New insights into the pathogenesis of Streptococcus pneumoniae–associated hemolytic uremic syndrome

Abstract

The purpose of this review is to describe Streptococcus pneumoniae–associated hemolytic uremic syndrome (P-HUS) with emphasis on new insights into the pathophysiology and management over the past 10 years. Even though awareness of this clinico-pathological entity has increased, it likely remains under-recognized. Recent observations indicate that although neuraminidase activity and exposure of the T-antigen are necessary for development of P-HUS, they are not sufficient; activation of the alternate pathway of complement may also contribute. It is unclear, however, whether or not eculizumab and/or plasmapheresis are of value.

This is a preview of subscription content, log in to check access.

References

  1. 1.

    Szilágyi A, Kiss N, Bereczki C, Tálosi G, Rácz K, Túri S, Györke Z, Simon E, Horváth E, Kelen K, Reusz GS, Szabó AJ, Tulassay T, Prohászka Z (2013) The role of complement in Streptococcus pneumoniae-associated haemolytic uraemic syndrome. Nephrol Dial Transplant 28:2237–2245. https://doi.org/10.1093/ndt/gft198

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Kaplan BS, Ruebner RL, Spinale JM, Copelovitch L (2014) Current treatment of atypical hemolytic uremic syndrome. Intractable Rare Dis Res 3:34–45. https://doi.org/10.5582/irdr.2014.01001

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Fakhouri F, Zuber J, Frémeaux-Bacchi V, Loirat C (2017) Haemolytic uraemic syndrome. Lancet 390:681–696. https://doi.org/10.1016/S0140-6736(17)30062-4

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Ruebner RL, Kaplan BS, Copelovitch L (2012) A time for reappraisal of “atypical” hemolytic uremic syndrome: should all patients be treated the same? Eur J Pediatr 171:1519–1525. https://doi.org/10.1007/s00431-012-1763-z

    Article  PubMed  Google Scholar 

  5. 5.

    Waters AM, Kerecuk L, Luk D, Haq MR, Fitzpatrick MM, Gilbert RD, Inward C, Jones C, Pichon B, Reid C, Slack MPE, Van’t Hoff W, Dillon MJ, Taylor CM, Tullus K (2007) Hemolytic uremic syndrome associated with invasive pneumococcal disease: the United Kingdom experience. J Pediatr 151:140–144. https://doi.org/10.1016/j.jpeds.2007.03.055

    Article  PubMed  Google Scholar 

  6. 6.

    Spinale JM, Ruebner RL, Kaplan BS, Copelovitch L (2013) Update on Streptococcus pneumoniae associated hemolytic uremic syndrome. Curr Opin Pediatr 25:203–208. https://doi.org/10.1097/MOP.0b013e32835d7f2c

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Copelovitch L, Kaplan BS (2010) Streptococcus pneumoniae-associated hemolytic uremic syndrome: classification and the emergence of serotype 19A. Pediatrics 125:e174–e182. https://doi.org/10.1542/peds.2007-2017

    Article  PubMed  Google Scholar 

  8. 8.

    Banerjee R, Hersh AL, Newland J, Beekmann SE, Polgreen PM, Bender J, Shaw J, Copelovitch L, Kaplan BS, Shah SS, Emerging Infections Network Hemolytic-Uremic Syndrome Study Group (2011) Streptococcus pneumoniae-associated hemolytic uremic syndrome among children in North America. Pediatr Infect Dis J 30:736–739. https://doi.org/10.1097/INF.0b013e3182191c58

    Article  PubMed  Google Scholar 

  9. 9.

    Copelovitch L, Kaplan BS (2008) Streptococcus pneumoniae-associated hemolytic uremic syndrome. Pediatr Nephrol 23:1951–1956. https://doi.org/10.1007/s00467-007-0518-y

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Vierbuchen M, Klein PJ (1983) Histochemical demonstration of neuraminidase effects in pneumococcal meningitis. Lab Investig 48:181–186

    CAS  PubMed  Google Scholar 

  11. 11.

    Chen J-P, Chen S-M, Sheu J-N (2007) Unusual manifestation of severe conjugated hyperbilirubinemia in an infant with Streptococcus pneumoniae-associated hemolytic uremic syndrome. J Formos Med Assoc 106:S17–S22. https://doi.org/10.1016/S0929-6646(09)60347-8

    Article  PubMed  Google Scholar 

  12. 12.

    Pan CG, Leichter HE, Werlin SL (1995) Hepatocellular injury in Streptococcus pneumoniae-associated hemolytic uremic syndrome in children. Pediatr Nephrol 9:690–693

    CAS  Article  Google Scholar 

  13. 13.

    Patel MG, Porto AF (2013) Conjugated hyperbilirubinemia in a child with Streptococcus pneumoniae-associated Hemolytic Uremic Syndrome. ACG Case Rep J 1:64–67. https://doi.org/10.14309/crj.2013.22

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Anastaze Stelle K, Cachat F, Perez M-H, Chehade H (2016) Streptococcus pneumoniae–associated hemolytic and uremic syndrome with cholestasis: a case report and brief literature review. Clin Pediatr (Phila) 55:189–191. https://doi.org/10.1177/0009922815580406

    Article  Google Scholar 

  15. 15.

    Obaro SK, Madhi SA (2006) Bacterial pneumonia vaccines and childhood pneumonia: are we winning, refining, or redefining? Lancet Infect Dis 6:150–161. https://doi.org/10.1016/S1473-3099(06)70411-X

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Klein PJ, Bulla M, Newman RA, Müller P, Uhlenbruck G, Schaefer HE, Krüger G, Fisher R (1977) Thomsen-Friedenreich antigen in haemolytic-uraemic syndrome. Lancet 2:1024–1025

    CAS  Article  Google Scholar 

  17. 17.

    Oliver JW, Akins RS, Bibens MK, Dunn DM (2010) Pneumococcal induced T-activation with resultant thrombotic microangiopathy. Clin Med Insights Pathol 3:13–17

    CAS  Article  Google Scholar 

  18. 18.

    Veesenmeyer AF, Edmonson MB (2013) Trends in US hospital stays for Streptococcus pneumoniae-associated hemolytic uremic syndrome. Pediatr Infect Dis J 32:731–735. https://doi.org/10.1097/INF.0b013e31828b31c8

    Article  PubMed  Google Scholar 

  19. 19.

    Bender JM, Ampofo K, Byington CL, Grinsell M, Korgenski K, Daly JA, Mason EO, Pavia AT (2010) Epidemiology of Streptococcus pneumoniae-induced hemolytic uremic syndrome in Utah children. Pediatr Infect Dis J 29:712–716. https://doi.org/10.1097/INF.0b013e3181db03a7

    Article  PubMed  Google Scholar 

  20. 20.

    Lawrence J, Gwee A, Quinlan C (2018) Pneumococcal haemolytic uraemic syndrome in the postvaccine era. Arch Dis Child 103:957–961. https://doi.org/10.1136/archdischild-2017-313923

    Article  PubMed  Google Scholar 

  21. 21.

    Kent A, Makwana A, Sheppard CL, Collins S, Fry NK, Heath PT, Ramsay M, Ladhani SN (2019) Invasive pneumococcal disease in UK children <1 year of age in the post-13-valent pneumococcal conjugate vaccine era: what are the risks now? Clin Infect Dis 69:84–90. https://doi.org/10.1093/cid/ciy842

    Article  PubMed  Google Scholar 

  22. 22.

    Huang DT-N, Chi H, Lee H-C, Chiu N-C, Huang F-Y (2006) T-antigen activation for prediction of pneumococcus-induced hemolytic uremic syndrome and hemolytic anemia. Pediatr Infect Dis J 25:608–610. https://doi.org/10.1097/01.inf.0000223494.83542.ad

    Article  PubMed  Google Scholar 

  23. 23.

    Janapatla R-P, Hsu M-H, Hsieh Y-C, Lee H-Y, Lin T-Y, Chiu C-H (2013) Necrotizing pneumonia caused by nanC-carrying serotypes is associated with pneumococcal haemolytic uraemic syndrome in children. Clin Microbiol Infect 19:480–486. https://doi.org/10.1111/j.1469-0691.2012.03894.x

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Burin des Roziers N, Chadebech P, Bodivit G, Guinchard E, Bruneel A, Dupré T, Chevret L, Jugie M, Gallon P, Bierling P, Noizat-Pirenne F (2015) Red blood cell Thomsen-Friedenreich antigen expression and galectin-3 plasma concentrations in Streptococcus pneumoniae-associated hemolytic uremic syndrome and hemolytic anemia. Transfusion (Paris) 55:1563–1571. https://doi.org/10.1111/trf.12981

    CAS  Article  Google Scholar 

  25. 25.

    von Vigier RO, Fossali E, Crosazzo L, Bianchetti MG (2005) Positive Coombs test in postpneumococcal hemolytic-uremic syndrome. Pediatr Infect Dis J 24:1028–1029

    Article  Google Scholar 

  26. 26.

    Loupiac A, Elayan A, Cailliez M, Adra A-L, Decramer S, Thouret M-C, Harambat J, Guigonis V (2013) Diagnosis of Streptococcus pneumoniae-associated hemolytic uremic syndrome. Pediatr Infect Dis J 32:1045–1049. https://doi.org/10.1097/INF.0b013e31829ee872

    Article  PubMed  Google Scholar 

  27. 27.

    Burin des Roziers N, Bodivit G, Chadebech P, Nzouakou R, Bierling P, Noizat-Pirenne F (2011) Anti-T haemolysins: the effects of sialic acid removal and 2-aminoethylisothiouronium bromide treatment of erythrocytes on immune lysis. Vox Sang 100:401–408. https://doi.org/10.1111/j.1423-0410.2010.01450.x

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Crookston KP, Reiner AP, Cooper LJ, Sacher RA, Blajchman MA, Heddle NM (2000) RBC T activation and hemolysis: implications for pediatric transfusion management. Transfusion (Paris) 40:801–812

    CAS  Article  Google Scholar 

  29. 29.

    Eder AF, Manno CS (2001) Does red-cell T activation matter? Br J Haematol 114:25–30

    CAS  Article  Google Scholar 

  30. 30.

    Aoki H, Shiomi M, Ikeda T, Ishii T, Shimizu N, Togawa M, Okamoto N, Kadoya M, Wada Y (2013) Decreased sialylation of IgA1 O-glycans associated with pneumococcal hemolytic uremic syndrome. Pediatr Int 55:e143–e145. https://doi.org/10.1111/ped.12166

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Wada Y, Azadi P, Costello CE, Dell A, Dwek RA, Geyer H, Geyer R, Kakehi K, Karlsson NG, Kato K, Kawasaki N, Khoo K-H, Kim S, Kondo A, Lattova E, Mechref Y, Miyoshi E, Nakamura K, Narimatsu H, Novotny MV, Packer NH, Perreault H, Peter-Katalinic J, Pohlentz G, Reinhold VN, Rudd PM, Suzuki A, Taniguchi N (2007) Comparison of the methods for profiling glycoprotein glycans--HUPO Human Disease Glycomics/Proteome Initiative multi-institutional study. Glycobiology 17:411–422. https://doi.org/10.1093/glycob/cwl086

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Smith A, Johnston C, Inverarity D, Slack M, Paterson GK, Diggle M, Mitchell T (2013) Investigating the role of pneumococcal neuraminidase a activity in isolates from pneumococcal haemolytic uraemic syndrome. J Med Microbiol 62:1735–1742. https://doi.org/10.1099/jmm.0.063479-0

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Singh AK, Osman AS, Woodiga SA, White P, Mahan JD, King SJ (2016) Defining the role of pneumococcal neuraminidases and O-glycosidase in pneumococcal haemolytic uraemic syndrome. J Med Microbiol 65:975–984. https://doi.org/10.1099/jmm.0.000322

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Pettigrew MM, Fennie KP, York MP, Daniels J, Ghaffar F (2006) Variation in the presence of neuraminidase genes among Streptococcus pneumoniae isolates with identical sequence types. Infect Immun 74:3360–3365. https://doi.org/10.1128/IAI.01442-05

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    de Loos F, Huijben KMLC, van der Kar NCAJ, Monnens LAH, van den Heuvel LPWJ, Groener JEM, de Moor RA, Wevers RA (2002) Hemolytic uremic syndrome attributable to Streptococcus pneumoniae infection: a novel cause for secondary protein N-glycan abnormalities. Clin Chem 48:781–784

    Article  Google Scholar 

  36. 36.

    Sato S, Ouellet N, Pelletier I, Simard M, Rancourt A, Bergeron MG (2002) Role of galectin-3 as an adhesion molecule for neutrophil extravasation during streptococcal pneumonia. J Immunol 168:1813–1822

    CAS  Article  Google Scholar 

  37. 37.

    Ahmad N, Gabius H-J, André S, Kaltner H, Sabesan S, Roy R, Liu B, Macaluso F, Brewer CF (2004) Galectin-3 precipitates as a pentamer with synthetic multivalent carbohydrates and forms heterogeneous cross-linked complexes. J Biol Chem 279:10841–10847. https://doi.org/10.1074/jbc.M312834200

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Fearon DT (1978) Regulation by membrane sialic acid of beta1H-dependent decay-dissociation of amplification C3 convertase of the alternative complement pathway. Proc Natl Acad Sci U S A 75:1971–1975

    CAS  Article  Google Scholar 

  39. 39.

    Brown EJ, Joiner KA, Frank MM (1983) Interaction of desialated guinea pig erythrocytes with the classical and alternative pathways of guinea pig complement in vivo and in vitro. J Clin Invest 71:1710–1719

    CAS  Article  Google Scholar 

  40. 40.

    Ault BH (2000) Factor H and the pathogenesis of renal diseases. Pediatr Nephrol 14:1045–1053

    CAS  Article  Google Scholar 

  41. 41.

    Kerr H, Wong E, Makou E, Yang Y, Marchbank K, Kavanagh D, Richards A, Herbert AP, Barlow PN (2017) Disease-linked mutations in factor H reveal pivotal role of cofactor activity in self-surface-selective regulation of complement activation. J Biol Chem 292:13345–13360. https://doi.org/10.1074/jbc.M117.795088

    Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Bitzan M, AlKandari O, Whittemore B, Yin X-L (2018) Complement depletion and Coombs positivity in pneumococcal hemolytic uremic syndrome (pnHUS). Case series and plea to revisit an old pathogenetic concept. Int J Med Microbiol 308:1096–1104. https://doi.org/10.1016/j.ijmm.2018.08.007

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Gilbert RD, Nagra A, Haq MR (2013) Does dysregulated complement activation contribute to haemolytic uraemic syndrome secondary to Streptococcus pneumoniae? Med Hypotheses 81:400–403. https://doi.org/10.1016/j.mehy.2013.05.030

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Meinel C, Spartà G, Dahse H-M, Hörhold F, König R, Westermann M, Coldewey SM, Cseresnyés Z, Figge MT, Hammerschmidt S, Skerka C, Zipfel PF (2018) Streptococcus pneumoniae from patients with hemolytic uremic syndrome binds human plasminogen via the surface protein PspC and uses plasmin to damage human endothelial cells. J Infect Dis 217:358–370. https://doi.org/10.1093/infdis/jix305

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Eber SW, Polster H, Quentin SH, Rumpf KW, Lynen R (1993) Hemolytic-uremic syndrome in pneumococcal meningitis and infection. Importance of T-transformation. Monatsschr Kinderheilkd 141:219–222

    CAS  PubMed  Google Scholar 

  46. 46.

    Seges RA, Kenny A, Bird GW, Wingham J, Baals H, Stauffer UG (1981) Pediatric surgical patients with severe anaerobic infection: report of 16 T-antigen positive cases and possible hazards of blood transfusion. J Pediatr Surg 16:905–910

    CAS  Article  Google Scholar 

  47. 47.

    Simell B, Jaakkola T, Lahdenkari M, Briles D, Hollingshead S, Kilpi TM, Käyhty H (2006) Serum antibodies to pneumococcal neuraminidase NanA in relation to pneumococcal carriage and acute otitis media. Clin Vaccine Immunol 13:1177–1179. https://doi.org/10.1128/CVI.00257-06

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Jeantet G, Pernin V, Brunot V, Roccabianca A, Macombe A, Szwarc I, Klouche K, Loirat C, Mourad G, Frémeaux-Bacchi V, Le Quintrec M (2019) Successful treatment of a Streptococcus pneumoniae-associated haemolytic uraemic syndrome by eculizumab. Clin Kidney J 12:106–109. https://doi.org/10.1093/ckj/sfy019

    CAS  Article  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Lawrence Copelovitch.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Scobell, R.R., Kaplan, B.S. & Copelovitch, L. New insights into the pathogenesis of Streptococcus pneumoniae–associated hemolytic uremic syndrome. Pediatr Nephrol 35, 1585–1591 (2020). https://doi.org/10.1007/s00467-019-04342-3

Download citation

Keywords

  • P-HUS
  • Alternative complement pathway
  • Eculizumab
  • Plasmapheresis