Zoonotic Bacterial Infections Triggering Cytokine Storm Syndrome

  • Zaher K. OtrockEmail author
  • Charles S. Eby


Zoonotic infections can result in life-threatening complications that can manifest with hemophagocytic lymphohistiocytosis (HLH)/cytokine storm syndrome (CSS). Zoonotic bacterial infections constitute the largest group of reported cases associated with HLH among other zoonotic infections. There is a growing list of zoonotic bacterial infections associated with HLH/CSS and these include Brucella spp., Rickettsia spp., Ehrlichia, Coxiella burnetii, and Mycobacterium spp.


Zoonotic Bacteria Brucella Rickettsia Ehrlichia Trigger Hemophagocytic lymphohistiocytosis Case reports Review Cytokine storm syndrome 


  1. 1.
    Cascio, A., Pernice, L. M., Barberi, G., Delfino, D., Biondo, C., Beninati, C., et al. (2012). Secondary hemophagocytic lymphohistiocytosis in zoonoses. A systematic review. European Review for Medical and Pharmacological Sciences, 16, 1324–1337.PubMedGoogle Scholar
  2. 2.
    Lecronier, M., Prendki, V., Gerin, M., Schneerson, M., Renvoisé, A., Larroche, C., et al. (2013). Q fever and Mediterranean spotted fever associated with hemophagocytic syndrome: Case study and literature review. International Journal of Infectious Diseases, 17, e629–e633.CrossRefGoogle Scholar
  3. 3.
    Otrock, Z. K., Gonzalez, M. D., & Eby, C. S. (2015). Ehrlichia-induced hemophagocytic lymphohistiocytosis: A case series and review of literature. Blood Cells, Molecules & Diseases, 55, 191–193.CrossRefGoogle Scholar
  4. 4.
    Pappas, G., Papadimitriou, P., Akritidis, N., Christou, L., & Tsianos, E. V. (2006). The new global map of human brucellosis. The Lancet Infectious Diseases, 6, 91–99.CrossRefGoogle Scholar
  5. 5.
    Dean, A. S., Crump, L., Greter, H., Schelling, E., & Zinsstag, J. (2012). Global burden of human brucellosis: A systematic review of disease frequency. PLoS Neglected Tropical Diseases, 6, e1865.CrossRefGoogle Scholar
  6. 6.
    Dean, A. S., Crump, L., Greter, H., Hattendorf, J., Schelling, E., & Zinsstag, J. (2012). Clinical manifestations of human brucellosis: A systematic review and meta-analysis. PLoS Neglected Tropical Diseases, 6, e1929.CrossRefGoogle Scholar
  7. 7.
    Karaman, K., Akbayram, S., Kaba, S., Karaman, S., Garipardiç, M., Aydin, I., et al. (2016). An analysis of children with brucellosis associated with haemophagocytic lymphohistiocytosis. Le Infezioni in Medicina, 24, 123–130.PubMedGoogle Scholar
  8. 8.
    Yaman, Y., Gözmen, S., Özkaya, A. K., Oymak, Y., Apa, H., Vergin, C., et al. (2015). Secondary hemophagocytic lymphohistiocytosis in children with brucellosis: Report of three cases. Journal of Infection in Developing Countries, 9, 1172–1176.CrossRefGoogle Scholar
  9. 9.
    Erduran, E., Makuloglu, M., & Mutlu, M. (2010). A rare hematological manifestation of brucellosis: Reactive hemophagocytic syndrome. Journal of Microbiology, Immunology, and Infection, 43, 159–162.CrossRefGoogle Scholar
  10. 10.
    Mondal, N., Suresh, R., Acharya, N. S., Praharaj, I., Harish, B. N., & Mahadevan, S. (2010). Hemophagocytic syndrome in a child with brucellosis. Indian Journal of Pediatrics, 77, 1434–1436.CrossRefGoogle Scholar
  11. 11.
    David, A., Iaria, C., Giordano, S., Iaria, M., & Cascio, A. (2012). Secondary hemophagocytic lymphohistiocytosis: Forget me not! Transplant Infectious Disease, 14, E121–E123.CrossRefGoogle Scholar
  12. 12.
    Dumler, J. S., Madigan, J. E., Pusterla, N., & Bakken, J. S. (2007). Ehrlichioses in humans: Epidemiology, clinical presentation, diagnosis, and treatment. Clinical Infectious Diseases, 45(Suppl 1), S45–S51.CrossRefGoogle Scholar
  13. 13.
    Parola, P., Paddock, C. D., & Raoult, D. (2005). Tick-borne rickettsioses around the world: Emerging diseases challenging old concepts. Clinical Microbiology Reviews, 18, 719–756.CrossRefGoogle Scholar
  14. 14.
    Jayakrishnan, M. P., Veny, J., & Feroze, M. (2011). Rickettsial infection with hemophagocytosis. Tropical Doctor, 41, 111–112.CrossRefGoogle Scholar
  15. 15.
    Walter, G., Botelho-Nevers, E., Socolovschi, C., Raoult, D., & Parola, P. (2012). Murine typhus in returned travelers: A report of thirty-two cases. The American Journal of Tropical Medicine and Hygiene, 86, 1049–1053.CrossRefGoogle Scholar
  16. 16.
    Cascio, A., Giordano, S., Dones, P., Venezia, S., Iaria, C., & Ziino, O. (2011). Haemophagocytic syndrome and rickettsial diseases. Journal of Medical Microbiology, 60, 537–542.CrossRefGoogle Scholar
  17. 17.
    Premaratna, R., Williams, H. S., Chandrasena, T. G., Rajapakse, R. P., Kularatna, S. A., & de Silva, H. J. (2009). Unusual pancytopenia secondary to haemophagocytosis syndrome in rickettsioses. Transactions of the Royal Society of Tropical Medicine and Hygiene, 103, 961–963.CrossRefGoogle Scholar
  18. 18.
    Basheer, A., Padhi, S., Boopathy, V., Mallick, S., Nair, S., Varghese, R. G., et al. (2015 Jan 1). Hemophagocytic Lymphohistiocytosis: an Unusual Complication of Orientia tsutsugamushi Disease (Scrub Typhus). Mediterr J Hematol Infect Dis., 7(1), e2015008.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Kwon, H. J., Yoo, I. H., Lee, J. W., Chung, N. G., Cho, B., Kim, H. K., et al. (2013 Feb). Life-threatening scrub typhus with hemophagocytosis and acute respiratory distress syndrome in an infant. J Trop Pediatr., 59(1), 67–69.CrossRefGoogle Scholar
  20. 20.
    Otsuki, S., Iwamoto, S., Azuma, E., Nashida, Y., Akachi, S., Taniguchi, K., et al. (2015). Hemophagocytic Lymphohistiocytosis due to rickettsia japonica in a 3-month-old infant. Journal of Pediatric Hematology/Oncology, 37, 627–628.CrossRefGoogle Scholar
  21. 21.
    Dumler, J. S. (2005). Anaplasma and Ehrlichia infection. Annals of the New York Academy of Sciences, 1063, 361–373.CrossRefGoogle Scholar
  22. 22.
    Paddock, C. D., & Childs, J. E. (2003). Ehrlichia chaffeensis: A prototypical emerging pathogen. Clinical Microbiology Reviews, 16, 37–64.CrossRefGoogle Scholar
  23. 23.
    Dumler, J. S., Choi, K. S., Garcia-Garcia, J. C., Barat, N. S., Scorpio, D. G., Garyu, J. W., et al. (2005). Human granulocytic anaplasmosis and Anaplasma phagocytophilum. Emerging Infectious Diseases, 11, 1828–1834.CrossRefGoogle Scholar
  24. 24.
    Lantos, P. M., & Krause, P. J. (2002). Ehrlichiosis in children. Seminars in Pediatric Infectious Diseases, 13, 249–256.CrossRefGoogle Scholar
  25. 25.
    Pujalte, G. G., & Chua, J. V. (2013). Tick-borne infections in the United States. Primary Care, 40, 619–635.CrossRefGoogle Scholar
  26. 26.
    Dahlgren, F. S., Heitman, K. N., & Behravesh, C. B. (2016). Undetermined human ehrlichiosis and anaplasmosis in the United States, 2008–2012: A catch-all for passive surveillance. The American Journal of Tropical Medicine and Hygiene, 94, 299–301.CrossRefGoogle Scholar
  27. 27.
    Dahlgren, F. S., Mandel, E. J., Krebs, J. W., Massung, R. F., & McQuiston, J. H. (2011). Increasing incidence of Ehrlichia chaffeensis and Anaplasma phagocytophilum in the United States, 2000–2007. The American Journal of Tropical Medicine and Hygiene, 85, 124–131.CrossRefGoogle Scholar
  28. 28.
    Ismail, N., Olano, J. P., Feng, H. M., & Walker, D. H. (2002). Current status of immune mechanisms of killing of intracellular microorganisms. FEMS Microbiology Letters, 207, 111–120.CrossRefGoogle Scholar
  29. 29.
    Ismail, N., Soong, L., McBride, J. W., Valbuena, G., Olano, J. P., Feng, H. M., et al. (2004). Overproduction of TNF-alpha by CD8+ type 1 cells and down-regulation of IFN-gamma production by CD4+ Th1 cells contribute to toxic shock-like syndrome in an animal model of fatal monocytotropic ehrlichiosis. Journal of Immunology, 172, 1786–1800.CrossRefGoogle Scholar
  30. 30.
    Ismail, N., Stevenson, H. L., & Walker, D. H. (2006). Role of tumor necrosis factor alpha (TNF-alpha) and interleukin-10 in the pathogenesis of severe murine monocytotropic ehrlichiosis: Increased resistance of TNF receptor p55- and p75-deficient mice to fatal ehrlichial infection. Infection and Immunity, 74, 1846–1856.CrossRefGoogle Scholar
  31. 31.
    Otrock, Z. K., Eby, C. S., & Burnham, C. D. (2019). Human ehrlichiosis at a tertiary-care academic medical center: Clinical associations and outcomes of transplant patients and patients with hemophagocytic lymphohistiocytosis. Blood Cells Mol Dis., 77, 17–22.CrossRefGoogle Scholar
  32. 32.
    Statler, V. A., & Marshall, G. S. (2015). Hemophagocytic lymphohistiocytosis induced by monocytic ehrlichiosis. The Journal of Pediatrics, 166, 499–99.e1.CrossRefGoogle Scholar
  33. 33.
    Kumar, N., Goyal, J., Goel, A., Shakoory, B., & Chatham, W. (2014). Macrophage activation syndrome secondary to human monocytic ehrlichiosis. Indian Journal of Hematology and Blood Transfusion, 30(Suppl 1), 145–147.CrossRefGoogle Scholar
  34. 34.
    Naqash, A. R., Yogarajah, M., Vallangeon, B. D., Hafiz, M., Patel, D., Kolychev, E., et al. (2017). Hemophagocytic lymphohistiocytosis (HLH) secondary to Ehrlichia chaffeensis with bone marrow involvement. Annals of Hematology, 96, 1755–1758.CrossRefGoogle Scholar
  35. 35.
    Cheng, A., Williams, F., Fortenberry, J., Preissig, C., Salinas, S., & Kamat, P. (2016). Use of extracorporeal support in Hemophagocytic Lymphohistiocytosis secondary to Ehrlichiosis. Pediatrics, 138(4), e20154176.CrossRefGoogle Scholar
  36. 36.
    Kaplan, R. M., Swat, S. A., & Singer, B. D. (2016). Human monocytic ehrlichiosis complicated by hemophagocytic lymphohistiocytosis and multi-organ dysfunction syndrome. Diagnostic Microbiology and Infectious Disease, 86, 327–328.CrossRefGoogle Scholar
  37. 37.
    Vijayan, V., Thambundit, A., & Sukumaran, S. (2015). Hemophagocytic lymphohistiocytosis secondary to ehrlichiosis in a child. Clinical Pediatrics (Phila), 54, 84–86.CrossRefGoogle Scholar
  38. 38.
    Pandey, R., Kochar, R., Kemp, S., Rotaru, D., & Shah, S. V. (2013). Ehrlichiosis presenting with toxic shock-like syndrome and secondary hemophagocytic lymphohistiocytosis. The Journal of the Arkansas Medical Society, 109, 280–282.PubMedGoogle Scholar
  39. 39.
    Hanson, D., Walter, A. W., & Powell, J. (2011). Ehrlichia-induced hemophagocytic lymphohistiocytosis in two children. Pediatric Blood & Cancer, 56, 661–663.CrossRefGoogle Scholar
  40. 40.
    Burns, S., Saylors, R., & Mian, A. (2010). Hemophagocytic lymphohistiocytosis secondary to Ehrlichia chaffeensis infection: A case report. Journal of Pediatric Hematology/Oncology, 32, e142–e143.CrossRefGoogle Scholar
  41. 41.
    Otrock, Z. K., & Eby, C. S. (2015). Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis. American Journal of Hematology, 90, 220–224.CrossRefGoogle Scholar
  42. 42.
    Parikh, S. A., Kapoor, P., Letendre, L., Kumar, S., & Wolanskyj, A. P. (2014). Prognostic factors and outcomes of adults with hemophagocytic lymphohistiocytosis. Mayo Clinic Proceedings, 89, 484–492.CrossRefGoogle Scholar
  43. 43.
    Shabbir, M., Lucas, J., Lazarchick, J., & Shirai, K. (2011). Secondary hemophagocytic syndrome in adults: A case series of 18 patients in a single institution and a review of literature. Hematological Oncology, 29, 100–106.CrossRefGoogle Scholar
  44. 44.
    Anderson, A., Bijlmer, H., Fournier, P. E., Graves, S., Hartzell, J., Kersh, G. J., et al. (2013). Diagnosis and management of Q fever–United States, 2013: Recommendations from CDC and the Q fever working group. MMWR - Recommendations and Reports, 62, 1–30.PubMedGoogle Scholar
  45. 45.
    Million, M., & Raoult, D. (2015). Recent advances in the study of Q fever epidemiology, diagnosis and management. The Journal of Infection, 71(Suppl 1), S2–S9.CrossRefGoogle Scholar
  46. 46.
    Amara, A. B., Bechah, Y., & Mege, J. L. (2012). Immune response and Coxiella burnetii invasion. Advances in Experimental Medicine and Biology, 984, 287–298.CrossRefGoogle Scholar
  47. 47.
    Chen, T. C., Chang, K., Lu, P. L., Liu, Y. C., Chen, Y. H., Hsieh, H. C., et al. (2006). Acute Q fever with hemophagocytic syndrome: Case report and literature review. Scandinavian Journal of Infectious Diseases, 38, 1119–1122.CrossRefGoogle Scholar
  48. 48.
    Harris, P., Dixit, R., & Norton, R. (2011). Coxiella burnetii causing haemophagocytic syndrome: A rare complication of an unusual pathogen. Infection, 39, 579–582.CrossRefGoogle Scholar
  49. 49.
    Paine, A., Miya, T., & Webb, B. J. (2015). Coxiella burnetii infection with severe hyperferritinemia in an asplenic patient. Open Forum Infectious Diseases, 2, ofv125.CrossRefGoogle Scholar
  50. 50.
    Padhi, S., Ravichandran, K., Sahoo, J., Varghese, R. G., & Basheer, A. (2015). Hemophagocytic lymphohistiocytosis: An unusual complication in disseminated Mycobacterium tuberculosis. Lung India, 32, 593–601.CrossRefGoogle Scholar
  51. 51.
    Grandjean Lapierre, S., Toro, A., & Drancourt, M. (2017). Mycobacterium iranicum bacteremia and hemophagocytic lymphohistiocytosis: A case report. BMC Research Notes, 10, 372.CrossRefGoogle Scholar
  52. 52.
    Castelli, A. A., Rosenthal, D. G., Bender Ignacio, R., & Chu, H. Y. (2015). Hemophagocytic Lymphohistiocytosis secondary to human immunodeficiency virus-associated Histoplasmosis. Open Forum Infectious Diseases, 2, ofv140.CrossRefGoogle Scholar
  53. 53.
    Yang, W. K., Fu, L. S., Lan, J. L., Shen, G. H., Chou, G., Tseng, C. F., et al. (2003). Mycobacterium avium complex-associated hemophagocytic syndrome in systemic lupus erythematosus patient: Report of one case. Lupus, 12, 312–316.CrossRefGoogle Scholar
  54. 54.
    Chamsi-Pasha, M. A., Alraies, M. C., Alraiyes, A. H., & Hsi, E. D. (2013). Mycobacterium avium complex-associated hemophagocytic lymphohistiocytosis in a sickle cell patient: An unusual fatal association. Case Reports in Hematology, 2013, 291518.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory MedicineHenry Ford HospitalDetroitUSA
  2. 2.Department of Pathology and ImmunologyWashington University School of MedicineSt. LouisUSA

Personalised recommendations