Streptococcus Pneumoniae-Associated Hemolytic Uremic Syndrome in the Era of Pneumococcal Vaccine

Agarwal, Hemant; Latifi, Samir

doi:10.3390/pathogens10060727

“…This difference could be attributed to the inherently higher virulence and invasiveness of pneumococcal infections, which often result in more extensive pulmonary involvement and systemic complications, thereby necessitating a more prolonged and intensive approach to respiratory support that is typically required for patients with Shiga-toxin-producing HUS. [8][9][10][11][12][13][14][15] Prolonged MV in children is of importance as there can be significant associated morbidity and mortality. Younger age, black race, pneumonia, pneumothorax, liver dysfunction, ileus with perforation, presence of pneumococcal disease, and sepsis were independent risk factors for prolonged MV utilization in our study.…”

Section: Discussionmentioning

confidence: 99%

Predictors of Prolonged Mechanical Ventilation in Pediatric Patients with Hemolytic Uremic Syndrome

Bhakta,

Brown,

Garcia

et al. 2024

J Pediatr Intensive Care

0

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This study aimed to analyze factors associated with mechanical ventilation (MV) and prolonged MV (≥12 days) in pediatric hemolytic uremic syndrome (HUS) patients. Retrospective multicenter cohort study analyzed data from 3,831 pediatric HUS (age <18 years) patients between 2004 and 2018 from Pediatric Health Information System database. Multivariate logistic regression was used to pinpoint factors associated with MV and prolonged MV. Among 3,831 patients analyzed, 769 (20%) patients required MV, 166 (23.6%) of them were prolonged MV. Factors independently associated with prolonged MV include African American (adjusted odds ratio [aOR]: 1.98, 95% confidence interval [CI]: 1.11–3.54, p = 0.02), children aged between 1 and 5 years (aOR: 7.69, 95% CI: 3.71–15.93, p < 0.001), pneumonia (aOR: 2.54, 95% CI: 1.51–4.25, p < 0.001), pneumothorax (aOR: 2.41, 95% CI: 1.08–5.39, p = 0.032), liver dysfunction (aOR: 3.22, 95% CI: 1.68–6.16, p < 0.001), ileus with perforation (aOR: 1.83, 95% CI: 1.03–3.25, p = 0.039), and sepsis (aOR: 1.97, 95% CI: 1.26–3.08, p = 0.003). In pediatric HUS cases, 20% required MV, and 23.6% of them were prolonged MV. Factors associated with prolong MV include African American race, children aged between 1 and 5 years, pneumonia, pneumothorax, liver dysfunction, ileus with perforation, and sepsis.

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“…Pneumococcal serotypes are defined by the biochemical structure of their polysaccharide capsule; they are of greatest relevance in the rollout of infection and more than 100 serotypes have been described to date ( 72 ). The prominent serotypes of Sp-HUS, before the introduction of the pneumococcal vaccine, were 3, 6B, 8, 9V, 14, 19, and 23F ( 5 ). Soon after the introduction of the 7- and 13-valent pneumococcal protein conjugate vaccines in 2000 and 2010, respectively, there was a shift of Sp-HUS-associated serotypes to those that were not covered by the vaccines.…”

Section: Discussionmentioning

confidence: 99%

“…However, the pathophysiology of the infection-associated form of HUS remains largely unclear ( 4 ). In around 90% of cases, an infection-related HUS is caused by Shiga-like toxin-producing bacteria, such as enterohemorrhagic Escherichia coli (EHEC) or Shigella dysenteriae type 1 ( 5 ). Sp-HUS accounts for approximately 5% of all HUS cases and occurs mainly among children under 2 years old, and the predicted mortality rate is 12.3% ( 6 , 7 ).…”

Section: Introductionmentioning

confidence: 99%

The role of pneumococcal extracellular vesicles on the pathophysiology of the kidney disease hemolytic uremic syndrome

Battista

¹

,

Hoffmann

²

,

Bachelot

³

et al. 2023

mSphere

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Streptococcus pneumoniae -induced hemolytic uremic syndrome (Sp-HUS) is a kidney disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. This disease is frequently underdiagnosed and its pathophysiology is poorly understood. In this work, we compared clinical strains, isolated from infant Sp-HUS patients, with a reference pathogenic strain D39, for host cytotoxicity and further explored the role of Sp-derived extracellular vesicles (EVs) in the pathogenesis of an HUS infection. In comparison with the wild-type strain, pneumococcal HUS strains caused significant lysis of human erythrocytes and increased the release of hydrogen peroxide. Isolated Sp-HUS EVs were characterized by performing dynamic light-scattering microscopy and proteomic analysis. Sp-HUS strain released EVs at a constant concentration during growth, yet the size of the EVs varied and several subpopulations emerged at later time points. The cargo of the Sp-HUS EVs included several virulence factors at high abundance, i.e., the ribosomal subunit assembly factor BipA, the pneumococcal surface protein A, the lytic enzyme LytC, several sugar utilization, and fatty acid synthesis proteins. Sp-HUS EVs strongly downregulated the expression of the endothelial surface marker platelet endothelial cell adhesion molecule-1 and were internalized by human endothelial cells. Sp-HUS EVs elicited the release of pro-inflammatory cytokines (interleukin [IL]-1β, IL-6) and chemokines (CCL2, CCL3, CXCL1) by human monocytes. These findings shed new light on the overall function of Sp-EVs, in the scope of infection-mediated HUS, and suggest new avenues of research for exploring the usefulness of Sp-EVs as therapeutic and diagnostic targets. IMPORTANCE Streptococcus pneumoniae -associated hemolytic uremic syndrome (Sp-HUS) is a serious and underdiagnosed deadly complication of invasive pneumococcal disease. Despite the introduction of the pneumococcal vaccine, cases of Sp-HUS continue to emerge, especially in children under the age of 2. While a lot has been studied regarding pneumococcal proteins and their role on Sp-HUS pathophysiology, little is known about the role of extracellular vesicles (EVs). In our work, we isolate and initially characterize EVs from a reference pathogenic strain (D39) and a strain isolated from a 2-year-old patient suffering from Sp-HUS. We demonstrate that despite lacking cytotoxicity toward human cells, Sp-HUS EVs are highly internalized by endothelial cells and can trigger cytokine and chemokine production in monocytes. In addition, this work specifically highlights the distinct morphological characteristics of Sp-HUS EVs and their unique cargo. Overall, this work sheds new light into potentially relevant players contained in EVs that might elucidate about pneumococcal EVs biogenesis or pose as interesting candidates for vaccine design.

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“…Pneumococcal serotypes are defined by the biochemical structure of their polysaccharide capsule; they are of greatest relevance in the rollout of infection and more than 100 serotypes have been described to date(74). The prominent serotypes of Sp-HUS, before the introduction of the pneumococcal vaccine, were 3, 6B, 8, 9V, 14, 19, and 23F(5). Soon after the introduction of the 7- and 13-valent pneumococcal protein conjugate vaccines in 2000 and 2010, respectively, there was a shift of Sp-HUS-associated serotypes to those that were not covered by the vaccines.…”

Section: Discussionmentioning

confidence: 99%

“…However, the pathophysiology of the infection-associated form of HUS remains largely unclear (4). In around 90% of cases, an infection-related HUS is caused by Shiga-like toxin-producing bacteria, such as enterohaemorrhagic Escherichia coli (STEC) or Shigella dysenteriae type 1 (5). Sp-HUS accounts for approximately 5% of all HUS cases and occurs mainly among children under 2 years old, and the predicted mortality rate is 12.3% (6,7).…”

Section: Introductionmentioning

confidence: 99%

The role of pneumococcal extracellular vesicles on the pathophysiology of the kidney disease Hemolytic Uremic Syndrome

Battista¹,

Hoffmann²,

Bachelot³

et al. 2023

Preprint

0

View full text Add to dashboard Cite

Streptococcus pneumoniae-induced hemolytic uremic syndrome (Sp-HUS) is a kidney disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. This disease is frequently underdiagnosed and its pathophysiology is poorly understood. In this work, we compared clinical strains, isolated from infant Sp-HUS patients, to a reference pathogenic strain D39, for host cytotoxicity and further explored the role of Sp-derived extracellular vesicles (EVs) in the pathogenesis of a HUS infection. In comparison with the WT strain, pneumococcal HUS strains caused significant lysis of human erythrocytes and increased the release of hydrogen peroxide. Isolated Sp-HUS EVs were characterized by performing dynamic light-scattering microscopy and proteomic analysis. Sp-HUS strain released EVs at a constant concentration during growth, yet the size of the EVs varied and several subpopulations emerged at later time points. The cargo of the Sp-HUS EVs included several virulence factors at high abundance, i.e., the ribosomal subunit assembly factor BipA, the Pneumococcal Surface Protein A (PspA), the lytic enzyme LytC, several sugar utilization and fatty acid synthesis proteins. Sp-HUS EVs strongly downregulated the expression of the endothelial surface marker PECAM-1 and were internalized by human endothelial cells. Sp-HUS EVs elicited the release of pro-inflammatory cytokines (IL-1b, IL-6) and chemokines (CCL2, CCL3, CXCL1) by human monocytes. These findings shed new light on the overall function of Sp-EVs, in the scope of infection-mediated HUS, and suggest new avenues of research for exploring the usefulness of Sp-EVs as therapeutic and diagnostic targets.

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Streptococcus Pneumoniae-Associated Hemolytic Uremic Syndrome in the Era of Pneumococcal Vaccine

Cited by 13 publications

References 108 publications

Predictors of Prolonged Mechanical Ventilation in Pediatric Patients with Hemolytic Uremic Syndrome

Predictors of Prolonged Mechanical Ventilation in Pediatric Patients with Hemolytic Uremic Syndrome

The role of pneumococcal extracellular vesicles on the pathophysiology of the kidney disease hemolytic uremic syndrome

The role of pneumococcal extracellular vesicles on the pathophysiology of the kidney disease Hemolytic Uremic Syndrome

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