CFH gene mutation in a case of Shiga toxin-associated hemolytic uremic syndrome (STEC-HUS)

Caillaud, Caroline; Zaloszyc, Ariane; Licht, Christoph; Pichault, Valérie; Frémeaux‐Bacchi, Véronique; Fischbach, Michel

doi:10.1007/s00467-015-3207-2

Cited by 19 publications

(8 citation statements)

References 31 publications

(81 reference statements)

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“…Still, when we focused our analysis on very rare pathogenic variants with minor allele frequency ,0.1%, we showed that such very rare pathogenic variants were associated with a fivefold higher risk of developing Shiga toxin-positive HUS. Thus, although Shiga toxin-associated HUS is mostly driven by the infectious agent, our study highlights that in rare cases, genetic abnormalities may contribute to complement activation in Shiga toxin-associated HUS, consistent with published data (9,10,(20)(21)(22)(23)(24)(25)(26)(27)(28). However, our study did not include patients with Shiga toxin infection who did not develop HUS (a study difficult to complete outside of large epidemics) and thus cannot prove the role of genetics in the risk of developing HUS after Shiga toxin infection.…”

Section: Discussionsupporting

confidence: 92%

“…Altogether, 17 children with postdiarrheal/Shiga toxin-producing Escherichia coli (STEC) HUS were subsequently reported who carried rare variants in complement genes (9,10,20-28). In nine of them, genetic screening was motivated by an unusually severe outcome, relapses, or post-transplant recurrence, suggesting that STEC infection triggers aHUS onset and/or preexisting complement variants amplify Shiga toxin-induced complement activation and endothelial/podocyte damage, and worsen disease severity (20)(21)(22)(23)(24)(25)(26)(27). However, seven reported patients who had complement variants had a favorable outcome (9,10,28), leaving the issue of the role of genetics in Shiga toxinassociated HUS unclear.…”

Section: Introductionmentioning

confidence: 99%

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Complement Gene Variants and Shiga Toxin–Producing Escherichia coli–Associated Hemolytic Uremic Syndrome

Frémeaux‐Bacchi

Sellier‐Leclerc

Vieira-Martins

et al. 2019

CJASN

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Background and objectives Inherited complement hyperactivation is critical for the pathogenesis of atypical hemolytic uremic syndrome (HUS) but undetermined in postdiarrheal HUS. Our aim was to investigate complement activation and variants of complement genes, and their association with disease severity in children with Shiga toxin-associated HUS. Design, setting, participants, & measurements Determination of complement biomarkers levels and nextgeneration sequencing for the six susceptibility genes for atypical HUS were performed in 108 children with a clinical diagnosis of post-diarrheal HUS (75 Shiga toxin-positive, and 33 Shiga toxin-negative) and 80 French controls. As an independent control cohort, we analyzed the genotypes in 503 European individuals from the 1000 Genomes Project. Results During the acute phase of HUS, plasma levels of C3 and sC5b-9 were increased, and half of patients had decreased membrane cofactor protein expression, which normalized after 2 weeks. Variants with minor allele frequency ,1% were identified in 12 Shiga toxin-positive patients with HUS (12 out of 75, 16%), including pathogenic variants in four (four out of 75, 5%), with no significant differences compared with Shiga toxinnegative patients with HUS and controls. Pathogenic variants with minor allele frequency ,0.1% were found in three Shiga toxin-positive patients with HUS (three out of 75, 4%) versus only four European controls (four out of 503, 0.8%) (odds ratio, 5.2; 95% confidence interval, 1.1 to 24; P=0.03). The genetic background did not significantly affect dialysis requirement, neurologic manifestations, and sC5b-9 level during the acute phase, and incident CKD during follow-up. However, the only patient who progressed to ESKD within 3 years carried a factor H pathogenic variant. Conclusions Rare variants and complement activation biomarkers were not associated with severity of Shiga toxin-associated HUS. Only pathogenic variants with minor allele frequency ,0.1% are more frequent in Shiga toxin-positive patients with HUS than in controls.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Complement Gene Variants and Shiga Toxin–Producing Escherichia coli–Associated Hemolytic Uremic Syndrome

Frémeaux‐Bacchi

Sellier‐Leclerc

Vieira-Martins

et al. 2019

CJASN

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“…STEC-HUS does not usually recur, and a second bout of the disease should lead to the suspicion of alternative complement pathway dysregulation [260]. Patients develop antibodies that may, in part, be protective [101], but in the case of repeated exposition to Stx, recurrence has been described [261,262], for example with the atypical O80 serogroup [46].…”

Section: Recurrencementioning

confidence: 99%

Shiga Toxin-Associated Hemolytic Uremic Syndrome: A Narrative Review

Joseph

Cointe

Kurkdjian

et al. 2020

Toxins

155

148

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The severity of human infection by one of the many Shiga toxin-producing Escherichia coli (STEC) is determined by a number of factors: the bacterial genome, the capacity of human societies to prevent foodborne epidemics, the medical condition of infected patients (in particular their hydration status, often compromised by severe diarrhea), and by our capacity to devise new therapeutic approaches, most specifically to combat the bacterial virulence factors, as opposed to our current strategies that essentially aim to palliate organ deficiencies. The last major outbreak in 2011 in Germany, which killed more than 50 people in Europe, was evidence that an effective treatment was still lacking. Herein, we review the current knowledge of STEC virulence, how societies organize the prevention of human disease, and how physicians treat (and, hopefully, will treat) its potentially fatal complications. In particular, we focus on STEC-induced hemolytic and uremic syndrome (HUS), where the intrusion of toxins inside endothelial cells results in massive cell death, activation of the coagulation within capillaries, and eventually organ failure.

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“…Accordingly, two cases of STEC-HUS have been reported in a 4-year old child and an 18-month infant, both shown to carry MCP mutations. The outcome proved fatal in the former case while eculizumab resulted in protracted remission in the latter [11,12]. Similarly, Alberti et al reported two additional cases of STEC-HUS resulting in ESRD, yet, post-transplantation recurrence of HUS revealed a mutation of CFI and MCP respectively [13].…”

Section: Discussionmentioning

confidence: 98%

Ockham’s razor defeated: about two atypical cases of hemolytic uremic syndrome

et al. 2020

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Background: Medical investigation is a favorite application of Ockham's razor, in virtue of which when presented with competing hypotheses, the solution with the fewest assumptions should be privileged. Hemolytic uremic syndrome (HUS) encompasses diseases with distinct pathological mechanisms, such as HUS due to shiga-like toxinproducing bacteria (STEC-HUS) and atypical HUS, linked to defects in the alternate complement pathway. Other etiologies such as Parvovirus B19 infection are exceptional. All these causes are rare to such extent that we usually consider them mutually exclusive. We report here two cases of HUS that could be traced to multiple causes. Cases presentation: Case 1 presented as vomiting and diarrhea. All biological characteristics of HUS were present. STEC was found in stool (by PCR and culture). After initial remission, a recurrence occurred and patient was started on Eculizumab. Genetic analysis revealed the heterozygous presence of a CFHR1/CFH hybrid gene. The issue was favorable under treatment. In case 2, HUS presented as fever, vomiting and purpura of the lower limbs. Skin lesions and erythroblastopenia led to suspect Parvovirus B19 primo-infection, which was confirmed by peripheral blood and medullar PCR. Concurrently, stool culture and PCR revealed the presence of STEC. Evolution showed spontaneous recovery. Conclusions: Both cases defy Ockham's razor in the sense that multiple causes could be traced to a single outcome; furthermore, they invite us to reflect on the physiopathology of HUS as they question the classical distinction between STEC-HUS and atypical HUS. We propose a two-hit mechanism model leading to HUS. Indeed, in case 1, HUS unfolded as a result of the synergistic interaction between an infectious trigger and a genetic predisposition. In case 2 however, it is the simultaneous occurrence of two infectious triggers that led to HUS. In dissent from Ockham's razor, an exceptional disease such as HUS may stem from the sequential occurrence or cooccurrence of several rare conditions.

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CFH gene mutation in a case of Shiga toxin-associated hemolytic uremic syndrome (STEC-HUS)

Cited by 19 publications

References 31 publications

Complement Gene Variants and Shiga Toxin–Producing Escherichia coli–Associated Hemolytic Uremic Syndrome

Complement Gene Variants and Shiga Toxin–Producing Escherichia coli–Associated Hemolytic Uremic Syndrome

Shiga Toxin-Associated Hemolytic Uremic Syndrome: A Narrative Review

Ockham’s razor defeated: about two atypical cases of hemolytic uremic syndrome

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