Critical Care Management: Sepsis and Disseminated and Local Infections

  • Caitlin Hurley
  • Matt ZinterEmail author


Local and systemic infections are a significant cause of morbidity and mortality among immunocompromised children, including but not limited to patients with hematologic and solid malignancies, congenital or acquired immunodeficiencies, or hematopoietic cell or solid organ transplantation patients. Progression to septic shock can be rapid and profound and thus requires specific diagnostic and treatment approaches. This chapter will discuss the diagnosis and the initial hemodynamic management strategies of septic shock in immunocompromised children, including strategies to improve oxygen delivery, reduce metabolic demand, and monitor hemodynamic response to resuscitation. This chapter also discusses strategies to reverse septic shock pathobiology, including the use of both empiric and targeted anti-infective strategies and pharmacologic and cell therapy-based immunomodulation. Specific consideration is also paid to the management of high-risk subpopulations and the care of septic shock patients with resolving injury.


Pediatric Sepsis Shock, septic Immunocompromised host Hematopoietic stem cell transplantation Cardiopulmonary resuscitation 


  1. 1.
    Goldstein B, Giroir B, Randolph A, et al. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. 2005;6:2–8. Scholar
  2. 2.
    Agulnik A, Mendez Aceituno A, Mora Robles LN, et al. Validation of a pediatric early warning system for hospitalized pediatric oncology patients in a resource-limited setting. Cancer. 2017;123:4903–13. Scholar
  3. 3.
    Sano H, Kobayashi R, Iguchi A, et al. Risk factors for sepsis-related death in children and adolescents with hematologic and malignant diseases. J Microbiol Immunol Infect = Wei mian yu gan ran za zhi. 2017;50:232–8. Scholar
  4. 4.
    Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368–77. Scholar
  5. 5.
    Kalil AC, Johnson DW, Lisco SJ, et al. Early goal-directed therapy for sepsis: a novel solution for discordant survival outcomes in clinical trials. Crit Care Med. 2017;45:607–14. Scholar
  6. 6.
    Investigators P, Rowan KM, Angus DC, et al. Early, goal-directed therapy for septic shock – a patient-level meta-analysis. N Engl J Med. 2017;376:2223–34. Scholar
  7. 7.
    Han YY, Carcillo JA, Dragotta MA, et al. Early reversal of pediatric-neonatal septic shock by community physicians is associated with improved outcome. Pediatrics. 2003;112:793–9.CrossRefGoogle Scholar
  8. 8.
    Inwald DP, Tasker RC, Peters MJ, et al. Emergency management of children with severe sepsis in the United Kingdom: the results of the Paediatric Intensive Care Society sepsis audit. Arch Dis Child. 2009;94:348–53. Scholar
  9. 9.
    Oliveira CF, Nogueira de Sa FR, Oliveira DS, et al. Time- and fluid-sensitive resuscitation for hemodynamic support of children in septic shock: barriers to the implementation of the American College of Critical Care Medicine/Pediatric advanced life support guidelines in a pediatric intensive care unit in a developing world. Pediatr Emerg Care. 2008;24:810–5. Scholar
  10. 10.
    Gelbart B, Glassford NJ, Bellomo R. Fluid bolus therapy-based resuscitation for severe sepsis in hospitalized children: a systematic review. Pediatr Crit Care Med. 2015;16:e297–307. Scholar
  11. 11.
    Brierley J, Carcillo JA, Choong K, et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med. 2009;37:666–88. Scholar
  12. 12.
    Davis AL, Carcillo JA, Aneja RK, et al. American College of Critical Care Medicine clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock. Crit Care Med. 2017;45:1061–93. Scholar
  13. 13.
    Akech S, Ledermann H, Maitland K. Choice of fluids for resuscitation in children with severe infection and shock: systematic review. Br Med J. 2010;341:c4416. Scholar
  14. 14.
    Emrath ET, Fortenberry JD, Travers C, et al. Resuscitation with balanced fluids is associated with improved survival in pediatric severe sepsis. Crit Care Med. 2017;45:1177–83. Scholar
  15. 15.
    Weiss SL, Keele L, Balamuth F, et al. Crystalloid fluid choice and clinical outcomes in pediatric sepsis: a matched retrospective cohort study. J Pediatr. 2017;182:304–10 e310. Scholar
  16. 16.
    Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017;45:486–552. Scholar
  17. 17.
    de Caen AR, Berg MD, Chameides L, et al. Part 12: pediatric advanced life support: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2015;132:S526–42. Scholar
  18. 18.
    Choi SJ, Ha EJ, Jhang WK, et al. Elevated central venous pressure is associated with increased mortality in pediatric septic shock patients. BMC Pediatr. 2018;18:58. Scholar
  19. 19.
    Sankar J, Das RR, Jain A, et al. Prevalence and outcome of diastolic dysfunction in children with fluid refractory septic shock—a prospective observational study. Pediatr Crit Care Med. 2014;15:e370–8. Scholar
  20. 20.
    Lanspa MJ, Pittman JE, Hirshberg EL, et al. Association of left ventricular longitudinal strain with central venous oxygen saturation and serum lactate in patients with early severe sepsis and septic shock. Crit Care. 2015;19:304. Scholar
  21. 21.
    Gan H, Cannesson M, Chandler JR, et al. Predicting fluid responsiveness in children: a systematic review. Anesth Analg. 2013;117:1380–92. Scholar
  22. 22.
    Michard F, Boussat S, Chemla D, et al. Relation between respiratory changes in arterial pulse pressure and fluid responsiveness in septic patients with acute circulatory failure. Am J Respir Crit Care Med. 2000;162:134–8. Scholar
  23. 23.
    Lacroix J, Hebert PC, Hutchison JS, et al. Transfusion strategies for patients in pediatric intensive care units. N Engl J Med. 2007;356:1609–19. Scholar
  24. 24.
    Karam O, Tucci M, Ducruet T, et al. Red blood cell transfusion thresholds in pediatric patients with sepsis. Pediatr Crit Care Med. 2011;12:512–8. Scholar
  25. 25.
    Shieh HH, Barreira ER, Goes PF, et al. Mortality associated with restrictive threshold for red blood cell transfusion in pediatric patients with sepsis. Pediatr Crit Care Med. 2012;13:494–495; author reply 495. Scholar
  26. 26.
    Du Pont-Thibodeau G, Tucci M, Ducruet T, et al. Survey on stated transfusion practices in PICUs*. Pediatr Crit Care Med. 2014;15:409–16. Scholar
  27. 27.
    Mirouse A, Resche-Rigon M, Lemiale V, et al. Red blood cell transfusion in the resuscitation of septic patients with hematological malignancies. Ann Intensive Care. 2017;7:62. Scholar
  28. 28.
    Shah N, Andrews J, Goodnough LT. Transfusions for anemia in adult and pediatric patients with malignancies. Blood Rev. 2015;29:291–9. Scholar
  29. 29.
    Azoulay E, Pickkers P, Soares M, et al. Acute hypoxemic respiratory failure in immunocompromised patients: the Efraim multinational prospective cohort study. Intensive Care Med. 2017;43:1808–19. Scholar
  30. 30.
    Lemiale V, Resche-Rigon M, Mokart D, et al. High-flow nasal cannula oxygenation in immunocompromised patients with acute hypoxemic respiratory failure: a groupe de recherche respiratoire en reanimation onco-hematologique study. Crit Care Med. 2017;45:e274–80. Scholar
  31. 31.
    Neuschwander A, Lemiale V, Darmon M, et al. Noninvasive ventilation during acute respiratory distress syndrome in patients with cancer: trends in use and outcome. J Crit Care. 2017;38:295–9. Scholar
  32. 32.
    Rowan CM, Smith LS, Loomis A, et al. Pediatric acute respiratory distress syndrome in pediatric allogeneic hematopoietic stem cell transplants: a multicenter study. Pediatr Crit Care Med. 2017;18:304–9. Scholar
  33. 33.
    Antonucci E, Fiaccadori E, Donadello K, et al. Myocardial depression in sepsis: from pathogenesis to clinical manifestations and treatment. J Crit Care. 2014;29:500–11. Scholar
  34. 34.
    Fernandes CJ Jr, Akamine N, Knobel E. Myocardial depression in sepsis. Shock. 2008;30(Suppl 1):14–7. Scholar
  35. 35.
    Ramaswamy KN, Singhi S, Jayashree M, et al. Double-blind randomized clinical trial comparing dopamine and epinephrine in pediatric fluid-refractory hypotensive septic shock. Pediatr Crit Care Med. 2016;17:e502–12. Scholar
  36. 36.
    Ventura AM, Shieh HH, Bousso A, et al. Double-blind prospective randomized controlled trial of dopamine versus epinephrine as first-line vasoactive drugs in pediatric septic shock. Crit Care Med. 2015;43:2292–302. Scholar
  37. 37.
    Vasu TS, Cavallazzi R, Hirani A, et al. Norepinephrine or dopamine for septic shock: systematic review of randomized clinical trials. J Intensive Care Med. 2012;27:172–8. Scholar
  38. 38.
    Ranjit S, Natraj R, Kandath SK, et al. Early norepinephrine decreases fluid and ventilatory requirements in pediatric vasodilatory septic shock. Indian J Crit Care Med. 2016;20:561–9. Scholar
  39. 39.
    Loar RW, Noel CV, Tunuguntla H, et al. State of the art review: chemotherapy-induced cardiotoxicity in children. Congenit Heart Dis. 2018;13:5–15. Scholar
  40. 40.
    Barbaro RP, Paden ML, Guner YS, et al. Pediatric extracorporeal life support organization registry international report 2016. ASAIO J. 2017;63:456–63. Scholar
  41. 41.
    Gow KW, Heiss KF, Wulkan ML, et al. Extracorporeal life support for support of children with malignancy and respiratory or cardiac failure: the extracorporeal life support experience. Crit Care Med. 2009;37:1308–16. Scholar
  42. 42.
    Roussos C, Macklem PT. The respiratory muscles. N Engl J Med. 1982;307:786–97. Scholar
  43. 43.
    Stock MC, Davis DW, Manning JW, et al. Lung mechanics and oxygen consumption during spontaneous ventilation and severe heart failure. Chest. 1992;102:279–83.CrossRefGoogle Scholar
  44. 44.
    Delbove A, Darreau C, Hamel JF, et al. Impact of endotracheal intubation on septic shock outcome: a post hoc analysis of the SEPSISPAM trial. J Crit Care. 2015;30:1174–8. Scholar
  45. 45.
    Jung B, Clavieras N, Nougaret S, et al. Effects of etomidate on complications related to intubation and on mortality in septic shock patients treated with hydrocortisone: a propensity score analysis. Crit Care. 2012;16:R224. Scholar
  46. 46.
    Dmello D, Taylor S, O’Brien J, et al. Outcomes of etomidate in severe sepsis and septic shock. Chest. 2010;138:1327–32. Scholar
  47. 47.
    Eisen DP. Manifold beneficial effects of acetyl salicylic acid and nonsteroidal anti-inflammatory drugs on sepsis. Intensive Care Med. 2012;38:1249–57. Scholar
  48. 48.
    Aronoff DM. Cyclooxygenase inhibition in sepsis: is there life after death? Mediat Inflamm. 2012;2012:696897. Scholar
  49. 49.
    Janz DR, Bastarache JA, Rice TW, et al. Randomized, placebo-controlled trial of acetaminophen for the reduction of oxidative injury in severe sepsis: the Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis trial. Crit Care Med. 2015;43:534–41. Scholar
  50. 50.
    Lee BH, Inui D, Suh GY, et al. Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study. Crit Care. 2012;16:R33. Scholar
  51. 51.
    Mallat J, Michel D, Salaun P, et al. Defining metabolic acidosis in patients with septic shock using Stewart approach. Am J Emerg Med. 2012;30:391–8. Scholar
  52. 52.
    Deep A, Goonasekera CD, Wang Y, et al. Evolution of haemodynamics and outcome of fluid-refractory septic shock in children. Intensive Care Med. 2013;39:1602–9. Scholar
  53. 53.
    Brierley J, Peters MJ. Distinct hemodynamic patterns of septic shock at presentation to pediatric intensive care. Pediatrics. 2008;122:752–9. Scholar
  54. 54.
    Raimer PL, Han YY, Weber MS, et al. A normal capillary refill time of </= 2 seconds is associated with superior vena cava oxygen saturations of >/= 70%. J Pediatr. 2011;158:968–72. Scholar
  55. 55.
    Sankar J, Sankar MJ, Suresh CP, et al. Early goal-directed therapy in pediatric septic shock: comparison of outcomes “with” and “without” intermittent superior venacaval oxygen saturation monitoring: a prospective cohort study*. Pediatr Crit Care Med. 2014;15:e157–67. Scholar
  56. 56.
    Boulain T, Garot D, Vignon P, et al. Prevalence of low central venous oxygen saturation in the first hours of intensive care unit admission and associated mortality in septic shock patients: a prospective multicentre study. Crit Care. 2014;18:609. Scholar
  57. 57.
    Proulx F, Lemson J, Choker G, et al. Hemodynamic monitoring by transpulmonary thermodilution and pulse contour analysis in critically ill children. Pediatr Crit Care Med. 2011;12:459–66. Scholar
  58. 58.
    Handrup MM, Moller JK, Rutkjaer C, et al. Importance of blood cultures from peripheral veins in pediatric patients with cancer and a central venous line. Pediatr Blood Cancer. 2015;62:99–102. Scholar
  59. 59.
    Scheinemann K, Ethier MC, Dupuis LL, et al. Utility of peripheral blood cultures in bacteremic pediatric cancer patients with a central line. Support Care Cancer. 2010;18:913–9. Scholar
  60. 60.
    Blot F, Schmidt E, Nitenberg G, et al. Earlier positivity of central-venous- versus peripheral-blood cultures is highly predictive of catheter-related sepsis. J Clin Microbiol. 1998;36:105–9.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Weiss SL, Fitzgerald JC, Balamuth F, et al. Delayed antimicrobial therapy increases mortality and organ dysfunction duration in pediatric sepsis. Crit Care Med. 2014;42:2409–17. Scholar
  62. 62.
    Han M, Fitzgerald JC, Balamuth F, et al. Association of delayed antimicrobial therapy with one-year mortality in pediatric sepsis. Shock. 2017;48:29–35. Scholar
  63. 63.
    Celebi S, Sezgin ME, Cakir D, et al. Catheter-associated bloodstream infections in pediatric hematology-oncology patients. Pediatr Hematol Oncol. 2013;30:187–94. Scholar
  64. 64.
    Slade M, Goldsmith S, Romee R, et al. Epidemiology of infections following haploidentical peripheral blood hematopoietic cell transplantation. Transpl Infect Dis. 2017;19 Scholar
  65. 65.
    Chang AK, Foca MD, Jin Z, et al. Bacterial bloodstream infections in pediatric allogeneic hematopoietic stem cell recipients before and after implementation of a central line-associated bloodstream infection protocol: a single-center experience. Am J Infect Control. 2016;44:1650–5. Scholar
  66. 66.
    Sim SA, Leung VKY, Ritchie D, et al. Viral respiratory tract infections in allogeneic hematopoietic stem cell transplantation recipients in the era of molecular testing. Biol Blood Marrow Transplant. 2018; Scholar
  67. 67.
    Hiwarkar P, Gaspar HB, Gilmour K, et al. Impact of viral reactivations in the era of pre-emptive antiviral drug therapy following allogeneic haematopoietic SCT in paediatric recipients. Bone Marrow Transplant. 2013;48:803–8. Scholar
  68. 68.
    Steinbach WJ, Roilides E, Berman D, et al. Results from a prospective, international, epidemiologic study of invasive candidiasis in children and neonates. Pediatr Infect Dis J. 2012;31:1252–7. Scholar
  69. 69.
    Wattier RL, Dvorak CC, Hoffman JA, et al. A prospective, international cohort study of invasive mold infections in children. J Pediatr Infect Dis Soc. 2015;4:313–22. Scholar
  70. 70.
    Alexander MD, Rao KV, Khan TS, et al. ReCAP: pharmacists’ impact in hematopoietic stem-cell transplantation: economic and humanistic outcomes. J Oncol Pract. 2016;12:147–148, e118–126. Scholar
  71. 71.
    Lucena M, Bondarenka C, Luehrs-Hayes G, et al. Evaluation of a medication intensity screening tool used in malignant hematology and bone marrow transplant services to identify patients at risk for medication-related problems. J Oncol Pharm Pract. 2018;24:243–52. Scholar
  72. 72.
    El-Nawawy A, Khater D, Omar H, et al. Evaluation of early corticosteroid therapy in management of pediatric septic shock in pediatric intensive care patients: a randomized clinical study. Pediatr Infect Dis J. 2017;36:155–9. Scholar
  73. 73.
    Markovitz BP, Goodman DM, Watson RS, et al. A retrospective cohort study of prognostic factors associated with outcome in pediatric severe sepsis: what is the role of steroids? Pediatr Crit Care Med. 2005;6:270–4. Scholar
  74. 74.
    Zimmerman JJ, Williams MD. Adjunctive corticosteroid therapy in pediatric severe sepsis: observations from the RESOLVE study. Pediatr Crit Care Med. 2011;12:2–8. Scholar
  75. 75.
    Atkinson SJ, Cvijanovich NZ, Thomas NJ, et al. Corticosteroids and pediatric septic shock outcomes: a risk stratified analysis. PLoS One. 2014;9:e112702. Scholar
  76. 76.
    Weiss SL, Fitzgerald JC, Pappachan J, et al. Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study. Am J Respir Crit Care Med. 2015;191:1147–57. Scholar
  77. 77.
    Menon K, McNally JD, Choong K, et al. A cohort study of pediatric shock: frequency of corticosteriod use and association with clinical outcomes. Shock. 2015;44:402–9. Scholar
  78. 78.
    Wong HR, Cvijanovich NZ, Allen GL, et al. Corticosteroids are associated with repression of adaptive immunity gene programs in pediatric septic shock. Am J Respir Crit Care Med. 2014;189:940–6. Scholar
  79. 79.
    Keh D, Trips E, Marx G, et al. Effect of hydrocortisone on development of shock among patients with severe sepsis: the HYPRESS randomized clinical trial. JAMA. 2016;316:1775–85. Scholar
  80. 80.
    Zimmerman JJ. Adjunctive steroid therapy for treatment of pediatric septic shock. Pediatr Clin N Am. 2017;64:1133–46. Scholar
  81. 81.
    Phillips R, Hancock B, Graham J, et al. Prevention and management of neutropenic sepsis in patients with cancer: summary of NICE guidance. Br Med J. 2012;345:e5368. Scholar
  82. 82.
    Price TH, Boeckh M, Harrison RW, et al. Efficacy of transfusion with granulocytes from G-CSF/dexamethasone-treated donors in neutropenic patients with infection. Blood. 2015;126:2153–61. Scholar
  83. 83.
    Yoshihara S, Kato R, Inoue T, et al. Successful treatment of life-threatening human herpesvirus-6 encephalitis with donor lymphocyte infusion in a patient who had undergone human leukocyte antigen-haploidentical nonmyeloablative stem cell transplantation. Transplantation. 2004;77:835–8.CrossRefGoogle Scholar
  84. 84.
    Bao L, Cowan MJ, Dunham K, et al. Adoptive immunotherapy with CMV-specific cytotoxic T lymphocytes for stem cell transplant patients with refractory CMV infections. J Immunother. 2012;35:293–8. Scholar
  85. 85.
    Roddie C, Peggs KS. Immunotherapy for transplantation-associated viral infections. J Clin Invest. 2017;127:2513–22. Scholar
  86. 86.
    Group IC, Brocklehurst P, Farrell B, et al. Treatment of neonatal sepsis with intravenous immune globulin. N Engl J Med. 2011;365:1201–11. Scholar
  87. 87.
    Kumagai T, Takeyama N, Yabuki T, et al. Apheresis of activated leukocytes with an immobilized polymyxin B filter in patients with septic shock. Shock. 2010;34:461–6. Scholar
  88. 88.
    Bengsch S, Boos KS, Nagel D, et al. Extracorporeal plasma treatment for the removal of endotoxin in patients with sepsis: clinical results of a pilot study. Shock. 2005;23:494–500.PubMedGoogle Scholar
  89. 89.
    Goldstein B, Nadel S, Peters M, et al. ENHANCE: results of a global open-label trial of drotrecogin alfa (activated) in children with severe sepsis. Pediatr Crit Care Med. 2006;7:200–11. Scholar
  90. 90.
    Dalton HJ, Carcillo JA, Woodward DB, et al. Biomarker response to drotrecogin alfa (activated) in children with severe sepsis: results from the RESOLVE clinical trial*. Pediatr Crit Care Med. 2012;13:639–45. Scholar
  91. 91.
    Ranieri VM, Thompson BT, Barie PS, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012;366:2055–64. Scholar
  92. 92.
    Rowan CM, Gertz SJ, McArthur J, et al. Invasive mechanical ventilation and mortality in pediatric hematopoietic stem cell transplantation: a multicenter study. Pediatr Crit Care Med. 2016;17:294–302. Scholar
  93. 93.
    Santiago MJ, Lopez-Herce J, Urbano J, et al. Clinical course and mortality risk factors in critically ill children requiring continuous renal replacement therapy. Intensive Care Med. 2010;36:843–9. Scholar
  94. 94.
    Hall MW, Knatz NL, Vetterly C, et al. Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome. Intensive Care Med. 2011;37:525–32. Scholar
  95. 95.
    Mehrholz J, Thomas S, Burridge JH, et al. Fitness and mobility training in patients with Intensive Care Unit-acquired muscle weakness (FITonICU): study protocol for a randomised controlled trial. Trials. 2016;17:559. Scholar
  96. 96.
    Zinter MS, Holubkov R, Steurer MA, et al. Pediatric hematopoietic cell transplant patients who survive critical illness frequently have significant but recoverable decline in functional status. Biol Blood Marrow Transplant. 2018;24:330–6. Scholar
  97. 97.
    Ammann RA, Hirt A, Luthy AR, et al. Identification of children presenting with fever in chemotherapy-induced neutropenia at low risk for severe bacterial infection. Med Pediatr Oncol. 2003;41:436–43. Scholar
  98. 98.
    Hakim H, Flynn PM, Srivastava DK, et al. Risk prediction in pediatric cancer patients with fever and neutropenia. Pediatr Infect Dis J. 2010;29:53–9. Scholar
  99. 99.
    Santolaya ME, Alvarez AM, Becker A, et al. Prospective, multicenter evaluation of risk factors associated with invasive bacterial infection in children with cancer, neutropenia, and fever. J Clin Oncol. 2001;19:3415–21. Scholar
  100. 100.
    Tezcan G, Kupesiz A, Ozturk F, et al. Episodes of fever and neutropenia in children with cancer in a tertiary care medical center in Turkey. Pediatr Hematol Oncol. 2006;23:217–29. Scholar
  101. 101.
    West DC, Marcin JP, Mawis R, et al. Children with cancer, fever, and treatment-induced neutropenia: risk factors associated with illness requiring the administration of critical care therapies. Pediatr Emerg Care. 2004;20:79–84.CrossRefGoogle Scholar
  102. 102.
    Ramzi J, Mohamed Z, Yosr B, et al. Predictive factors of septic shock and mortality in neutropenic patients. Hematology. 2007;12:543–8. Scholar
  103. 103.
    Neutropenic sepsis: prevention and management of neutropenic sepsis in cancer patients. London; 2012.
  104. 104.
    Ammann RA, Bodmer N, Hirt A, et al. Predicting adverse events in children with fever and chemotherapy-induced neutropenia: the prospective multicenter SPOG 2003 FN study. J Clin Oncol. 2010;28:2008–14. Scholar
  105. 105.
    Hargrave DR, Hann II, Richards SM, et al. Progressive reduction in treatment-related deaths in Medical Research Council childhood lymphoblastic leukaemia trials from 1980 to 1997 (UKALL VIII, X and XI). Br J Haematol. 2001;112:293–9.CrossRefGoogle Scholar
  106. 106.
    Pui CH, Sandlund JT, Pei D, et al. Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children’s Research Hospital. Blood. 2004;104:2690–6. Scholar
  107. 107.
    Rungoe C, Malchau EL, Larsen LN, et al. Infections during induction therapy for children with acute lymphoblastic leukemia. The role of sulfamethoxazole-trimethoprim (SMX-TMP) prophylaxis. Pediatr Blood Cancer. 2010;55:304–8. Scholar
  108. 108.
    Lindell RB, Gertz SJ, Rowan CM, et al. High levels of morbidity and mortality among pediatric hematopoietic cell transplant recipients with severe sepsis: insights from the sepsis PRevalence, OUtcomes, and therapies international point prevalence study. Pediatr Crit Care Med. 2017;18:1114–25. Scholar
  109. 109.
    Tamburro R. Pediatric cancer patients in clinical trials of sepsis: factors that predispose to sepsis and stratify outcome. Pediatr Crit Care Med. 2005;6:S87–91. Scholar
  110. 110.
    Ogonek J, Kralj Juric M, Ghimire S, et al. Immune reconstitution after allogeneic hematopoietic stem cell transplantation. Front Immunol. 2016;7:507. Scholar
  111. 111.
    Bosch M, Khan FM, Storek J. Immune reconstitution after hematopoietic cell transplantation. Curr Opin Hematol. 2012;19:324–35. Scholar
  112. 112.
    Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial. N Engl J Med. 1986;314:1593–9. Scholar
  113. 113.
    Miller ST. How I treat acute chest syndrome in children with sickle cell disease. Blood. 2011;117:5297–305. Scholar
  114. 114.
    Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med. 2000;342:1855–65. Scholar
  115. 115.
    Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312:1033–48. Scholar
  116. 116.
    Morimoto A, Nakazawa Y, Ishii E. Hemophagocytic lymphohistiocytosis: pathogenesis, diagnosis, and management. Pediatr Int. 2016;58:817–25. Scholar
  117. 117.
    Weitzman S. Approach to hemophagocytic syndromes. Hematol Am Soc Hematol Educ Program. 2011;2011:178–83. Scholar
  118. 118.
    Pihusch R, Holler E, Muhlbayer D, et al. The impact of antithymocyte globulin on short-term toxicity after allogeneic stem cell transplantation. Bone Marrow Transplant. 2002;30:347–54. Scholar
  119. 119.
    Feng X, Scheinberg P, Biancotto A, et al. In vivo effects of horse and rabbit antithymocyte globulin in patients with severe aplastic anemia. Haematologica. 2014;99:1433–40. Scholar

Copyright information

© Springer International Publishing 2019

Authors and Affiliations

  1. 1.Division of Critical Care Medicine and Department of Bone Marrow TransplantationSt. Jude Children’s Research HospitalMemphisUSA
  2. 2.Department of Pediatrics, Division of Critical Care Medicine, UCSF Benioff Children’s HospitalsUniversity of California, San FranciscoSan FranciscoUSA

Personalised recommendations