# Shiga Toxin-Associated Hemolytic Uremic Syndrome in Adults, France, 2009-2017

Benoit Travert, Antoine Dossier, Matthieu Jamme, Aurelie Cointe, Yahsou Delmas, Sandrine Malot, Alain Wynckel, Amelie Seguin, Claire Presne, Miguel Hie, et al.

► To cite this version:

Benoit Travert, Antoine Dossier, Matthieu Jamme, Aurelie Cointe, Yahsou Delmas, et al. Shiga Toxin-Associated Hemolytic Uremic Syndrome in Adults, France, 2009-2017. Emerging Infectious Diseases, 2021, 27 (7), pp.1876-1885. 10.3201/eid2707.204638. hal-03572956

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# Shiga Toxin-Associated Hemolytic Uremic Syndrome in Adults, France, 2009-2017

Benoit Travert, Antoine Dossier, Matthieu Jamme, Aurelie Cointe, Yahsou Delmas, Sandrine Malot, Alain Wynckel, Amelie Seguin, Claire Presne, Miguel Hie, et al.

► To cite this version:

Benoit Travert, Antoine Dossier, Matthieu Jamme, Aurelie Cointe, Yahsou Delmas, et al. Shiga Toxin-Associated Hemolytic Uremic Syndrome in Adults, France, 2009-2017. Emerging Infectious Diseases, 2021, 27 (7), pp.1876-1885. 10.3201/eid2707.204638. hal-03572956

HAL Id: hal-03572956

https://u-picardie.hal.science/hal-03572956v1

Submitted on 6 May 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# Shiga Toxin-Associated Hemolytic Uremic Syndrome in Adults, France, 2009–2017

Benoît Travert,<fnref n="1" /> Antoine Dossier,<fnref n="1" /> Matthieu Jamme, Aurélie Cointe, Yahsou Delmas, Sandrine Malot, Alain Wynckel, Amélie Seguin, Claire Presne, Miguel Hie, Ygal Benhamou, David Ribes, Gabriel Choukroun, Steven Grangé, Alexandre Hertig, Emilie Cornec-Le Gall, Lionel Galicier, Eric Daugas, Lila Bouadma, François-Xavier Weill, Elie Azoulay, Fadi Fakhouri, Agnès Veyradier, Stéphane Bonacorsi, Julien Hogan, Véronique Frémeaux-Bacchi, Eric Rondeau, Patricia Mariani-Kurkdjian, Paul Coppo, Centre de Référence des Microangiopathies Thrombotiques<fnref n="2" />

We conducted a retrospective study on hemolytic uremic syndrome caused by Shiga toxin-producing *Escherichia coli* (STEC) in 96 adults enrolled in the cohort of the National Reference Center for Thrombotic Microangiopathies network in France during 2009–2017. Most infections were caused by STEC strains not belonging to the O157 or O104 serogroups. Thirty (31.3%) patients had multiple risk factors for thrombotic microangiopathy. In total, 61 (63.5%) patients required dialysis, 50 (52.1%) had a serious neurologic complication, 34 (35.4%) required mechanical ventilation, and 19 (19.8%) died during hospitalization. We used multivariate analysis to determine that the greatest risk factors for death were underlying immunodeficiency (hazard ratio 3.54) and severe neurologic events (hazard ratio 3.40). According to multivariate analysis and propensity score-matching, eculizumab treatment was not associated with survival. We found that underlying conditions, especially immunodeficiency, are strongly associated with decreased survival in adults who have hemolytic uremic syndrome caused by STEC.

Shiga toxin-producing *Escherichia coli* (STEC) infection is an environmental foodborne or waterborne disease that causes bloody diarrhea. Approximately 5%–20% of cases are complicated by hemolytic uremic syndrome (HUS) (1,2). Shiga toxins (Stx) can cause acute microvascular injury, leading to thrombotic microangiopathy (TMA), which is characterized by hemolytic anemia and thrombocytopenia, and in the scenario of HUS, associated with acute kidney injury (3). Researchers estimate that the global prevalence of STEC infection is ≈43.1 acute illnesses/100,000 person-years, causing ≈3,890 annual cases of STEC-associated HUS (4). STEC-associated HUS occurs mostly in children; sporadic cases are rare in adults.

Among children, STEC-associated HUS is the most frequent form of TMA and the leading cause of acute renal failure (3). In France, surveillance for STEC-associated HUS in children <15 years of age

Author affiliations: Centre de Référence des Microangiopathies Thrombotiques, Paris, France (B. Travert, A. Dossier, M. Jamme, Y. Delmas, S. Malot, A. Wynckel, A. Seguin, C. Presne, M. Hie, Y. Benhamou, G. Choukroun, S. Grangé, A. Hertig, L. Galicier, E. Azoulay, F. Fakhouri, A. Veyradier, V. Frémeaux-Bacchi, E. Rondeau, P. Coppo); Université de Paris, Paris (B. Travert, A. Dossier, A. Cointe, L. Galicier, E. Daugas, L. Bouadma, E. Azoulay, A. Veyradier, S. Bonacorsi, J. Hogan, V. Frémeaux-Bacchi, P. Mariani-Kurkdjian); Hôpital Bichat—Claude Bernard, Paris (B. Travert, A. Dossier, E. Daugas, L. Bouadma); Sorbonne-Université, Paris (M. Jamme, M. Hie, A. Hertig, E. Rondeau, P. Coppo); Hôpital Tenon, Paris (M. Jamme, E. Rondeau); Hôpital Robert-Debré, Paris (A. Cointe, S. Bonacorsi, J. Hogan, P. Mariani-Kurkdjian); Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France (Y. Delmas); Hôpital Maison Blanche, Reims, France (A. Wynckel); Centre Hospitalier Universitaire de Caen, Caen, France (A. Seguin); Centre

Hospitalier Universitaire d'Amiens, Amiens, France (C. Presne, G. Choukroun); Groupement Hospitalier Pitié-Salpêtrière, Paris (M. Hie, A. Hertig); Centre Hospitalier Universitaire de Rouen, Rouen, France (Y. Benhamou, S. Grangé); Centre Hospitalier Universitaire de Toulouse, Toulouse, France (D. Ribes); Centre Hospitalier Universitaire de Brest, Brest, France (E. Cornec-Le Gall); Hôpital Saint-Louis, Paris (L. Galicier, E. Azoulay); Institut Pasteur, Paris (F.-X. Weill); Centre Hospitalier Universitaire de Nantes, Nantes, France (F. Fakhouri); Hôpital Lariboisière, Paris (A. Veyradier); Hôpital Européen Georges Pompidou, Paris (V. Frémeaux-Bacchi); Hôpital Saint Antoine, Paris (P. Coppo)

DOI: https://doi.org/10.3201/eid2707.204638

<footnote n="1">¹These first authors contributed equally to this article.</footnote>

<footnote n="2">²Members of this group are listed at the end of this article.</footnote>
# Shiga Toxin-Associated Hemolytic Uremic Syndrome in Adults, France, 2009–2017

Benoît Travert,<fnref n="1" /> Antoine Dossier,<fnref n="1" /> Matthieu Jamme, Aurélie Cointe, Yahsou Delmas, Sandrine Malot, Alain Wynckel, Amélie Seguin, Claire Presne, Miguel Hie, Ygal Benhamou, David Ribes, Gabriel Choukroun, Steven Grangé, Alexandre Hertig, Emilie Cornec-Le Gall, Lionel Galicier, Eric Daugas, Lila Bouadma, François-Xavier Weill, Elie Azoulay, Fadi Fakhouri, Agnès Veyradier, Stéphane Bonacorsi, Julien Hogan, Véronique Frémeaux-Bacchi, Eric Rondeau, Patricia Mariani-Kurkdjian, Paul Coppo, Centre de Référence des Microangiopathies Thrombotiques<fnref n="2" />

We conducted a retrospective study on hemolytic uremic syndrome caused by Shiga toxin-producing *Escherichia coli* (STEC) in 96 adults enrolled in the cohort of the National Reference Center for Thrombotic Microangiopathies network in France during 2009–2017. Most infections were caused by STEC strains not belonging to the O157 or O104 serogroups. Thirty (31.3%) patients had multiple risk factors for thrombotic microangiopathy. In total, 61 (63.5%) patients required dialysis, 50 (52.1%) had a serious neurologic complication, 34 (35.4%) required mechanical ventilation, and 19 (19.8%) died during hospitalization. We used multivariate analysis to determine that the greatest risk factors for death were underlying immunodeficiency (hazard ratio 3.54) and severe neurologic events (hazard ratio 3.40). According to multivariate analysis and propensity score-matching, eculizumab treatment was not associated with survival. We found that underlying conditions, especially immunodeficiency, are strongly associated with decreased survival in adults who have hemolytic uremic syndrome caused by STEC.

Shiga toxin-producing *Escherichia coli* (STEC) infection is an environmental foodborne or waterborne disease that causes bloody diarrhea. Approximately 5%–20% of cases are complicated by hemolytic uremic syndrome (HUS) (1,2). Shiga toxins (Stx) can cause acute microvascular injury, leading to thrombotic microangiopathy (TMA), which is characterized by hemolytic anemia and thrombocytopenia, and in the scenario of HUS, associated with acute kidney injury (3). Researchers estimate that the global prevalence of STEC infection is ≈43.1 acute illnesses/100,000 person-years, causing ≈3,890 annual cases of STEC-associated HUS (4). STEC-associated HUS occurs mostly in children; sporadic cases are rare in adults.

Among children, STEC-associated HUS is the most frequent form of TMA and the leading cause of acute renal failure (3). In France, surveillance for STEC-associated HUS in children <15 years of age

Author affiliations: Centre de Référence des Microangiopathies Thrombotiques, Paris, France (B. Travert, A. Dossier, M. Jamme, Y. Delmas, S. Malot, A. Wynckel, A. Seguin, C. Presne, M. Hie, Y. Benhamou, G. Choukroun, S. Grangé, A. Hertig, L. Galicier, E. Azoulay, F. Fakhouri, A. Veyradier, V. Frémeaux-Bacchi, E. Rondeau, P. Coppo); Université de Paris, Paris (B. Travert, A. Dossier, A. Cointe, L. Galicier, E. Daugas, L. Bouadma, E. Azoulay, A. Veyradier, S. Bonacorsi, J. Hogan, V. Frémeaux-Bacchi, P. Mariani-Kurkdjian); Hôpital Bichat—Claude Bernard, Paris (B. Travert, A. Dossier, E. Daugas, L. Bouadma); Sorbonne-Université, Paris (M. Jamme, M. Hie, A. Hertig, E. Rondeau, P. Coppo); Hôpital Tenon, Paris (M. Jamme, E. Rondeau); Hôpital Robert-Debré, Paris (A. Cointe, S. Bonacorsi, J. Hogan, P. Mariani-Kurkdjian); Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France (Y. Delmas); Hôpital Maison Blanche, Reims, France (A. Wynckel); Centre Hospitalier Universitaire de Caen, Caen, France (A. Seguin); Centre

Hospitalier Universitaire d'Amiens, Amiens, France (C. Presne, G. Choukroun); Groupement Hospitalier Pitié-Salpêtrière, Paris (M. Hie, A. Hertig); Centre Hospitalier Universitaire de Rouen, Rouen, France (Y. Benhamou, S. Grangé); Centre Hospitalier Universitaire de Toulouse, Toulouse, France (D. Ribes); Centre Hospitalier Universitaire de Brest, Brest, France (E. Cornec-Le Gall); Hôpital Saint-Louis, Paris (L. Galicier, E. Azoulay); Institut Pasteur, Paris (F.-X. Weill); Centre Hospitalier Universitaire de Nantes, Nantes, France (F. Fakhouri); Hôpital Lariboisière, Paris (A. Veyradier); Hôpital Européen Georges Pompidou, Paris (V. Frémeaux-Bacchi); Hôpital Saint Antoine, Paris (P. Coppo)

DOI: https://doi.org/10.3201/eid2707.204638

<footnote n="1">¹These first authors contributed equally to this article.</footnote>

<footnote n="2">²Members of this group are listed at the end of this article.</footnote>
has existed since 1996. This surveillance system comprises 32 pediatric healthcare centers, including all 21 university hospital units specializing in pediatric nephrology. These centers notify public health authorities of cases of STEC-associated HUS. The National Reference Center for *Escherichia coli*, *Shigella* and *Salmonella* at the Institut Pasteur (NRC-Ec; Paris, France) and its associated laboratory at the Robert Debré University Hospital (Paris, France) confirm and characterize STEC infections in children and adults. This surveillance network estimated the annual incidence of HUS in France to be 1.00 case/100,000 child-years, causing a ≈1% death rate during 2007–2016 (5).

Despite the much lower incidence of HUS among adults than children, most deaths caused by STEC-associated HUS occur among persons ≥60 years of age (2,6). The French national health authorities do not have a dedicated surveillance system for STEC-associated HUS in adults. In 2011, a large STEC outbreak in Europe sickened 3,816 persons in Germany, causing 845 cases of HUS and 54 deaths; 24 persons were affected in the Bordeaux region of France, including 9 who had HUS, 8 of whom were adults (7,8). The outbreak was linked to an atypical hybrid pathotype *E. coli* O104:H4 strain characterized by enteroaggregative and enterohemorrhagic virulence; the strain also produced an extended spectrum β-lactamase. Most (88%) patients involved in this outbreak, which was associated with consumption of organic fenn Greek sprouts, were adults, and the median age was 42 years. Publicity surrounding this outbreak raised awareness of STEC-associated HUS in adults. However, cases of STEC-associated HUS in adults remain rare (9,10). Hence, the clinical characteristics of adult STEC-associated HUS and the effects of therapeutic strategies on outcome remain uncertain. We describe the epidemiologic and clinical features of adults with STEC-associated HUS, identify predictors of patient outcomes, and assess the effectiveness of therapeutic interventions in this population.

## Methods

### Study Design, Settings, and Data Sources

We conducted a retrospective cohort study of STEC-associated HUS cases in adults registered during January 2009–December 2017 in France by the Centre National de Référence des Microangiopathies Thrombotiques (CNR-MAT; https://www.cnr-mat.fr). We reviewed all medical files from the CNR-MAT database. This work was part of the TMA study approved by our institutional review board (Comité pour la protection des personnes Ile-de-France; approval no.

CPP04807) in accordance with the Declaration of Helsinki and the French Data Protection Authority.

### Diagnostic Criteria

The diagnosis of HUS required the coexistence of TMA (i.e., thrombocytopenia [platelet levels <150,000 cells/µL] and microangiopathic hemolytic anemia [hemoglobin levels <12 g/dL]) and an acute kidney injury (AKI). We included all TMA patients ≥18 years of age in the CNR-MAT cohort who had an AKI and a positive PCR result for the Stx genes stx1, stx2, or both. We considered patients to have fever if they had a temperature of ≥38°C within 24 hours after admission.

### Microbiological Data

Participating laboratories conducted PCR specific for stx1 and stx2 on *E. coli* strains isolated from stool, blood, and urine samples. Laboratory technicians also cultured samples from stx-positive stools. To characterize the isolated STEC strains, technicians used an O-serogroup multiplex PCR selective for the 10 most frequent serogroups affecting humans in France: O157, O26, O145, O55, O103, O104, O111, O91, O121, and O80 (11). Strains belonging to other serogroups were characterized by PCR of the restriction fragment length polymorphism of the O operon, rfb (rfb-RFLP) (12). In April 2017, NRC-Ec and local laboratories also began to characterize strains using whole-genome sequencing, when available. If a strain was stx-positive but its serogroup was not identified by culture, we classified that strain as not isolated.

### Variables

Participating laboratories and physicians submitted data on each patient's medical history, clinical and biological features, microbiological findings, and treatment at admission and during hospitalization (13). We retrospectively calculated each patient's age-weighted Charlson Comorbidity Index (CCI) (14) and classified AKI according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria published by the International Society of Nephrology (15). We investigated ADAMTS13 and complement alternative pathway (CAP) activity as previously described (16).

### Treatments and Outcomes

Treatment consisted mainly of therapeutic plasma exchange (TPE) or best supportive care (BSC) according to the discretion of the treating physician. The C5 complement blocker eculizumab (Soliris; Alexion Pharmaceuticals, Inc., https://alexion.com) also
has existed since 1996. This surveillance system comprises 32 pediatric healthcare centers, including all 21 university hospital units specializing in pediatric nephrology. These centers notify public health authorities of cases of STEC-associated HUS. The National Reference Center for *Escherichia coli*, *Shigella* and *Salmonella* at the Institut Pasteur (NRC-Ec; Paris, France) and its associated laboratory at the Robert Debré University Hospital (Paris, France) confirm and characterize STEC infections in children and adults. This surveillance network estimated the annual incidence of HUS in France to be 1.00 case/100,000 child-years, causing a ≈1% death rate during 2007–2016 (5).

Despite the much lower incidence of HUS among adults than children, most deaths caused by STEC-associated HUS occur among persons ≥60 years of age (2,6). The French national health authorities do not have a dedicated surveillance system for STEC-associated HUS in adults. In 2011, a large STEC outbreak in Europe sickened 3,816 persons in Germany, causing 845 cases of HUS and 54 deaths; 24 persons were affected in the Bordeaux region of France, including 9 who had HUS, 8 of whom were adults (7,8). The outbreak was linked to an atypical hybrid pathotype *E. coli* O104:H4 strain characterized by enteroaggregative and enterohemorrhagic virulence; the strain also produced an extended spectrum β-lactamase. Most (88%) patients involved in this outbreak, which was associated with consumption of organic fenn Greek sprouts, were adults, and the median age was 42 years. Publicity surrounding this outbreak raised awareness of STEC-associated HUS in adults. However, cases of STEC-associated HUS in adults remain rare (9,10). Hence, the clinical characteristics of adult STEC-associated HUS and the effects of therapeutic strategies on outcome remain uncertain. We describe the epidemiologic and clinical features of adults with STEC-associated HUS, identify predictors of patient outcomes, and assess the effectiveness of therapeutic interventions in this population.

## Methods

### Study Design, Settings, and Data Sources

We conducted a retrospective cohort study of STEC-associated HUS cases in adults registered during January 2009–December 2017 in France by the Centre National de Référence des Microangiopathies Thrombotiques (CNR-MAT; https://www.cnr-mat.fr). We reviewed all medical files from the CNR-MAT database. This work was part of the TMA study approved by our institutional review board (Comité pour la protection des personnes Ile-de-France; approval no.

CPP04807) in accordance with the Declaration of Helsinki and the French Data Protection Authority.

### Diagnostic Criteria

The diagnosis of HUS required the coexistence of TMA (i.e., thrombocytopenia [platelet levels <150,000 cells/µL] and microangiopathic hemolytic anemia [hemoglobin levels <12 g/dL]) and an acute kidney injury (AKI). We included all TMA patients ≥18 years of age in the CNR-MAT cohort who had an AKI and a positive PCR result for the Stx genes stx1, stx2, or both. We considered patients to have fever if they had a temperature of ≥38°C within 24 hours after admission.

### Microbiological Data

Participating laboratories conducted PCR specific for stx1 and stx2 on *E. coli* strains isolated from stool, blood, and urine samples. Laboratory technicians also cultured samples from stx-positive stools. To characterize the isolated STEC strains, technicians used an O-serogroup multiplex PCR selective for the 10 most frequent serogroups affecting humans in France: O157, O26, O145, O55, O103, O104, O111, O91, O121, and O80 (11). Strains belonging to other serogroups were characterized by PCR of the restriction fragment length polymorphism of the O operon, rfb (rfb-RFLP) (12). In April 2017, NRC-Ec and local laboratories also began to characterize strains using whole-genome sequencing, when available. If a strain was stx-positive but its serogroup was not identified by culture, we classified that strain as not isolated.

### Variables

Participating laboratories and physicians submitted data on each patient's medical history, clinical and biological features, microbiological findings, and treatment at admission and during hospitalization (13). We retrospectively calculated each patient's age-weighted Charlson Comorbidity Index (CCI) (14) and classified AKI according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria published by the International Society of Nephrology (15). We investigated ADAMTS13 and complement alternative pathway (CAP) activity as previously described (16).

### Treatments and Outcomes

Treatment consisted mainly of therapeutic plasma exchange (TPE) or best supportive care (BSC) according to the discretion of the treating physician. The C5 complement blocker eculizumab (Soliris; Alexion Pharmaceuticals, Inc., https://alexion.com) also
was given at the discretion of the treating physician; however, physicians were encouraged to discuss eculizumab use with a member of the CNR-MAT team. The primary outcome of this study was patient survival at the time of most recent follow-up.

## Statistics

We reported qualitative variables as frequencies and percentages; we reported quantitative discrete and continuous variables as medians and interquartile ranges (IQRs). We estimated survival using the Kaplan-Meier method. We used Cox proportional hazards regression to identify factors independently associated with survival. The proportional hazard assumption was supported by a nonsignificant relationship between scaled Schoenfeld residuals and time and refuted by a significant relationship using an alpha ($\alpha$) risk set at 5%. We reported the results using hazard ratios (HRs) and 95% CIs, using an $\alpha$ risk set at 5% statistical significance. To quantify the effect of eculizumab on survival, we calculated and compared the propensity scores of patients who did and did not use eculizumab (Appendix, https://wwwnc.cdc.gov/EID/article/27/7/20-4638-App1.pdf). We used R software version 3.6.1 (The R Project for Statistical Computing, https://www.r-project.org) for statistical analysis. For propensity score analysis, we used MatchIt package (17).

## Results

Of the 4,048 patients in the CNR-MAT cohort, we first identified 61 adult STEC-associated HUS patients with complete data during January 2009–December 2017. After comparing the NRC-Ec and CNR-MAT surveillance data, we identified 35 additional patients to be included in the study cohort. In total, the study cohort comprised 96 patients (Appendix Figure 1). This cohort included patients from hospitals throughout France, most of which were part of the CNR-MAT network (Figure 1, panel A). The women-to-men ratio was 1.7 and median age was 60.5 years (IQR 47.0–71.0 years) (Figure 1, panel B). Geographic, temporal, and microbiological characteristics of the cases suggested an outbreak among 13 patients (Figure 1). The cohort also included 8 patients affected by the 2011 O104:H4 outbreak in France described previously (8). We found a patient in our cohort who was infected in a family cluster of STEC-associated HUS in 2014, but the strain could not be identified. We also found 4 patients (2 in Marne, 1 in Nord, 1 in Paris) who tested positive for STEC O91 in summer 2013 but did not share a known infection source.

In total, 69 (71.9%) patients had underlying conditions; the median CCI was 2.00 (IQR 1.00–4.25) (Table

1). Of the 96 patients, 27 (28.1%) had an underlying immunodeficiency and 30 (31.3%) had ≥1 condition that might contribute to TMA.

Most (83.3%) patients had diarrhea and nearly half (49.0%) had bloody diarrhea; 11 patients had severe colitis, including 4 who required emergency surgery (Table 2). All patients had renal impairment. In 2011, 2 patients with STEC O104:H4 infection had proteinuria (i.e., >1 g/L) but not serum creatinine elevation; these patients also had microangiopathic hemolytic anemia and peripheral thrombocytopenia (8). The other 94 patients all had AKI stage 1 or higher according to KDIGO criteria, of which 61 (63.5%) required dialysis. Of 12 patients who underwent kidney biopsy, 11 showed signs of TMA. Most (76%) patients had neurologic symptoms, mainly confusion (56.3%) and headache (18.8%). Approximately half (52.1%) of patients had a serious neurologic complication such as seizure, coma, or focal deficiency. In addition, 34 (35.4%) patients required mechanical ventilation. In total, 42 patients had high blood pressure (≥150/90 mm Hg) at admission; severe hypertension (≥170/110 mm Hg) subsequently developed in 11 patients and hypertensive retinopathy developed in 6 patients. Only 2 patients had hypotension (≤90/60 mm Hg) at admission. In total, 41 (42.7%) patients had cardiac events; in 26 of 43 cases with available data, patients had troponin levels above the defined threshold of their respective laboratory (Table 2).

CAP measurements during the acute phase of illness were recorded in 69 patients. Of these patients, 36 (52.2%) had values within the reference range (Table 2). Less than 10% of patients had low levels of C3, C4, factor H, or factor I, whereas 26 (38.8%) patients had low levels of CH50. CD46 levels were low in 65.7% (23/35) patients. Two patients had low levels of anti-factor H antibodies (242 and 800 arbitrary units) (Table 2). ADAMTS13 activity was detectable (≥10%) in all 69 patients in whom it was tested.

Among the 84 cases in which *stx* type was detected, *stx1*/*stx2*+ was the most common genotype (85.7%). The *stx1*/*stx2*− genotype was significantly associated with increased CCI and immunodeficiency (Appendix Table 1). As expected, the most common STEC isolation site was stool (93.8%), whereas only 10 patients had STEC-positive urine or blood samples. Seven (7.3%) patients had STEC-positive urine samples, including 5 who had a urologic infection without associated colitis. Four patients had STEC-positive blood samples, including 1 patient for whom STEC was identified in blood samples only. In total, 5 patients had a multisite infection.
was given at the discretion of the treating physician; however, physicians were encouraged to discuss eculizumab use with a member of the CNR-MAT team. The primary outcome of this study was patient survival at the time of most recent follow-up.

## Statistics

We reported qualitative variables as frequencies and percentages; we reported quantitative discrete and continuous variables as medians and interquartile ranges (IQRs). We estimated survival using the Kaplan-Meier method. We used Cox proportional hazards regression to identify factors independently associated with survival. The proportional hazard assumption was supported by a nonsignificant relationship between scaled Schoenfeld residuals and time and refuted by a significant relationship using an alpha ($\alpha$) risk set at 5%. We reported the results using hazard ratios (HRs) and 95% CIs, using an $\alpha$ risk set at 5% statistical significance. To quantify the effect of eculizumab on survival, we calculated and compared the propensity scores of patients who did and did not use eculizumab (Appendix, https://wwwnc.cdc.gov/EID/article/27/7/20-4638-App1.pdf). We used R software version 3.6.1 (The R Project for Statistical Computing, https://www.r-project.org) for statistical analysis. For propensity score analysis, we used MatchIt package (17).

## Results

Of the 4,048 patients in the CNR-MAT cohort, we first identified 61 adult STEC-associated HUS patients with complete data during January 2009–December 2017. After comparing the NRC-Ec and CNR-MAT surveillance data, we identified 35 additional patients to be included in the study cohort. In total, the study cohort comprised 96 patients (Appendix Figure 1). This cohort included patients from hospitals throughout France, most of which were part of the CNR-MAT network (Figure 1, panel A). The women-to-men ratio was 1.7 and median age was 60.5 years (IQR 47.0–71.0 years) (Figure 1, panel B). Geographic, temporal, and microbiological characteristics of the cases suggested an outbreak among 13 patients (Figure 1). The cohort also included 8 patients affected by the 2011 O104:H4 outbreak in France described previously (8). We found a patient in our cohort who was infected in a family cluster of STEC-associated HUS in 2014, but the strain could not be identified. We also found 4 patients (2 in Marne, 1 in Nord, 1 in Paris) who tested positive for STEC O91 in summer 2013 but did not share a known infection source.

In total, 69 (71.9%) patients had underlying conditions; the median CCI was 2.00 (IQR 1.00–4.25) (Table

1). Of the 96 patients, 27 (28.1%) had an underlying immunodeficiency and 30 (31.3%) had $\ge$1 condition that might contribute to TMA.

Most (83.3%) patients had diarrhea and nearly half (49.0%) had bloody diarrhea; 11 patients had severe colitis, including 4 who required emergency surgery (Table 2). All patients had renal impairment. In 2011, 2 patients with STEC O104:H4 infection had proteinuria (i.e., >1 g/L) but not serum creatinine elevation; these patients also had microangiopathic hemolytic anemia and peripheral thrombocytopenia (8). The other 94 patients all had AKI stage 1 or higher according to KDIGO criteria, of which 61 (63.5%) required dialysis. Of 12 patients who underwent kidney biopsy, 11 showed signs of TMA. Most (76%) patients had neurologic symptoms, mainly confusion (56.3%) and headache (18.8%). Approximately half (52.1%) of patients had a serious neurologic complication such as seizure, coma, or focal deficiency. In addition, 34 (35.4%) patients required mechanical ventilation. In total, 42 patients had high blood pressure ($\ge$150/90 mm Hg) at admission; severe hypertension ($\ge$170/110 mm Hg) subsequently developed in 11 patients and hypertensive retinopathy developed in 6 patients. Only 2 patients had hypotension ($\le$90/60 mm Hg) at admission. In total, 41 (42.7%) patients had cardiac events; in 26 of 43 cases with available data, patients had troponin levels above the defined threshold of their respective laboratory (Table 2).

CAP measurements during the acute phase of illness were recorded in 69 patients. Of these patients, 36 (52.2%) had values within the reference range (Table 2). Less than 10% of patients had low levels of C3, C4, factor H, or factor I, whereas 26 (38.8%) patients had low levels of CH50. CD46 levels were low in 65.7% (23/35) patients. Two patients had low levels of anti-factor H antibodies (242 and 800 arbitrary units) (Table 2). ADAMTS13 activity was detectable ($\ge$10%) in all 69 patients in whom it was tested.

Among the 84 cases in which *stx* type was detected, *stx1*/*stx2*+ was the most common genotype (85.7%). The *stx1*/*stx2*− genotype was significantly associated with increased CCI and immunodeficiency (Appendix Table 1). As expected, the most common STEC isolation site was stool (93.8%), whereas only 10 patients had STEC-positive urine or blood samples. Seven (7.3%) patients had STEC-positive urine samples, including 5 who had a urologic infection without associated colitis. Four patients had STEC-positive blood samples, including 1 patient for whom STEC was identified in blood samples only. In total, 5 patients had a multisite infection.
<figure><img src="image_2.png" /><figcaption>**Figure 1.** Distribution of adults with Shiga toxin-associated hemolytic uremic syndrome, France, 2009–2017. A) Geographic distribution of cases and thrombotic microangiopathy reference centers. The Centre National de Référence des Microangiopathies Thrombotiques is a national network comprising 1 coordination center, 5 constitutive centers, and 21 competence centers. B) Age and sex distribution of cases. C) Bimonthly distribution of cases according to serogroup. Of patients with minor serogroups, 4 had strains belonging to O106, 3 to O128, 3 to O174, 2 to O113, 1 to O100, 1 to O126, 1 to O148, 1 to O177, 1 to O78, 1 to O84, and 7 to an O serogroup not typable at the time of identification. ND, not determined.</figcaption></figure>

Most (60; 62.5%) had a serogroup typable by the NRC-Ec; 7 (7.3%) patients had an untypable serogroup. The most common serogroups were O91 (12; 17.9%) and O157 (10; 14.9%) (Table 2). The STEC isolates from urine samples belonged to the O104, O91, O106, O126, O174, and O148 serogroups; isolates from blood samples belonged to the O80, O103, and O128 serogroups (Appendix Table 2).

In total, 19 (19.8%) patients died during hospitalization (Figure 2, panel A; Appendix Table 3). Patients died 3–152 days after admission and had a median follow-up period of 112 days (IQR 49–238). After follow-up, 1 patient had HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome; the patient was STEC-negative at the time of the episode. None of the surviving patients had a further episode of TMA during follow-up.

Patients were treated mainly with BSC, TPE, or eculizumab; 3 patients also received immunoadsorption treatment (Appendix Table 4). Of the 61 patients who required dialysis, 17 (25.4%) died. At the end of the follow-up period, 6 (9.8%) patients still required dialysis, including 4 who had a follow-up period of >90 days. Patients who received dialysis were treated for a median duration of 13.5 days (IQR 8–28 days); 38 patients no longer required dialysis at the end of the follow-up period. After a median follow-up period of 34 days (IQR 23–75 days), the median serum creatinine value was 92 µmol/L (IQR 74–124 µmol/L). Of the 50 patients with a severe neurologic complication, 14 (28.0%) died. Of the 25 surviving patients with available data, 8 (32.0%) patients had neurologic sequelae, including persistent sensorimotor deficit (7, 28.0%), epilepsy (2, 8.0%), and cognitive impairment (2, 8.0%).
<figure><img src="image_2.png" /><figcaption>**Figure 1.** Distribution of adults with Shiga toxin-associated hemolytic uremic syndrome, France, 2009–2017. A) Geographic distribution of cases and thrombotic microangiopathy reference centers. The Centre National de Référence des Microangiopathies Thrombotiques is a national network comprising 1 coordination center, 5 constitutive centers, and 21 competence centers. B) Age and sex distribution of cases. C) Bimonthly distribution of cases according to serogroup. Of patients with minor serogroups, 4 had strains belonging to O106, 3 to O128, 3 to O174, 2 to O113, 1 to O100, 1 to O126, 1 to O148, 1 to O177, 1 to O78, 1 to O84, and 7 to an O serogroup not typable at the time of identification. ND, not determined.</figcaption></figure>

Most (60; 62.5%) had a serogroup typable by the NRC-Ec; 7 (7.3%) patients had an untypable serogroup. The most common serogroups were O91 (12; 17.9%) and O157 (10; 14.9%) (Table 2). The STEC isolates from urine samples belonged to the O104, O91, O106, O126, O174, and O148 serogroups; isolates from blood samples belonged to the O80, O103, and O128 serogroups (Appendix Table 2).

In total, 19 (19.8%) patients died during hospitalization (Figure 2, panel A; Appendix Table 3). Patients died 3–152 days after admission and had a median follow-up period of 112 days (IQR 49–238). After follow-up, 1 patient had HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome; the patient was STEC-negative at the time of the episode. None of the surviving patients had a further episode of TMA during follow-up.

Patients were treated mainly with BSC, TPE, or eculizumab; 3 patients also received immunoadsorption treatment (Appendix Table 4). Of the 61 patients who required dialysis, 17 (25.4%) died. At the end of the follow-up period, 6 (9.8%) patients still required dialysis, including 4 who had a follow-up period of >90 days. Patients who received dialysis were treated for a median duration of 13.5 days (IQR 8–28 days); 38 patients no longer required dialysis at the end of the follow-up period. After a median follow-up period of 34 days (IQR 23–75 days), the median serum creatinine value was 92 µmol/L (IQR 74–124 µmol/L). Of the 50 patients with a severe neurologic complication, 14 (28.0%) died. Of the 25 surviving patients with available data, 8 (32.0%) patients had neurologic sequelae, including persistent sensorimotor deficit (7, 28.0%), epilepsy (2, 8.0%), and cognitive impairment (2, 8.0%).
In total, 26 (27.1%) patients were treated with macrolides, including 3 who received the treatment to prevent infectious meningoencephalitis associated with eculizumab. Fifty-seven (59.4%) patients received β-lactam antimicrobial drugs, aminoglycosides, or quinolones; 22 (22.9%) patients received metronidazole.

After unadjusted analysis, we found that age (HR 1.04, 95% CI 1.01–1.07; p = 0.01), CCI (HR 1.15, 95% CI 1.03–1.28; p = 0.02) (Figure 2, panel B), underlying immunodeficiency (HR 4.36, 95% CI 1.72–11.07;

p<0.01), and associated digestive disease (HR 4.07, 95% CI 1.63–10.14; p<0.01) were significantly associated with death of all causes (Table 3). We also found that severe neurologic events (HR 2.90, 95% CI 1.04–8.06; p = 0.04), mechanical ventilation (HR 2.71, 95% CI 1.09–6.74; p = 0.03), and dialysis (HR 5.57, 95% CI 1.29–24.16; p = 0.02) were predictive of death. High troponin levels and stx types were not associated with survival (Table 3). Most patients who died had STEC strains belonging to non-O104 and non-O157

<table><caption>**Table 1.** Characteristics of adults with Shiga toxin-associated hemolytic uremic syndrome, France, 2009–2017*</caption><thead><tr><th>Characteristic</th><th>Value</th></tr></thead><tbody><tr><td>Median age, y (IQR)</td><td>60.5 (47.00–71.00)</td></tr><tr><td>Sex</td><td></td></tr><tr><td>M</td><td>35 (36.5)</td></tr><tr><td>F</td><td>61 (63.5)</td></tr><tr><td>Median age-weighted Charlson Comorbidity Index (IQR)</td><td>2.00 (1.00–4.25)</td></tr><tr><td>Tobacco use within previous 3 y</td><td>12 (12.5)</td></tr><tr><td>&gt;1 underlying condition</td><td>69 (71.9)</td></tr><tr><td>Cardiovascular disease</td><td>48 (50.0)</td></tr><tr><td>Arterial hypertension</td><td>38 (39.6)</td></tr><tr><td>Diabetes mellitus</td><td>12 (12.5)</td></tr><tr><td>Venous thromboembolic disease</td><td>11 (11.5)</td></tr><tr><td>Heart disease†</td><td>20 (20.8)</td></tr><tr><td>CKD‡</td><td>15 (15.6)</td></tr><tr><td>History of kidney transplant</td><td>5 (5.2)</td></tr><tr><td>Stage 2 CKD</td><td>4 (4.2)</td></tr><tr><td>Stage 3 CKD</td><td>8 (8.3)</td></tr><tr><td>Stage 4 CKD</td><td>3 (3.1)</td></tr><tr><td>Digestive disorder§</td><td>29 (30.2)</td></tr><tr><td>Gastrointestinal disorder</td><td>18 (18.8)</td></tr><tr><td>Biliopancreatic disorder</td><td>9 (9.4)</td></tr><tr><td>Hepatic disorder</td><td>4 (4.2)</td></tr><tr><td>Autoimmune or inflammatory disease¶</td><td>11 (11.5)</td></tr><tr><td>Immunodeficiency</td><td>27 (28.1)</td></tr><tr><td>History of bone marrow or solid organ transplant#</td><td>8 (8.3)</td></tr><tr><td>Hematologic disease**</td><td>8 (8.3)</td></tr><tr><td>Active cancer††</td><td>8 (8.3)</td></tr><tr><td>HIV‡‡</td><td>3 (3.1)</td></tr><tr><td>Primary immunodeficiency§§</td><td>2 (2.1)</td></tr><tr><td>Neuropsychiatric disorder¶¶</td><td>18 (18.8)</td></tr><tr><td>Treatment</td><td></td></tr><tr><td>Immunosuppressive treatment</td><td>12 (12.5)</td></tr><tr><td>Corticosteroids</td><td>11 (11.5)</td></tr><tr><td>Calcineurin inhibitors</td><td>7 (7.3)</td></tr><tr><td>Azathioprine or mycophenolate mofetil</td><td>7 (7.3)</td></tr></tbody></table>

*Values are no. (%) patients except as indicated. CKD, chronic kidney disease; IQR, interquartile range.

†‡ patients had hypertensive disease, 4 had ischemic disease, 4 had hypertensive and ischemic disease, 2 had valvular cardiopathy, 1 had pulmonary hypertension, and 1 had unspecified heart disease.

‡According to Kidney Disease Improving Global Outcomes guidelines (15).

§8 patients had gastric, small bowel, or colonic resection; 2 had history of bariatric surgery; 3 had chronic diarrhea from diverticulosis; 1 had graft-versus-host disease; 1 had colonic endometriosis; 1 had microscopic colitis; 1 had AA amyloidosis; 1 had neurovegetative disorder (1 each); 3 had recurrent pyogenic cholangitis; 1 had sclerosing cholangitis; 2 had a double kidney-pancreas transplantation; 3 had chronic pancreatitis; 2 had cirrhosis; 1 had history of liver transplant; and 1 had autoimmune hepatitis.

¶2 patients had mixed connective tissue disease, 1 had systemic sclerosis, 1 had sclerosing cholangitis, 1 had microscopic polyangiitis, 3 had type 1 diabetes, 1 had multiple sclerosis, and 2 had psoriasis.

#3 patients had a history of kidney, 2 of double kidney-pancreas, 2 of bone marrow, and 1 of liver transplant.

**1 patient had acute myeloid leukemia, 1 had chronic lymphocytic leukemia, 1 had Hodgkin's lymphoma, 1 had clonal B-cell lymphocytosis, 1 had monoclonal gammopathy of undetermined significance, 1 had Waldenström's disease, 1 had myeloproliferative disorder, and 1 had myelodysplastic syndrome.

††3 patients had breast cancer, 1 had metastatic lung cancer, 1 had a gastrointestinal stromal cell tumor, 1 had bladder cancer, 1 had cervical cancer, and 1 had gastric cancer.

‡‡3 patients had AIDS, including 2 patients who received HIV diagnoses during treatment.

§§2 patients had hypogammaglobulinemia, including 1 patient who had ICF1 syndrome caused by a DNMT3b germinal mutation.

¶¶5 patients had stroke sequelae, 3 had Parkinson's disease, 1 had multiple sclerosis, 4 had cognitive impairment (including 1 patient who had Korsakoff syndrome and 1 who had vascular dementia), 1 had epilepsy, 1 had chronic polyradiculoneuropathy, and 5 had major depressive or bipolar disorder.
In total, 26 (27.1%) patients were treated with macrolides, including 3 who received the treatment to prevent infectious meningoencephalitis associated with eculizumab. Fifty-seven (59.4%) patients received β-lactam antimicrobial drugs, aminoglycosides, or quinolones; 22 (22.9%) patients received metronidazole.

After unadjusted analysis, we found that age (HR 1.04, 95% CI 1.01–1.07; p = 0.01), CCI (HR 1.15, 95% CI 1.03–1.28; p = 0.02) (Figure 2, panel B), underlying immunodeficiency (HR 4.36, 95% CI 1.72–11.07;

p<0.01), and associated digestive disease (HR 4.07, 95% CI 1.63–10.14; p<0.01) were significantly associated with death of all causes (Table 3). We also found that severe neurologic events (HR 2.90, 95% CI 1.04–8.06; p = 0.04), mechanical ventilation (HR 2.71, 95% CI 1.09–6.74; p = 0.03), and dialysis (HR 5.57, 95% CI 1.29–24.16; p = 0.02) were predictive of death. High troponin levels and stx types were not associated with survival (Table 3). Most patients who died had STEC strains belonging to non-O104 and non-O157

<table><caption>**Table 1.** Characteristics of adults with Shiga toxin-associated hemolytic uremic syndrome, France, 2009–2017*</caption><thead><tr><th>Characteristic</th><th>Value</th></tr></thead><tbody><tr><td>Median age, y (IQR)</td><td>60.5 (47.00–71.00)</td></tr><tr><td>Sex</td><td></td></tr><tr><td>M</td><td>35 (36.5)</td></tr><tr><td>F</td><td>61 (63.5)</td></tr><tr><td>Median age-weighted Charlson Comorbidity Index (IQR)</td><td>2.00 (1.00–4.25)</td></tr><tr><td>Tobacco use within previous 3 y</td><td>12 (12.5)</td></tr><tr><td>&gt;1 underlying condition</td><td>69 (71.9)</td></tr><tr><td>Cardiovascular disease</td><td>48 (50.0)</td></tr><tr><td>Arterial hypertension</td><td>38 (39.6)</td></tr><tr><td>Diabetes mellitus</td><td>12 (12.5)</td></tr><tr><td>Venous thromboembolic disease</td><td>11 (11.5)</td></tr><tr><td>Heart disease†</td><td>20 (20.8)</td></tr><tr><td>CKD‡</td><td>15 (15.6)</td></tr><tr><td>History of kidney transplant</td><td>5 (5.2)</td></tr><tr><td>Stage 2 CKD</td><td>4 (4.2)</td></tr><tr><td>Stage 3 CKD</td><td>8 (8.3)</td></tr><tr><td>Stage 4 CKD</td><td>3 (3.1)</td></tr><tr><td>Digestive disorder§</td><td>29 (30.2)</td></tr><tr><td>Gastrointestinal disorder</td><td>18 (18.8)</td></tr><tr><td>Biliopancreatic disorder</td><td>9 (9.4)</td></tr><tr><td>Hepatic disorder</td><td>4 (4.2)</td></tr><tr><td>Autoimmune or inflammatory disease¶</td><td>11 (11.5)</td></tr><tr><td>Immunodeficiency</td><td>27 (28.1)</td></tr><tr><td>History of bone marrow or solid organ transplant#</td><td>8 (8.3)</td></tr><tr><td>Hematologic disease**</td><td>8 (8.3)</td></tr><tr><td>Active cancer††</td><td>8 (8.3)</td></tr><tr><td>HIV‡‡</td><td>3 (3.1)</td></tr><tr><td>Primary immunodeficiency§§</td><td>2 (2.1)</td></tr><tr><td>Neuropsychiatric disorder¶¶</td><td>18 (18.8)</td></tr><tr><td>Treatment</td><td></td></tr><tr><td>Immunosuppressive treatment</td><td>12 (12.5)</td></tr><tr><td>Corticosteroids</td><td>11 (11.5)</td></tr><tr><td>Calcineurin inhibitors</td><td>7 (7.3)</td></tr><tr><td>Azathioprine or mycophenolate mofetil</td><td>7 (7.3)</td></tr></tbody></table>

*Values are no. (%) patients except as indicated. CKD, chronic kidney disease; IQR, interquartile range.

†‡ patients had hypertensive disease, 4 had ischemic disease, 4 had hypertensive and ischemic disease, 2 had valvular cardiopathy, 1 had pulmonary hypertension, and 1 had unspecified heart disease.

‡According to Kidney Disease Improving Global Outcomes guidelines (15).

§8 patients had gastric, small bowel, or colonic resection; 2 had history of bariatric surgery; 3 had chronic diarrhea from diverticulosis; 1 had graft-versus-host disease; 1 had colonic endometriosis; 1 had microscopic colitis; 1 had AA amyloidosis; 1 had neurovegetative disorder (1 each); 3 had recurrent pyogenic cholangitis; 1 had sclerosing cholangitis; 2 had a double kidney-pancreas transplantation; 3 had chronic pancreatitis; 2 had cirrhosis; 1 had history of liver transplant; and 1 had autoimmune hepatitis.

¶2 patients had mixed connective tissue disease, 1 had systemic sclerosis, 1 had sclerosing cholangitis, 1 had microscopic polyangiitis, 3 had type 1 diabetes, 1 had multiple sclerosis, and 2 had psoriasis.

#3 patients had a history of kidney, 2 of double kidney-pancreas, 2 of bone marrow, and 1 of liver transplant.

**1 patient had acute myeloid leukemia, 1 had chronic lymphocytic leukemia, 1 had Hodgkin's lymphoma, 1 had clonal B-cell lymphocytosis, 1 had monoclonal gammopathy of undetermined significance, 1 had Waldenström's disease, 1 had myeloproliferative disorder, and 1 had myelodysplastic syndrome.

††3 patients had breast cancer, 1 had metastatic lung cancer, 1 had a gastrointestinal stromal cell tumor, 1 had bladder cancer, 1 had cervical cancer, and 1 had gastric cancer.

‡‡3 patients had AIDS, including 2 patients who received HIV diagnoses during treatment.

§§2 patients had hypogammaglobulinemia, including 1 patient who had ICF1 syndrome caused by a DNMT3b germinal mutation.

¶¶5 patients had stroke sequelae, 3 had Parkinson's disease, 1 had multiple sclerosis, 4 had cognitive impairment (including 1 patient who had Korsakoff syndrome and 1 who had vascular dementia), 1 had epilepsy, 1 had chronic polyradiculoneuropathy, and 5 had major depressive or bipolar disorder.
serogroups (Figure 2, panel C; Appendix Table 3). We found that overall survival was comparable among patients treated by different combinations of BSC,

TPE, and eculizumab (p = 0.43 by log-rank test) (Table 3; Figure 2, panel D). The use of macrolides was not associated with survival (p = 0.77).

<figure><img src="image_3.png" /></figure>

<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /></figure>

<figure><img src="image_6.png" /></figure>

**Figure 2.** Kaplan-Meier survival plots of adults with Shiga toxin-associated hemolytic uremic syndrome, France, 2009–2017. A) Overall. B) By age-weighted Charlson comorbidity index. C) By STEC serogroup. D) By treatment. Plots show time from admission to death. p values determined using log-rank test. BSC, best standard of care; CCI, age-weighted Charlson comorbidity index; ECZ, eculizumab; TPE, therapeutic plasma exchange.
serogroups (Figure 2, panel C; Appendix Table 3). We found that overall survival was comparable among patients treated by different combinations of BSC,

TPE, and eculizumab (p = 0.43 by log-rank test) (Table 3; Figure 2, panel D). The use of macrolides was not associated with survival (p = 0.77).

<figure><img src="image_3.png" /></figure>

<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /></figure>

<figure><img src="image_6.png" /></figure>

**Figure 2.** Kaplan-Meier survival plots of adults with Shiga toxin-associated hemolytic uremic syndrome, France, 2009–2017. A) Overall. B) By age-weighted Charlson comorbidity index. C) By STEC serogroup. D) By treatment. Plots show time from admission to death. p values determined using log-rank test. BSC, best standard of care; CCI, age-weighted Charlson comorbidity index; ECZ, eculizumab; TPE, therapeutic plasma exchange.
Multivariate analysis showed that underlying immunodeficiency (HR 3.54, 95% CI 1.24–10.14; p = 0.02) and severe neurologic events (HR 3.40, 95% CI 1.05–11.04; p = 0.04) were negatively associated with survival (Table 3). After adjustment of determinants retained for the multivariate analysis, we found that eculizumab was not associated with survival (HR 0.77, 95% 0.25–2.33; p = 0.64). Propensity score-matching also indicated that eculizumab was not associated with survival (p = 0.34) (Appendix Table 5, Figure 2).

Discussion

We found that 20% of adults who had STEC-associ-
ated HUS died during hospitalization, in agreement
with previous findings (9,10); however, <1% of chil-
dren who had STEC-associated HUS died in France
during the same years, 2007–2016 (5). In addition,
adults had cerebral involvement 3 times more fre-
quently than children (2); 52.1% of adult patients had
severe neurologic manifestations, similar to the obser-
vations of Karpac et al. (10). Renal recovery was slow
and inconsistent; 4 patients still required dialysis 90
days after hospitalization (9). One third of patients re-
quired mechanical ventilation. These findings empha-
size that, in adults, STEC-associated HUS is a severe
systemic disease that can cause multiple organ fail-
ure. However, inclusion in the CNR-MAT registry re-
lied on voluntary physician reporting; thus, this case
series is not exhaustive and might disproportionately
reflect the most severe cases. As previously observed
for children (18), most cases in this cohort were spo-
radic and, for unclear reasons, in women. In regard to
age distribution, STEC-associated HUS has a U curve
from birth to old age (6,9,10,19). During the study
period, 1,095 STEC-associated HUS cases in children
were reported to Santé Publique France through the
country's pediatric surveillance network (5). By com-
parison, this disease appears to be much rarer among
adults, although underreporting is probable.

Our findings on underlying conditions and deaths
by age group resemble those of the FoodNet registry
of elderly adults with STEC-associated HUS (9). The
risk for death from STEC-associated HUS increases for
persons age >40 years, suggesting that young and mid-
dle-aged adults have similar clinical courses to those
observed in children. We found a strong association
between underlying conditions and decreased sur-
vival, especially for patients with immunodeficiency
(9,20–23). The prevalence of antibodies against Stx de-
creases for persons >40 years of age (24), which might
account for the more severe forms of STEC-associated
HUS in elderly persons. The expression of glomerular
globotriaosylceramide (Gb3), the main receptor of Stx,

was thought to decrease with age; however, research-
ers now believe that expression levels remain stable
throughout a person's lifetime (25). Renal and neuro-
logic signs similar to those caused by HUS develop
in immunocompromised mice after STEC inoculation
or Stx exposure, whereas wild-type mice are natu-
rally resistant to this disease (26,27). Together, these
findings highlight the role of the immune system in
preventing STEC-associated HUS. Immunodeficiency
probably contributes to disease severity.

The 2011 outbreak in Europe illustrated that mi-
crobiological characteristics play a key role in STEC-
associated HUS (7). The distribution of serotypes
among adults in our study was slightly different than
in a study on pediatric HUS in France in the same
timeframe (5). Non-O157 strains were more prevalent
in the pediatric series (5) and in ours, whereas O157
and O26 were more commonly observed among chil-
dren than adults (23% among children vs. 15% among
adults for O157; 11% among children vs. 6% among
adults for O26) (5). A similar overall distribution was
observed among children and adults with STEC in-
fection in Norway (23% for O157, 10% for O26) (28).
By contrast, serogroups O91 and O104 have been
mainly found among adults (29,30). The data might
have been skewed by the 2011 outbreak caused by a
strain belonging to the O104 serogroup; this outbreak
caused infections in younger persons who had fewer
underlying conditions, which could account for the
better outcomes of those patients. Other serogroups,
especially O80, O26, and O91, are emerging and might
be associated with increased pathogenicity (2,18).
STEC O91 was also the most common serogroup
among adults with STEC infections in Germany (30),
which raises the question of increased pathogenicity
in adults and in persons >40 years of age.

In agreement with previous reports of STEC-as-
sociated HUS in adults (29,31), we found that stx1+/
stx2- strains were more prevalent among adults
(14.3%) than had been previously documented among
children (2.0%) (5). One possible explanation for this
distribution might be that in some patients, HUS was
concurrent with but unrelated to infection or coloni-
zation by stx1+/stx2- STEC; however, this scenario is
unlikely because STEC-positive patients had typical
features of HUS in an infectious context. We cannot
exclude the possibility that the stx2 gene could have
been lost in human hosts during infection or ex vivo
during subculture, as already described for STEC O26
(32). In this series, all stx1+/stx2- strains belonged to
non-O157 serogroups. These findings are similar to
those of Käppeli et al. (29), who found that 15.8% of
cases of non-O157 STEC-associated HUS were caused
Multivariate analysis showed that underlying immunodeficiency (HR 3.54, 95% CI 1.24–10.14; p = 0.02) and severe neurologic events (HR 3.40, 95% CI 1.05–11.04; p = 0.04) were negatively associated with survival (Table 3). After adjustment of determinants retained for the multivariate analysis, we found that eculizumab was not associated with survival (HR 0.77, 95% 0.25–2.33; p = 0.64). Propensity score-matching also indicated that eculizumab was not associated with survival (p = 0.34) (Appendix Table 5, Figure 2).

Discussion

We found that 20% of adults who had STEC-associ-
ated HUS died during hospitalization, in agreement
with previous findings (9,10); however, <1% of chil-
dren who had STEC-associated HUS died in France
during the same years, 2007–2016 (5). In addition,
adults had cerebral involvement 3 times more fre-
quently than children (2); 52.1% of adult patients had
severe neurologic manifestations, similar to the obser-
vations of Karpac et al. (10). Renal recovery was slow
and inconsistent; 4 patients still required dialysis 90
days after hospitalization (9). One third of patients re-
quired mechanical ventilation. These findings empha-
size that, in adults, STEC-associated HUS is a severe
systemic disease that can cause multiple organ fail-
ure. However, inclusion in the CNR-MAT registry re-
lied on voluntary physician reporting; thus, this case
series is not exhaustive and might disproportionately
reflect the most severe cases. As previously observed
for children (18), most cases in this cohort were spo-
radic and, for unclear reasons, in women. In regard to
age distribution, STEC-associated HUS has a U curve
from birth to old age (6,9,10,19). During the study
period, 1,095 STEC-associated HUS cases in children
were reported to Santé Publique France through the
country's pediatric surveillance network (5). By com-
parison, this disease appears to be much rarer among
adults, although underreporting is probable.

Our findings on underlying conditions and deaths
by age group resemble those of the FoodNet registry
of elderly adults with STEC-associated HUS (9). The
risk for death from STEC-associated HUS increases for
persons age >40 years, suggesting that young and mid-
dle-aged adults have similar clinical courses to those
observed in children. We found a strong association
between underlying conditions and decreased sur-
vival, especially for patients with immunodeficiency
(9,20–23). The prevalence of antibodies against Stx de-
creases for persons >40 years of age (24), which might
account for the more severe forms of STEC-associated
HUS in elderly persons. The expression of glomerular
globotriaosylceramide (Gb3), the main receptor of Stx,

was thought to decrease with age; however, research-
ers now believe that expression levels remain stable
throughout a person's lifetime (25). Renal and neuro-
logic signs similar to those caused by HUS develop
in immunocompromised mice after STEC inoculation
or Stx exposure, whereas wild-type mice are natu-
rally resistant to this disease (26,27). Together, these
findings highlight the role of the immune system in
preventing STEC-associated HUS. Immunodeficiency
probably contributes to disease severity.

The 2011 outbreak in Europe illustrated that mi-
crobiological characteristics play a key role in STEC-
associated HUS (7). The distribution of serotypes
among adults in our study was slightly different than
in a study on pediatric HUS in France in the same
timeframe (5). Non-O157 strains were more prevalent
in the pediatric series (5) and in ours, whereas O157
and O26 were more commonly observed among chil-
dren than adults (23% among children vs. 15% among
adults for O157; 11% among children vs. 6% among
adults for O26) (5). A similar overall distribution was
observed among children and adults with STEC in-
fection in Norway (23% for O157, 10% for O26) (28).
By contrast, serogroups O91 and O104 have been
mainly found among adults (29,30). The data might
have been skewed by the 2011 outbreak caused by a
strain belonging to the O104 serogroup; this outbreak
caused infections in younger persons who had fewer
underlying conditions, which could account for the
better outcomes of those patients. Other serogroups,
especially O80, O26, and O91, are emerging and might
be associated with increased pathogenicity (2,18).
STEC O91 was also the most common serogroup
among adults with STEC infections in Germany (30),
which raises the question of increased pathogenicity
in adults and in persons >40 years of age.

In agreement with previous reports of STEC-as-
sociated HUS in adults (29,31), we found that stx1+/
stx2- strains were more prevalent among adults
(14.3%) than had been previously documented among
children (2.0%) (5). One possible explanation for this
distribution might be that in some patients, HUS was
concurrent with but unrelated to infection or coloni-
zation by stx1+/stx2- STEC; however, this scenario is
unlikely because STEC-positive patients had typical
features of HUS in an infectious context. We cannot
exclude the possibility that the stx2 gene could have
been lost in human hosts during infection or ex vivo
during subculture, as already described for STEC O26
(32). In this series, all stx1+/stx2- strains belonged to
non-O157 serogroups. These findings are similar to
those of Käppeli et al. (29), who found that 15.8% of
cases of non-O157 STEC-associated HUS were caused
by stx1+/stx2- strains, which could suggest that different serogroups might pose different risks for HUS associated with particular stx genotypes. Last, most (83%) patients with stx1+/stx2- genotypes had underlying immunodeficiency; one explanation could be that immunodeficient patients are more susceptible to Stx1. The alleles stx1 and stx2c have been associated with a lower risk for severe STEC infection and HUS (28). However, stx1a is associated with higher risk for severe STEC infection (33). We did not have data on stx subtypes in our study.

We observed CAP abnormalities similar to those previously reported in a cohort of 113 cases of STEC-associated HUS in children (16). We found that 65.7% of patients had low CD46 and 38.8% had low CH50 levels. However, a decrease in the concentration of complement factors, the interpretation of which remains equivocal, might be attributable to kidney damage and STEC-associated HUS (16). The presence of an inflammatory syndrome further complicates the interpretation of these data. In contrast to atypical HUS, pediatric STEC-associated HUS has not been linked to a constitutional or acquired dysregulation of the CAP. Screening for variants in complement genes is not usually conducted among children with STEC-associated HUS. Similarly, it seems unlikely that STEC infection reveals underlying CAP abnormalities in many adults.

We found that 7% of patients had STEC-positive urine samples, an underrecognized finding documented by Lavrek et al. (34). Although urine samples might be easily contaminated, especially in patients who have diarrhea, these findings encourage systematic STEC-specific PCR screening and culture confirmation of stool or other biological samples (in the event of extraintestinal *E. coli* infection) from adult TMA patients (2,34).

Because the effectiveness of specific treatments remains unclear, BSC is the cornerstone of STEC-associated HUS treatment (2,35,36). Univariate analysis indicated that TPE was not associated with overall survival improvement, although other studies have concluded differently (37–39). However, considering the substantial overlap between the signs and symptoms of STEC-associated HUS in adults and TMA of other etiologies, some researchers believe that plasma therapy should be given until TTP or atypical HUS are ruled out (13,40). Whether TPE should be continued after the determination of stx status remains unclear. As previously reported, we did not find a clear survival benefit from eculizumab (38,41). However, the small sample size and the strong differences between patients who did and did not receive eculizumab treatment preclude definitive conclusions.

The benefits of antimicrobial drugs in treating STEC-associated HUS are unclear (42,43). Previous studies suggest that the use of antimicrobial drugs during early stages of STEC infection is associated with the development of HUS. However, the effects of antimicrobial drugs administered after HUS diagnosis remain unknown (42). A retrospective study reported that azithromycin administered during STEC infection might reduce the duration of STEC carriage (43). We found that use of macrolides was not associated with survival. This observation might have been confounded by possible unreported administration of antimicrobial drugs before hospitalization, treatment for unstandardized indications at the discretion of the practitioner, or other variables. We also found that the prescription of multiple antimicrobial drugs was a common practice, especially in cases of severe infection.

In conclusion, STEC-associated HUS is rarer among adults than among children but causes more severe disease and death. Underlying conditions, especially immunodeficiency, are strongly associated with decreased survival. The severity of the disease, a probably underestimated prevalence, and the risk for outbreaks of emerging STEC-associated HUS provide strong arguments for active epidemiologic and microbiological surveillance of this disease.

Members of the Reference Center for Thrombotic Microangiopathies team: Jean-François Augusto, Elie Azoulay, Virginie Barbay, Ygal Benhamou, Dominique Bordessoule, Christophe Charasse, Anne Charvet-Rumpler, Dominique Chauveau, Gabriel Choukroun, Jean-Philippe Coindre, Paul Coppo, Elise Corre, Yahsou Delmas, Georges Deschenes, Alain Devidas, Antoine Dossier, Olivier Fain, Fadi Fakhouri, Véronique Frémeaux-Bacchi, Lionel Galicier, Steven Grangé, Bertrand Guidet, Jean-Michel Halimi, Mohamed Hamidou, Raoul Herbrecht, Miguel Hié, Frédéric Jacobs, Bérangère Joly, Tarik Kanouni, Gilles Kaplanski, Alexandre Lautrette, Véronique Le Guern, Bruno Moulin, Christiane Mousson, Mario Ojeda Uribe, Abdelkader Ouchenir, Nathalie Parquet, Frédéric Pène, Pierre Perez, Pascale Poullin, Claire Pouteil-Noble, Claire Presne, François Provôt, Eric Rondeau, Samir Saheb, Amélie Seguin, Aude Servais, Alain Stépanian, Agnès Veyradier, Cécile Vigneau, Alain Wynckel, and Patricia Zunic.

## Acknowledgments

We thank Eric Alamartine, Sandrine Bedon Carte, Gilles Bernardin, Severin Cabasson, Vincent Cadiergue, Jean-François Cerfon, Thomas Crepin, Vincent Das, Philippe De Swardt, Geneviève Dumont, Alexandre Hertig, Jean Claude Lacherade, Olivier Leroy, Julie Le Scanff, Didier Perez, Emilie Pinçon, Jean-Pierre Quenot, Felipe Suarez, Rachel Tetaz,
by stx1+/stx2- strains, which could suggest that different serogroups might pose different risks for HUS associated with particular stx genotypes. Last, most (83%) patients with stx1+/stx2- genotypes had underlying immunodeficiency; one explanation could be that immunodeficient patients are more susceptible to Stx1. The alleles stx1 and stx2c have been associated with a lower risk for severe STEC infection and HUS (28). However, stx1a is associated with higher risk for severe STEC infection (33). We did not have data on stx subtypes in our study.

We observed CAP abnormalities similar to those previously reported in a cohort of 113 cases of STEC-associated HUS in children (16). We found that 65.7% of patients had low CD46 and 38.8% had low CH50 levels. However, a decrease in the concentration of complement factors, the interpretation of which remains equivocal, might be attributable to kidney damage and STEC-associated HUS (16). The presence of an inflammatory syndrome further complicates the interpretation of these data. In contrast to atypical HUS, pediatric STEC-associated HUS has not been linked to a constitutional or acquired dysregulation of the CAP. Screening for variants in complement genes is not usually conducted among children with STEC-associated HUS. Similarly, it seems unlikely that STEC infection reveals underlying CAP abnormalities in many adults.

We found that 7% of patients had STEC-positive urine samples, an underrecognized finding documented by Lavrek et al. (34). Although urine samples might be easily contaminated, especially in patients who have diarrhea, these findings encourage systematic STEC-specific PCR screening and culture confirmation of stool or other biological samples (in the event of extraintestinal *E. coli* infection) from adult TMA patients (2,34).

Because the effectiveness of specific treatments remains unclear, BSC is the cornerstone of STEC-associated HUS treatment (2,35,36). Univariate analysis indicated that TPE was not associated with overall survival improvement, although other studies have concluded differently (37–39). However, considering the substantial overlap between the signs and symptoms of STEC-associated HUS in adults and TMA of other etiologies, some researchers believe that plasma therapy should be given until TTP or atypical HUS are ruled out (13,40). Whether TPE should be continued after the determination of stx status remains unclear. As previously reported, we did not find a clear survival benefit from eculizumab (38,41). However, the small sample size and the strong differences between patients who did and did not receive eculizumab treatment preclude definitive conclusions.

The benefits of antimicrobial drugs in treating STEC-associated HUS are unclear (42,43). Previous studies suggest that the use of antimicrobial drugs during early stages of STEC infection is associated with the development of HUS. However, the effects of antimicrobial drugs administered after HUS diagnosis remain unknown (42). A retrospective study reported that azithromycin administered during STEC infection might reduce the duration of STEC carriage (43). We found that use of macrolides was not associated with survival. This observation might have been confounded by possible unreported administration of antimicrobial drugs before hospitalization, treatment for unstandardized indications at the discretion of the practitioner, or other variables. We also found that the prescription of multiple antimicrobial drugs was a common practice, especially in cases of severe infection.

In conclusion, STEC-associated HUS is rarer among adults than among children but causes more severe disease and death. Underlying conditions, especially immunodeficiency, are strongly associated with decreased survival. The severity of the disease, a probably underestimated prevalence, and the risk for outbreaks of emerging STEC-associated HUS provide strong arguments for active epidemiologic and microbiological surveillance of this disease.

Members of the Reference Center for Thrombotic Microangiopathies team: Jean-François Augusto, Elie Azoulay, Virginie Barbay, Ygal Benhamou, Dominique Bordessoule, Christophe Charasse, Anne Charvet-Rumpler, Dominique Chauveau, Gabriel Choukroun, Jean-Philippe Coindre, Paul Coppo, Elise Corre, Yahsou Delmas, Georges Deschenes, Alain Devidas, Antoine Dossier, Olivier Fain, Fadi Fakhouri, Véronique Frémeaux-Bacchi, Lionel Galicier, Steven Grangé, Bertrand Guidet, Jean-Michel Halimi, Mohamed Hamidou, Raoul Herbrecht, Miguel Hié, Frédéric Jacobs, Bérangère Joly, Tarik Kanouni, Gilles Kaplanski, Alexandre Lautrette, Véronique Le Guern, Bruno Moulin, Christiane Mousson, Mario Ojeda Uribe, Abdelkader Ouchenir, Nathalie Parquet, Frédéric Pène, Pierre Perez, Pascale Poullin, Claire Pouteil-Noble, Claire Presne, François Provôt, Eric Rondeau, Samir Saheb, Amélie Seguin, Aude Servais, Alain Stépanian, Agnès Veyradier, Cécile Vigneau, Alain Wynckel, and Patricia Zunic.

### Acknowledgments

We thank Eric Alamartine, Sandrine Bedon Carte, Gilles Bernardin, Severin Cabasson, Vincent Cadiergue, Jean-François Cerfon, Thomas Crepin, Vincent Das, Philippe De Swardt, Geneviève Dumont, Alexandre Hertig, Jean Claude Lacherade, Olivier Leroy, Julie Le Scanff, Didier Perez, Emilie Pinçon, Jean-Pierre Quenot, Felipe Suarez, Rachel Tetaz,
Olivier Thaunat, Jean Marc Thouret, and Xavier Valette for their valuable collaboration with the CNR-MAT. These physicians played an active role in care of patients with STEC-associated HUS.

This work was partly funded by grants from the French Ministry of Health (Programme Hospitalier de Recherche Clinique [grant nos. P120118 and AOM12259]). B.T. has received a research grant from CSL Behring (https://www.cslbehring.com). E.R. and C.P. are members of the Advisory Board for Alexion Pharmaceuticals, Inc. (https://alexion.com). Y.D. has received lecture fees from Alexion Pharmaceuticals, Inc. and honorarium as advisory board member for Sanofi (https://www.sanofi.com). F.F. has received consultancy fees and speaker honoraria from F. Hoffmann-La Roche Ltd (https://www.roche.com); Alexion Pharmaceuticals, Inc.; Apellis Pharmaceuticals (https://apellis.com); Achillion Pharmaceuticals; Novartis AG (https://www.novartis.com); and Alnylam Pharmaceuticals, Inc. (https://www.alnylam.com). P.C. is member of the advisory boards of Alexion Pharmaceuticals, Inc.; Sanofi; Shire P.C.C. (http://shirepc.com); Takeda Pharmaceutical Company Limited (https://www.takeda.com); and Octapharma AG (https://www.octapharma.com); he has received consultancy fees and speaker honoraria from Sanofi; Alexion Pharmaceuticals, Inc.; and Takeda Pharmaceutical Company Limited.

## About the Author

Dr. Travert is a medical intern at Assistance Publique-Hôpitaux de Paris in Paris, France. His research interests include the epidemiology of STEC-associated HUS and environmental factors contributing to autoimmune diseases.

## References

1. Karmali MA, Steele BT, Petric M, Lim C. Sporadic cases of haemolytic-uraemic syndrome associated with faecal cytotoxin and cytotoxin-producing *Escherichia coli* in stools. Lancet. 1983;321:619-20. https://doi.org/10.1016/S0140-6736(83)91795-6

2. Joseph A, Cointe A, Mariani Kurkdjian P, Rafat C, Hertig A. Shiga toxin-associated haemolytic uremic syndrome: a narrative review. Toxins (Basel). 2020;12:67. https://doi.org/10.3390/toxins12020067

3. Fakhouri F, Zuber J, Frémeaux-Bacchi V, Loirat C. Haemolytic uraemic syndrome. Lancet. 2017;390:681-96. https://doi.org/10.1016/S0140-6736(17)30062-4

4. Majowicz SE, Scallan E, Jones-Bitton A, Sargeant JM, Stapleton J, Angulo FJ, et al. Global incidence of human Shiga toxin-producing *Escherichia coli* infections and deaths: a systematic review and knowledge synthesis. Foodborne Pathog Dis. 2014;11:447-55. https://doi.org/10.1089/fpd.2013.1704

5. Bruyand M, Mariani-Kurkdjian P, Le Hello S, King L-A, Van Cauteren D, Lefevre S, et al.; Réseau Français Hospitalier de Surveillance du Shu Pédiatrique. Paediatric haemolytic uraemic syndrome related to Shiga toxin-producing *Escherichia coli*, an overview of 10 years of

surveillance in France, 2007 to 2016. Euro Surveill. 2019;24:24. https://doi.org/10.2807/1560-7917.ES.2019.24.8.1800068

6. Gould LH, Demma L, Jones TF, Hurd S, Vugia DJ, Smith K, et al. Haemolytic uremic syndrome and death in persons with *Escherichia coli* O157:H7 infection, foodborne diseases active surveillance network sites, 2000–2006. Clin Infect Dis. 2009;49:1480–5. https://doi.org/10.1086/644621

7. Frank C, Werber D, Cramer JP, Askar M, Faber M, an der Heiden M, et al.; HUS Investigation Team. Epidemic profile of Shiga-toxin-producing *Escherichia coli* O104:H4 outbreak in Germany. N Engl J Med. 2011;365:1771–80. https://doi.org/10.1056/NEJMoa1106483

8. Delmas Y, Vendrely B, Clouzeau B, Bachir H, Bui H-N, Lacraz A, et al. Outbreak of *Escherichia coli* O104:H4 haemolytic uraemic syndrome in France: outcome with eculizumab. Nephrol Dial Transplant. 2014;29:565–72. https://doi.org/10.1093/ndt/gft470

9. Gould LH, Jordan JG, Dunn J, Apostol M, Griffin PM; Emerging Infections Program FoodNet Working Group. Postdiarrheal haemolytic uremic syndrome in persons aged 65 and older in FoodNet sites, 2000–2006. J Am Geriatr Soc. 2011;59:366–8. https://doi.org/10.1111/j.1532-5415.2011.03269.x

10. Karpac CA, Li X, Terrell DR, Kremer Hovinga JA, Lämmler B, Vesely SK, et al. Sporadic bloody diarrhoea-associated thrombotic thrombocytopenic purpura-haemolytic uraemic syndrome: an adult and paediatric comparison. Br J Haematol. 2008;141:696–707. https://doi.org/10.1111/j.1365-2141.2008.07116.x

11. Soysal N, Mariani-Kurkdjian P, Smail Y, Liguori S, Gouali M, Loukiadis E, et al. Enterohemorrhagic *Escherichia coli* hybrid pathotype O80:H2 as a new therapeutic challenge. Emerg Infect Dis. 2016;22:1604–12. https://doi.org/10.3201/eid2209.160304

12. Coimbra RS, Grimont F, Lenormand P, Burguière P, Beutin L, Grimont PA. Identification of *Escherichia coli* O-serogroups by restriction of the amplified O-antigen gene cluster (rfb-RFLP). Res Microbiol. 2000;151:639–54. https://doi.org/10.1016/S0923-2508(00)00134-0

13. Coppo P, Schwarzinger M, Buffet M, Wynckel A, Clabault K, Presne C, et al.; French Reference Center for Thrombotic Microangiopathies. Predictive features of severe acquired ADAMTS13 deficiency in idiopathic thrombotic microangiopathies: the French TMA reference center experience. PLoS One. 2010;5:e10208. https://doi.org/10.1371/journal.pone.0010208

14. Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol. 1994;47:1245–51. https://doi.org/10.1016/0895-4356(94)90129-5

15. International Society of Nephrology. KDIGO clinical practice guideline for acute kidney injury. 2012 [cited 2020 Jul 31]. https://kdigo.org/wp-content/uploads/2016/10/KDIGO-2012-AKI-Guideline-English.pdf

16. Frémeaux-Bacchi V, Sellier-Leclerc A-L, Vieira-Martins P, Limou S, Kwon T, Lahoche A, et al. Complement gene variants and Shiga toxin-producing *Escherichia coli*-associated haemolytic uremic syndrome. Clin J Am Soc Nephrol. 2019;14:364–77. https://doi.org/10.2215/CJN.05830518

17. Ho D, Imai K, King G, Stuart EA. MatchIt: nonparametric preprocessing for parametric causal inference. J Stat Softw. 2011;42:1–28. https://doi.org/10.18637/jss.v042.i08

18. Griffin PM, Karmali MA. Emerging public health challenges of Shiga toxin-producing *Escherichia coli* related to changes in the pathogen, the population, and the environment. Clin Infect Dis. 2017;64:371–6. https://doi.org/10.1093/cid/ciw708
Olivier Thaunat, Jean Marc Thouret, and Xavier Valette for their valuable collaboration with the CNR-MAT. These physicians played an active role in care of patients with STEC-associated HUS.

This work was partly funded by grants from the French Ministry of Health (Programme Hospitalier de Recherche Clinique [grant nos. P120118 and AOM12259]). B.T. has received a research grant from CSL Behring (https://www.cslbehring.com). E.R. and C.P. are members of the Advisory Board for Alexion Pharmaceuticals, Inc. (https://alexion.com). Y.D. has received lecture fees from Alexion Pharmaceuticals, Inc. and honorarium as advisory board member for Sanofi (https://www.sanofi.com). F.F. has received consultancy fees and speaker honoraria from F. Hoffmann-La Roche Ltd (https://www.roche.com); Alexion Pharmaceuticals, Inc.; Apellis Pharmaceuticals (https://apellis.com); Achillion Pharmaceuticals; Novartis AG (https://www.novartis.com); and Alnylam Pharmaceuticals, Inc. (https://www.alnylam.com). P.C. is member of the advisory boards of Alexion Pharmaceuticals, Inc.; Sanofi; Shire P.C.C. (http://shirepc.com); Takeda Pharmaceutical Company Limited (https://www.takeda.com); and Octapharma AG (https://www.octapharma.com); he has received consultancy fees and speaker honoraria from Sanofi; Alexion Pharmaceuticals, Inc.; and Takeda Pharmaceutical Company Limited.

## About the Author

Dr. Travert is a medical intern at Assistance Publique-Hôpitaux de Paris in Paris, France. His research interests include the epidemiology of STEC-associated HUS and environmental factors contributing to autoimmune diseases.

## References

1. Karmali MA, Steele BT, Petric M, Lim C. Sporadic cases of haemolytic-uraemic syndrome associated with faecal cytotoxin and cytotoxin-producing *Escherichia coli* in stools. Lancet. 1983;321:619-20. https://doi.org/10.1016/S0140-6736(83)91795-6

2. Joseph A, Cointe A, Mariani Kurkdjian P, Rafat C, Hertig A. Shiga toxin-associated haemolytic uremic syndrome: a narrative review. Toxins (Basel). 2020;12:67. https://doi.org/10.3390/toxins12020067

3. Fakhouri F, Zuber J, Frémeaux-Bacchi V, Loirat C. Haemolytic uraemic syndrome. Lancet. 2017;390:681-96. https://doi.org/10.1016/S0140-6736(17)30062-4

4. Majowicz SE, Scallan E, Jones-Bitton A, Sargeant JM, Stapleton J, Angulo FJ, et al. Global incidence of human Shiga toxin-producing *Escherichia coli* infections and deaths: a systematic review and knowledge synthesis. Foodborne Pathog Dis. 2014;11:447-55. https://doi.org/10.1089/fpd.2013.1704

5. Bruyand M, Mariani-Kurkdjian P, Le Hello S, King L-A, Van Cauteren D, Lefevre S, et al.; Réseau Français Hospitalier de Surveillance du Shu Pédiatrique. Paediatric haemolytic uraemic syndrome related to Shiga toxin-producing *Escherichia coli*, an overview of 10 years of

surveillance in France, 2007 to 2016. Euro Surveill. 2019;24:24. https://doi.org/10.2807/1560-7917.ES.2019.24.8.1800068

6. Gould LH, Demma L, Jones TF, Hurd S, Vugia DJ, Smith K, et al. Haemolytic uremic syndrome and death in persons with *Escherichia coli* O157:H7 infection, foodborne diseases active surveillance network sites, 2000–2006. Clin Infect Dis. 2009;49:1480–5. https://doi.org/10.1086/644621

7. Frank C, Werber D, Cramer JP, Askar M, Faber M, an der Heiden M, et al.; HUS Investigation Team. Epidemic profile of Shiga-toxin-producing *Escherichia coli* O104:H4 outbreak in Germany. N Engl J Med. 2011;365:1771–80. https://doi.org/10.1056/NEJMoa1106483

8. Delmas Y, Vendrely B, Clouzeau B, Bachir H, Bui H-N, Lacraz A, et al. Outbreak of *Escherichia coli* O104:H4 haemolytic uraemic syndrome in France: outcome with eculizumab. Nephrol Dial Transplant. 2014;29:565–72. https://doi.org/10.1093/ndt/gft470

9. Gould LH, Jordan JG, Dunn J, Apostol M, Griffin PM; Emerging Infections Program FoodNet Working Group. Postdiarrheal haemolytic uremic syndrome in persons aged 65 and older in FoodNet sites, 2000–2006. J Am Geriatr Soc. 2011;59:366–8. https://doi.org/10.1111/j.1532-5415.2011.03269.x

10. Karpac CA, Li X, Terrell DR, Kremer Hovinga JA, Lämmler B, Vesely SK, et al. Sporadic bloody diarrhoea-associated thrombotic thrombocytopenic purpura-haemolytic uraemic syndrome: an adult and paediatric comparison. Br J Haematol. 2008;141:696–707. https://doi.org/10.1111/j.1365-2141.2008.07116.x

11. Soysal N, Mariani-Kurkdjian P, Smail Y, Liguori S, Gouali M, Loukiadis E, et al. Enterohemorrhagic *Escherichia coli* hybrid pathotype O80:H2 as a new therapeutic challenge. Emerg Infect Dis. 2016;22:1604–12. https://doi.org/10.3201/eid2209.160304

12. Coimbra RS, Grimont F, Lenormand P, Burguière P, Beutin L, Grimont PA. Identification of *Escherichia coli* O-serogroups by restriction of the amplified O-antigen gene cluster (rfb-RFLP). Res Microbiol. 2000;151:639–54. https://doi.org/10.1016/S0923-2508(00)00134-0

13. Coppo P, Schwarzinger M, Buffet M, Wynckel A, Clabault K, Presne C, et al.; French Reference Center for Thrombotic Microangiopathies. Predictive features of severe acquired ADAMTS13 deficiency in idiopathic thrombotic microangiopathies: the French TMA reference center experience. PLoS One. 2010;5:e10208. https://doi.org/10.1371/journal.pone.0010208

14. Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol. 1994;47:1245–51. https://doi.org/10.1016/0895-4356(94)90129-5

15. International Society of Nephrology. KDIGO clinical practice guideline for acute kidney injury. 2012 [cited 2020 Jul 31]. https://kdigo.org/wp-content/uploads/2016/10/KDIGO-2012-AKI-Guideline-English.pdf

16. Frémeaux-Bacchi V, Sellier-Leclerc A-L, Vieira-Martins P, Limou S, Kwon T, Lahoche A, et al. Complement gene variants and Shiga toxin-producing *Escherichia coli*-associated haemolytic uremic syndrome. Clin J Am Soc Nephrol. 2019;14:364–77. https://doi.org/10.2215/CJN.05830518

17. Ho D, Imai K, King G, Stuart EA. MatchIt: nonparametric preprocessing for parametric causal inference. J Stat Softw. 2011;42:1–28. https://doi.org/10.18637/jss.v042.i08

18. Griffin PM, Karmali MA. Emerging public health challenges of Shiga toxin-producing *Escherichia coli* related to changes in the pathogen, the population, and the environment. Clin Infect Dis. 2017;64:371–6. https://doi.org/10.1093/cid/ciw708
19. Carter AO, Borczyk AA, Carlson JAK, Harvey B, Hockin JC, Karmali MA, et al. A severe outbreak of *Escherichia coli* O157:H7-associated hemorrhagic colitis in a nursing home. N Engl J Med. 1987;317:1496-500. https://doi.org/10.1056/NEJM198712103172403

20. Ville S, Ydee A, Garandeau C, Canet E, Tissot A, Cantarovich D, et al. Shiga toxin-producing *Escherichia coli*-associated hemolytic uremic syndrome in solid organ transplant recipients. Kidney Int. 2019;96:1423-4. https://doi.org/10.1016/j.kint.2019.08.024

21. Farina C, Gavazzeni G, Caprioli A, Remuzzi G. Hemolytic uremic syndrome associated with verocytotoxin-producing *Escherichia coli* infection in acquired immunodeficiency syndrome. Blood. 1990;75:2465. https://doi.org/10.1182/blood.V75.12.2465a.2465a

22. Vera-Aguilera J, Duma N, Gast K, Alkhateeb H, Tande A, Leung N, et al. Hemolytic uremic syndrome associated with *Escherichia coli* O157 infection in an allogenic stem cell transplant recipient. Mayo Clin Proc Innov Qual Outcomes. 2018;2:387-91. https://doi.org/10.1016/j.mayocpiqo.2018.07.001

23. Manière L, Domenger C, Camara B, Giovannini D, Malvezzi P, Rostaing L. An atypical case of Shiga toxin producing-*Escherichia coli* hemolytic and uremic syndrome (STEC-HUS) in a lung transplant recipient. Case Rep Transplant. 2019;2019:9465040. https://doi.org/10.1155/2019/9465040

24. Karmali MA, Mascarenhas M, Petric M, Dutil L, Rahn K, Ludwig K, et al. Age-specific frequencies of antibodies to *Escherichia coli* verocytotoxins (Shiga toxins) 1 and 2 among urban and rural populations in southern Ontario. J Infect Dis. 2003;188:1724-9. https://doi.org/10.1086/379726

25. Ergonoul Z, Clayton F, Fogo AB, Kohan DE. Shigatoxin-1 binding and receptor expression in human kidneys do not change with age. Pediatr Nephrol. 2003;18:246-53. https://doi.org/10.1007/s00467-002-1025-9

26. Brando RJF, Miliwebsky E, Bentancor L, Deza N, Baschkier A, Ramos MV, et al. Renal damage and death in weaned mice after oral infection with Shiga toxin 2-producing *Escherichia coli* strains. Clin Exp Immunol. 2008;153:297-306. https://doi.org/10.1111/j.1365-2249.2008.03698.x

27. Karpman D, Connell H, Svensson M, Scheutz F, Aim P, Svamborg C. The role of lipopolysaccharide and Shiga-like toxin in a mouse model of *Escherichia coli* O157:H7 infection. J Infect Dis. 1997;175:611-20. https://doi.org/10.1093/infdis/175.3.611

28. Brandal LT, Wester AL, Lange H, Løbersli I, Lindstedt B-A, Vold L, et al. Shiga toxin-producing *Escherichia coli* infections in Norway, 1992-2012: characterization of isolates and identification of risk factors for haemolytic uremic syndrome. BMC Infect Dis. 2015;15:324. https://doi.org/10.1186/s12879-015-1017-6

29. Käppeli U, Hächler H, Giezendanner N, Beutin L, Stephan R. Human infections with non-O157 Shiga toxin-producing *Escherichia coli*, Switzerland, 2000-2009. Emerg Infect Dis. 2011;17:180-5. https://doi.org/10.3201/eid1702.100909

30. Werber D, Beutin L, Pichner R, Stark K, Fruth A. Shiga toxin-producing *Escherichia coli* serogroups in food and patients, Germany. Emerg Infect Dis. 2008;14:1803-6. https://doi.org/10.3201/eid1411.080361

31. Adams NL, Byrne L, Smith GA, Elson R, Harris JP, Salmon R, et al. Shiga toxin-producing *Escherichia coli* O157, England and Wales, 1983-2012. Emerg Infect Dis. 2016;22:590-7. https://doi.org/10.3201/eid2204.151485

32. Bielaszewska M, Prager R, Köck R, Mellmann A, Zhang W, Tschäpe H, et al. Shiga toxin gene loss and transfer in vitro and in vivo during enterohemorrhagic *Escherichia coli* O26

infection in humans. Appl Environ Microbiol. 2007;73:3144-50. https://doi.org/10.1128/AEM.02937-06

33. Byrne L, Adams N, Jenkins C. Association between Shiga toxin-producing *Escherichia coli* O157:H7 stx gene subtype and disease severity, England, 2009-2019. Emerg Infect Dis. 2020;26:2394-400. https://doi.org/10.3201/eid2610.200319

34. Lavrek D, Lava SAG, Milani GP, Simonetti GD, Bianchetti MG, Giannini O. Hemolytic-uremic syndrome after *Escherichia coli* urinary tract infection in humans: systematic review of the literature. J Nephrol. 2018;31:919-24. https://doi.org/10.1007/s40620-018-0543-x

35. Michael M, Elliott EJ, Ridley GF, Hodson EM, Craig JC. Interventions for haemolytic uremic syndrome and thrombotic thrombocytopenic purpura. Cochrane Database Syst Rev. 2009;1:CD003595. https://doi.org/10.1002/14651858. CD003595.pub2

36. Grisaru S, Xie J, Samuel S, Hartling L, Tarr PI, Schnadower D, et al.; Alberta Provincial Pediatric Enteric Infection Team. Associations between hydration status, intravenous fluid administration, and outcomes of patients infected with Shiga toxin-producing *Escherichia coli*: a systematic review and meta-analysis. JAMA Pediatr. 2017;171:68-76. https://doi.org/10.1001/jamapediatrics.2016.2952

37. Keenswijk W, Raes A, De Clerck M, Vande Walle J. Is plasma exchange efficacious in Shiga toxin-associated hemolytic uremic syndrome? A narrative review of current evidence. Ther Apher Dial. 2019;23:118-25. https://doi.org/10.1111/1744-9987.12768

38. Kielstein JT, Beutel G, Fleig S, Steinhoff J, Meyer TN, Hafer C, et al.; Collaborators of the DGfN STEC-HUS registry. Best supportive care and therapeutic plasma exchange with or without eculizumab in Shiga-toxin-producing *E. coli* O104:H4 induced haemolytic-uraemic syndrome: an analysis of the German STEC-HUS registry. Nephrol Dial Transplant. 2012;27:3807-15. https://doi.org/10.1093/ndt/gfs394

39. Padmanabhan A, Connelly-Smith L, Aqui N, Balogun RA, Klingel R, Meyer E, et al. Guidelines on the use of therapeutic apheresis in clinical practice—evidence-based approach from the Writing Committee of the American Society for Apheresis: the eighth special issue. J Clin Apher. 2019;34:171-354. https://doi.org/10.1002/jca.21705

40. Joseph A, Rafat C, Zafrani L, Mariani-Kurkdjian P, Veyradier A, Hertig A, et al. Early differentiation of Shiga toxin-associated hemolytic uremic syndrome in critically ill adults with thrombotic microangiopathy syndromes. Crit Care Med. 2018;46:e904-11. https://doi.org/10.1097/CCM.0000000000003292

41. Lapeyraque A-L, Malina M, Fremeaux-Bacchi V, Boppel T, Kirschfink M, Oualha M, et al. Eculizumab in severe Shiga-toxin-associated HUS. N Engl J Med. 2011;364:2561-3. https://doi.org/10.1056/NEJMjc1100859

42. Wong CS, Mooney JC, Brandt JR, Staples AO, Jelacic S, Boster DR, et al. Risk factors for the hemolytic uremic syndrome in children infected with *Escherichia coli* O157:H7: a multivariable analysis. Clin Infect Dis. 2012;55:33-41. https://doi.org/10.1093/cid/cis299

43. Nitschke M, Sayk F, Härtel C, Roseland RT, Hauswaldt S, Steinhoff J, et al. Association between azithromycin therapy and duration of bacterial shedding among patients with Shiga toxin-producing enteroaggregative Escherichia coli O104:H4. JAMA. 2012;307:1046-52. https://doi.org/10.1001/jama.2012.264

Address for correspondence: Paul Coppo, AP-HP.6 and Sorbonne Université, 184 rue du Faubourg Saint-Antoine, Assistance Publique-Hôpitaux de Paris, 75012 Paris, France; email: paul.coppo@aphp.fr
19. Carter AO, Borczyk AA, Carlson JAK, Harvey B, Hockin JC, Karmali MA, et al. A severe outbreak of *Escherichia coli* O157:H7-associated hemorrhagic colitis in a nursing home. N Engl J Med. 1987;317:1496-500. https://doi.org/10.1056/NEJM198712103172403

20. Ville S, Ydee A, Garandeau C, Canet E, Tissot A, Cantarovich D, et al. Shiga toxin-producing *Escherichia coli*-associated hemolytic uremic syndrome in solid organ transplant recipients. Kidney Int. 2019;96:1423-4. https://doi.org/10.1016/j.kint.2019.08.024

21. Farina C, Gavazzeni G, Caprioli A, Remuzzi G. Hemolytic uremic syndrome associated with verocytotoxin-producing *Escherichia coli* infection in acquired immunodeficiency syndrome. Blood. 1990;75:2465. https://doi.org/10.1182/blood.V75.12.2465a.2465a

22. Vera-Aguilera J, Duma N, Gast K, Alkhateeb H, Tande A, Leung N, et al. Hemolytic uremic syndrome associated with *Escherichia coli* O157 infection in an allogenic stem cell transplant recipient. Mayo Clin Proc Innov Qual Outcomes. 2018;2:387-91. https://doi.org/10.1016/j.mayocpiqo.2018.07.001

23. Manière L, Domenger C, Camara B, Giovannini D, Malvezzi P, Rostaing L. An atypical case of Shiga toxin producing-*Escherichia coli* hemolytic and uremic syndrome (STEC-HUS) in a lung transplant recipient. Case Rep Transplant. 2019;2019:9465040. https://doi.org/10.1155/2019/9465040

24. Karmali MA, Mascarenhas M, Petric M, Dutil L, Rahn K, Ludwig K, et al. Age-specific frequencies of antibodies to *Escherichia coli* verocytotoxins (Shiga toxins) 1 and 2 among urban and rural populations in southern Ontario. J Infect Dis. 2003;188:1724-9. https://doi.org/10.1086/379726

25. Ergonoul Z, Clayton F, Fogo AB, Kohan DE. Shigatoxin-1 binding and receptor expression in human kidneys do not change with age. Pediatr Nephrol. 2003;18:246-53. https://doi.org/10.1007/s00467-002-1025-9

26. Brando RJF, Miliwebsky E, Bentancor L, Deza N, Baschkier A, Ramos MV, et al. Renal damage and death in weaned mice after oral infection with Shiga toxin 2-producing *Escherichia coli* strains. Clin Exp Immunol. 2008;153:297-306. https://doi.org/10.1111/j.1365-2249.2008.03698.x

27. Karpman D, Connell H, Svensson M, Scheutz F, Aim P, Svamborg C. The role of lipopolysaccharide and Shiga-like toxin in a mouse model of *Escherichia coli* O157:H7 infection. J Infect Dis. 1997;175:611-20. https://doi.org/10.1093/infdis/175.3.611

28. Brandal LT, Wester AL, Lange H, Løbersli I, Lindstedt B-A, Vold L, et al. Shiga toxin-producing *Escherichia coli* infections in Norway, 1992-2012: characterization of isolates and identification of risk factors for haemolytic uremic syndrome. BMC Infect Dis. 2015;15:324. https://doi.org/10.1186/s12879-015-1017-6

29. Käppeli U, Hächler H, Giezendanner N, Beutin L, Stephan R. Human infections with non-O157 Shiga toxin-producing *Escherichia coli*, Switzerland, 2000-2009. Emerg Infect Dis. 2011;17:180-5. https://doi.org/10.3201/eid1702.100909

30. Werber D, Beutin L, Pichner R, Stark K, Fruth A. Shiga toxin-producing *Escherichia coli* serogroups in food and patients, Germany. Emerg Infect Dis. 2008;14:1803-6. https://doi.org/10.3201/eid1411.080361

31. Adams NL, Byrne L, Smith GA, Elson R, Harris JP, Salmon R, et al. Shiga toxin-producing *Escherichia coli* O157, England and Wales, 1983-2012. Emerg Infect Dis. 2016;22:590-7. https://doi.org/10.3201/eid2204.151485

32. Bielaszewska M, Prager R, Köck R, Mellmann A, Zhang W, Tschäpe H, et al. Shiga toxin gene loss and transfer in vitro and in vivo during enterohemorrhagic *Escherichia coli* O26

infection in humans. Appl Environ Microbiol. 2007;73:3144-50. https://doi.org/10.1128/AEM.02937-06

33. Byrne L, Adams N, Jenkins C. Association between Shiga toxin-producing *Escherichia coli* O157:H7 stx gene subtype and disease severity, England, 2009-2019. Emerg Infect Dis. 2020;26:2394-400. https://doi.org/10.3201/eid2610.200319

34. Lavrek D, Lava SAG, Milani GP, Simonetti GD, Bianchetti MG, Giannini O. Hemolytic-uremic syndrome after *Escherichia coli* urinary tract infection in humans: systematic review of the literature. J Nephrol. 2018;31:919-24. https://doi.org/10.1007/s40620-018-0543-x

35. Michael M, Elliott EJ, Ridley GF, Hodson EM, Craig JC. Interventions for haemolytic uremic syndrome and thrombotic thrombocytopenic purpura. Cochrane Database Syst Rev. 2009;1:CD003595. https://doi.org/10.1002/14651858. CD003595.pub2

36. Grisaru S, Xie J, Samuel S, Hartling L, Tarr PI, Schnadower D, et al.; Alberta Provincial Pediatric Enteric Infection Team. Associations between hydration status, intravenous fluid administration, and outcomes of patients infected with Shiga toxin-producing *Escherichia coli*: a systematic review and meta-analysis. JAMA Pediatr. 2017;171:68-76. https://doi.org/10.1001/jamapediatrics.2016.2952

37. Keenswijk W, Raes A, De Clerck M, Vande Walle J. Is plasma exchange efficacious in Shiga toxin-associated hemolytic uremic syndrome? A narrative review of current evidence. Ther Apher Dial. 2019;23:118-25. https://doi.org/10.1111/1744-9987.12768

38. Kielstein JT, Beutel G, Fleig S, Steinhoff J, Meyer TN, Hafer C, et al.; Collaborators of the DGfN STEC-HUS registry. Best supportive care and therapeutic plasma exchange with or without eculizumab in Shiga-toxin-producing *E. coli* O104:H4 induced haemolytic-uraemic syndrome: an analysis of the German STEC-HUS registry. Nephrol Dial Transplant. 2012;27:3807-15. https://doi.org/10.1093/ndt/gfs394

39. Padmanabhan A, Connelly-Smith L, Aqui N, Balogun RA, Klingel R, Meyer E, et al. Guidelines on the use of therapeutic apheresis in clinical practice—evidence-based approach from the Writing Committee of the American Society for Apheresis: the eighth special issue. J Clin Apher. 2019;34:171-354. https://doi.org/10.1002/jca.21705

40. Joseph A, Rafat C, Zafrani L, Mariani-Kurkdjian P, Veyradier A, Hertig A, et al. Early differentiation of Shiga toxin-associated hemolytic uremic syndrome in critically ill adults with thrombotic microangiopathy syndromes. Crit Care Med. 2018;46:e904-11. https://doi.org/10.1097/CCM.0000000000003292

41. Lapeyraque A-L, Malina M, Fremeaux-Bacchi V, Boppel T, Kirschfink M, Oualha M, et al. Eculizumab in severe Shiga-toxin-associated HUS. N Engl J Med. 2011;364:2561-3. https://doi.org/10.1056/NEJMjc1100859

42. Wong CS, Mooney JC, Brandt JR, Staples AO, Jelacic S, Boster DR, et al. Risk factors for the hemolytic uremic syndrome in children infected with *Escherichia coli* O157:H7: a multivariable analysis. Clin Infect Dis. 2012;55:33-41. https://doi.org/10.1093/cid/cis299

43. Nitschke M, Sayk F, Härtel C, Roseland RT, Hauswaldt S, Steinhoff J, et al. Association between azithromycin therapy and duration of bacterial shedding among patients with Shiga toxin-producing enteroaggregative Escherichia coli O104:H4. JAMA. 2012;307:1046-52. https://doi.org/10.1001/jama.2012.264

Address for correspondence: Paul Coppo, AP-HP.6 and Sorbonne Université, 184 rue du Faubourg Saint-Antoine, Assistance Publique-Hôpitaux de Paris, 75012 Paris, France; email: paul.coppo@aphp.fr