was significantly greater than their control populations. The relative frequency of black race among patients who had systemic lupus erythematosus (SLE) preceding TTP was significantly greater than among a population of patients with SLE, and the relative frequency of black race among patients with other autoimmune disorders preceding TTP was significantly greater than their control population. No significant gender or race disparities were present among patients with hematopoietic stem cell transplantation-associated thrombotic microangiopathy, TTP associated with pregnancy, or TTP associated with drugs other than quinine. The validity of these observations is supported by the enrollment of all consecutive patients across 21 years from a defined geographic region, without selection or referral bias. These observations of different gender and race disparities among the TTP-HUS syndromes suggest the presence of different risk factors and may serve as starting points for novel investigations of pathogenesis.

Pulmonary renal syndrome in childhood: a report of twenty-one cases and a review of the literature

In adults, the term specific pulmonary renal syndrome describes disorders with pulmonary and glomerular manifestations and includes Wegener's granulomatosis, Goodpasture disease, and systemic lupus erythematosus. Nonspecific pulmonary renal syndrome refers to either pulmonary disease complicating glomerular disease, or glomerular diseases following pulmonary disease. Since little is known regarding pulmonary renal syndrome in childhood, we reviewed the charts of 21 pediatric patients with pulmonary renal syndromes treated by the Department of Pediatrics, University of Bern between 1991 and 1998; we also reviewed the pediatric literature that deals with specific pulmonary renal syndromes. Specific pulmonary renal syndrome was noted in 3 children with systemic vasculitis (Wegener granulomatosis, N = 2; microscopic polyangiitis, N = 1) and 2 with systemic lupus erythematosus. Nonspecific pulmonary renal syndrome was observed in 12 patients with pulmonary edema (N = 9), pulmonary thromboembolism (N = 2), and pulmonary infection (N = 1) complicating the course of a glomerular disease, and in 4 children with a pulmonary disease followed by a glomerular disease. Review of the literature disclosed 52 cases of specific pulmonary renal syndrome other than systemic lupus erythematosus: Wegener granulomatosis (N = 28), Goodpasture disease (N = 13), and Henoch-Schönlein purpura (N = 11). In addition, hemolytic uremic syndrome complicated pneumococcal pneumonia in 32 cases. We conclude that pulmonary renal syndromes need to be looked for in childhood. Apart from Wegener granulomatosis, Goodpasture disease, and systemic lupus erythematosus, Henoch-Schönlein purpura and hemolytic-uremic syndrome occasionally have both pulmonary and renal features.

Heme oxygenase-1 is a critical regulator of nitric oxide production in enterohemorrhagic Escherichia coli-infected human enterocytes

Enterohemorrhagic Escherichia coli (EHEC) are the causative agent of hemolytic-uremic syndrome. In the first stage of the infection, EHEC interact with human enterocytes to modulate the innate immune response. Inducible NO synthase (iNOS)-derived NO is a critical mediator of the inflammatory response of the infected intestinal mucosa. We therefore aimed to analyze the role of EHEC on iNOS induction in human epithelial cell lines. In this regard, we show that EHEC down-regulate IFN-gamma-induced iNOS mRNA expression and NO production in Hct-8, Caco-2, and T84 cells. This inhibitory effect occurs through the decrease of STAT-1 activation. In parallel, we demonstrate that EHEC stimulate the rapid inducible expression of the gene hmox-1 that encodes for the enzyme heme oxygenase-1 (HO-1). Knock-down of hmox-1 gene expression by small interfering RNA or the blockade of HO-1 activity by zinc protoporphyrin IX abrogated the EHEC-dependent inhibition of STAT-1 activation and iNOS mRNA expression in activated human enterocytes. These results highlight a new strategy elaborated by EHEC to control the host innate immune response.

Human microbiota-secreted factors inhibit shiga toxin synthesis by enterohemorrhagic Escherichia coli O157:H7

Escherichia coli O157:H7 is a food-borne pathogen causing hemorrhagic colitis and hemolytic-uremic syndrome, especially in children. The main virulence factor responsible for the more serious disease is the Shiga toxin 2 (Stx2), which is released in the gut after oral ingestion of the organism. Although it is accepted that the amount of Stx2 produced by E. coli O157:H7 in the gut is critical for the development of disease, the eukaryotic or prokaryotic gut factors that modulate Stx2 synthesis are largely unknown. In this study, we examined the influence of prokaryotic molecules released by a complex human microbiota on Stx2 synthesis by E. coli O157:H7. Stx2 synthesis was assessed after growth of E. coli O157:H7 in cecal contents of gnotobiotic rats colonized with human microbiota or in conditioned medium having supported the growth of complex human microbiota. Extracellular prokaryotic molecules produced by the commensal microbiota repress stx(2) mRNA expression and Stx2 production by inhibiting the spontaneous and induced lytic cycle mediated by RecA. These molecules, with a molecular mass of below 3 kDa, are produced in part by Bacteroides thetaiotaomicron, a predominant species of the normal human intestinal microbiota. The microbiota-induced stx(2) repression is independent of the known quorum-sensing pathways described in E. coli O157:H7 involving SdiA, QseA, QseC, or autoinducer 3. Our findings demonstrate for the first time the regulatory activity of a soluble factor produced by the complex human digestive microbiota on a bacterial virulence factor in a physiologically relevant context.

Frequency and significance of HIV infection among patients diagnosed with thrombotic thrombocytopenic purpura

BACKGROUND: Case series of patients with a diagnosis of thrombotic thrombocytopenic purpura (TTP) have reported different frequencies of human immunodeficiency virus (HIV) infection; some series suggest that HIV infection may cause TTP. METHODS: We systematically reviewed all reports of HIV infection in case series of patients with TTP. We analyzed data from the Oklahoma TTP-HUS (hemolytic uremic syndrome) Registry, an inception cohort of 362 consecutive patients, for 1989-2007. RESULTS: Nineteen case series reported the occurrence of HIV infection at the time of diagnosis of TTP in 0%-83% of patients; individual patient data were rarely described. The Oklahoma TTP-HUS Registry determined the HIV status at the time of diagnosis of TTP in 351 (97%) of 362 patients. HIV infection was documented in 6 (1.84%; 95% CI, 0.68%-4.01%) of 326 adult patients (age, 26-51 years); follow-up data were complete for all 6 patients. The period prevalence of HIV infection among all adults in the Oklahoma TTP-HUS Registry region for 1989-2007 was 0.30%. One patient had typical features of TTP with 5 relapses. Five patients had single episodes; in 4, the clinical features that had initially suggested the diagnosis of TTP were subsequently attributed to malignant hypertension (in 3 patients) and disseminated Kaposi sarcoma (in 1 patient). CONCLUSIONS: HIV infection, similar to other inflammatory conditions, may trigger acute episodes of TTP in susceptible patients. More commonly, acquired immunodeficiency syndrome-related disorders may mimic the clinical features of TTP. If the diagnosis of TTP is suggested in a patient with HIV infection, there should be careful evaluation for alternative diagnoses and cautious consideration of plasma exchange, the required treatment for TTP.

Multiple major morbidities and increased mortality during long-term follow-up after recovery from thrombotic thrombocytopenic purpura

Recovery from acute episodes of thrombotic thrombocytopenic purpura (TTP) appears complete except for minor cognitive abnormalities and risk for relapse. The Oklahoma TTP-HUS (hemolytic uremic syndrome) Registry enrolled 70 consecutive patients from 1995 to 2011 with ADAMTS13 activity <10% at their initial episode; 57 survived, with follow-up through 2012. The prevalence of body mass index (BMI), glomerular filtration rate (GFR), urine albumin/creatinine ratio (ACR), hypertension, major depression, systemic lupus erythematosus (SLE), and risk of death were compared with expected values based on the US reference population. At initial diagnosis, 57 survivors had a median age of 39 years; 45 (79%) were women; 21 (37%) were black; BMI and prevalence of SLE (7%) were greater (P < .001) than expected; prevalence of hypertension (19%; P = .463) was not different. GFR (P = .397) and ACR (P = .793) were not different from expected values. In 2011-2012, prevalence of hypertension (40% vs 23%; P = .013) and major depression (19% vs 6%; P = .005) was greater than expected values. Eleven patients (19%) have died, a proportion greater than expected compared with US and Oklahoma reference populations (P < .05). TTP survivors may have greater risk for poor health and premature death.

Children and adults with thrombotic thrombocytopenic purpura associated with severe, acquired Adamts13 deficiency: comparison of incidence, demographic and clinical features

BACKGROUND Thrombotic thrombocytopenic purpura (TTP) associated with severe, acquired ADAMTS13 deficiency is uncommonly reported in children. The incidence, demographic, and clinical features of these children, compared to adults, have not been described. PROCEDURES This study focused on children (<18 years old) and adults with TTP associated with severe, acquired ADAMTS13 deficiency, defined as activity <10%. The incidence rates for TTP in children and adults were calculated from patients enrolled in the Oklahoma TTP-HUS (Hemolytic-Uremic syndrome) Registry, 1996-2012. To describe demographic and clinical features, children with TTP were also identified from a systematic review of published reports and from samples sent to a reference laboratory for analysis of ADAMTS13. RESULTS The standardized annual incidence rate of TTP in children was 0.09 × 10(6) children per year, 3% of the incidence rate among adults (2.88 × 10(6) adults per year). Among the 79 children who were identified (one from the Oklahoma Registry, 55 from published reports, 23 from the reference laboratory), TTP appeared to be more common among females, similar to the relative increased frequency of women among adults with TTP, and more common in older children. Clinical data were available on 52 children; the frequency of severe renal failure, relapse, treatment with rituximab, and systemic lupus erythematosus in these children was similar to adults with TTP. CONCLUSIONS TTP associated with severe, acquired ADAMTS13 deficiency is uncommon in children. The demographic and clinical features of these children are similar to the features of adults with TTP.