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Journal of Clinical Oncology, Vol 22, No 7 (April 1), 2004: pp. 1222-1227 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.09.108 Predictors of Viridans Streptococcal Shock Syndrome in Bacteremic Children With Cancer and Stem-Cell Transplant RecipientsFrom the Divisions of Hematology/Oncology and Infectious Disease, Department of Pediatrics, and Departments of Microbiology and Laboratory Medicine and Pharmacy, Hospital for Sick Children, Toronto, Ontario, Canada. Address reprint requests to Lillian Sung, MD, Division of Hematology/Oncology, Hospital for Sick Children, 555 University Ave, Toronto, Ontario, M5G 1X8 Canada; e-mail: Lillian.sung{at}sickkids.ca
PURPOSE: To describe episodes of viridans streptococcal bacteremia (VSB) in a cohort of children with cancer and stem-cell transplant (SCT) recipients and to determine predictors of viridans streptococcal shock syndrome (VSSS) in this group of children.
PATIENTS AND METHODS: For this retrospective review, we included episodes of VSB isolated between March 1997 and September 2002, in children ( RESULTS: Eighty-eight episodes of VSB occurred in 79 children. The mean age of the children was 6.7 years (range, 0.6 to 18.0 years). The most common underlying diagnosis was acute myelogenous leukemia (AML) in 31 (35%) of 88 episodes, and 38 (43%) of 88 had undergone SCT. VSSS occurred in 16 (18%) of 88 episodes, and two children died from VSSS. Two variables were predictive of VSSS, namely peak temperature at presentation (odds ratio [OR], 6.3; 95% CI, 2.1 to 19.0; P = .001) and inpatient status (OR, 5.9; 95% CI, 1.3 to 28.0; P = .02). Diagnosis of AML (OR, 1.1; 95% CI, 0.4 to 3.5; P = .8), receipt of SCT (OR, 1.9; 95% CI, 0.6 to 5.7; P = .2), high-dose cytarabine (OR, 0.6; 95% CI, 0.1 to 3.2; P = .6), and mucositis (OR, 0.8; 95% CI, 0.3 to 2.6; P = .7) were not predictive of VSSS. CONCLUSION: VSSS occurred in 18% of episodes of VSB in children with cancer or SCT recipients. Peak temperature before antibiotic therapy and inpatient status were predictive of VSSS.
Viridans group streptococci are important causes of bacteremia in children with cancer and in the hematopoietic stem-cell transplantation (SCT) setting.1-8 Patients with viridans streptococcal infection are known to be at risk of developing a toxic shock-like syndrome or viridans streptococcal shock syndrome (VSSS), characterized by hypotension and acute respiratory distress syndrome (ARDS), which has a mortality rate ranging from 40% to 100%.9 Risk factors for the development of viridans streptococcal bacteremia have been well described and include degree of neutropenia, oral mucositis, high-dose cytarabine administration, antimicrobial prophylaxis with cotrimoxazole or a fluoroquinolone, diagnosis of acute myelogenous leukemia (AML), and administration of antilymphocyte monoclonal antibody.10-16 Risk factors for viridans streptococcal bacteremia in children with febrile neutropenia have also recently been described and include high-dose cytarabine and the presence of pneumonia.17 In contrast to risk factors for viridans streptococcal bacteremia, there are few data regarding predictors of VSSS among children with cancer or patients undergoing SCT, even though children may be at higher risk of VSSS when compared with adults.9,18 Our objectives were to describe episodes of viridans streptococcal bacteremia in a cohort of children with cancer and patients undergoing SCT and to evaluate potential clinical predictors of VSSS in this group of children. Delineation of a high-risk group will facilitate the evaluation of prophylactic or pre-emptive strategies targeted at improving the outcome of these children.
This retrospective study was approved by the Research Ethics Board at the Hospital for Sick Children (HSC). We included all episodes of viridans streptococcal bacteremia between March 1, 1997, and September 1, 2002, in children with cancer or children who had undergone SCT at HSC. HSC is the tertiary care pediatric center for the Greater Toronto area and is the site where all pediatric SCTs are performed for the province of Ontario.
Blood cultures were drawn from a peripheral site and all indwelling catheters in the event of fever, defined as an oral temperature of 38.0°C on two or more occasions over a 12-hour period or a single oral temperature of 38.5°C. Empiric therapy with broad spectrum antibiotics was initiated in the event of fever during neutropenia (absolute neutrophil count
We defined viridans streptococcal bacteremia as episodes with two blood cultures positive for viridans group streptococci. Those with one positive blood culture were also included if the child developed VSSS or, in the absence of VSSS, the bacteremia was treated with
The primary outcome was VSSS, which was defined as hypotension or other evidence of inadequate cardiac output requiring intravascular volume expansion or inotropic support and/or respiratory insufficiency presenting as ARDS necessitating assisted ventilation. Similar to others,20 the diagnosis of ARDS was based on respiratory failure with bilateral pulmonary infiltrates in the absence of cardiac failure or isolation of microorganisms from respiratory specimens. The following variables were examined as potential predictors of VSSS: age, an underlying diagnosis of AML, SCT, and receipt of high-dose cytarabine (defined as
Statistical Analysis
Eighty-eight episodes of viridans streptococcal bacteremia were identified in 79 patients during the study period. Seventy-one patients had one episode of bacteremia, seven children had two episodes, and one child had three episodes. The characteristics of these 88 episodes of bacteremia are listed in Table 1. The most common underlying diagnosis was AML in 31 episodes (35%). A clinical site of infection was associated with bacteremia in seven of these episodes (cellulitis in four episodes and pneumonia in three episodes). Central venous lines (CVLs) were present in 78 episodes, and both central and peripheral cultures were obtained in all cases before the initiation of antibiotic therapy. In 65 episodes, both central and peripheral cultures were positive. Of the 78 episodes with a CVL present, the CVL was removed in 15 cases (19%) because of viridans streptococcal bacteremia (seven were removed because of hemodynamic instability, six were removed because of persistent fever, and two were removed because of persistent bacteremia). The most common empiric therapy for febrile neutropenia was piperacillin and tobramycin in 66 (75%) of episodes. An echocardiogram was performed in 70 episodes to search for infective endocarditis, and cardiac vegetations were not seen in any of these studies. Of the nine recurrent episodes, seven had a CVL present during both the initial and recurrent episode(s).
VSSS occurred in 16 (18%) of 88 episodes. Table 2 shows that two factors were significantly associated with the development of VSSS, namely peak temperature at presentation (odds ratio [OR], 6.3; 95% CI, 2.1 to 19.0; P = .001) and inpatient status at onset of the episode (OR, 5.9; 95% CI, 1.3 to 28.0; P = .02). In a multivariable model, both factors were independently associated with VSSS; the adjusted OR for maximum temperature was 9.7 (95% CI, 2.5 to 37.7; P = .001), and the adjusted OR for inpatient status was 9.1 (95% CI, 1.5 to 54.8; P = .02). Age, diagnosis of AML, chemotherapy with high-dose cytarabine or cyclophosphamide, presence of a CVL, receipt of IVIG, neutropenia, duration of neutropenia, mucositis, and empiric addition of vancomycin and penicillin susceptibility were not significantly associated with VSSS (Table 2). Treatment with SCT versus chemotherapy was also not significantly associated with VSSS (OR, 2.1; 95% CI, 0.7 to 6.8; P = .2). Other variables not associated with VSSS were allogeneic SCT (OR, 1.0; 95% CI, 0.3 to 4.2; P = .9), high-dose cyclophosphamide as conditioning for SCT (OR, 1.8; 95% CI, 0.6 to 5.3; P = .3), and severe mucositis requiring morphine administration (OR, 1.0; 95% CI, 0.3 to 3.5; P = 1.0). The 16 episodes of VSSS are described in detail in Table 3. Two of these 16 episodes resulted in death directly attributed to the viridans streptococcal infection. One child was a 4-year old boy with Philadelphia chromosome–positive acute lymphoblastic leukemia in first remission who developed viridans streptococcal bacteremia on the day of stem-cell infusion during allogeneic transplantation. He rapidly deteriorated at the onset of fever with septic shock and multiorgan failure. The second child was a 3-year-old girl who was receiving chemotherapy for AML. She also rapidly deteriorated with septic shock and multiorgan failure. Both of these patients had recurrent episodes of viridans streptococcal bacteremia, with one patient dying during the second episode and the other patient dying during the third episode.
Our definition of viridans group streptococcal bacteremia incorporated the clinicians' judgment, as implied by treatment with parenteral antibiotics active against viridans group streptococci for at least 7 days for those who did not have two or more positive blood cultures and did not develop VSSS. We repeated the analysis with the more rigorous definition of viridans group streptococcal bacteremia of two positive blood cultures or the presence of VSSS. Using this definition, there were 55 episodes without VSSS and 16 episodes with VSSS. The predictors of VSSS were qualitatively similar, with an OR for peak temperature of 5.4 (95% CI, 1.8 to 16.7; P = .003) and an OR for inpatient status of 4.7 (95% CI, 1.0 to 22.6; P = .056); no other examined variable was significantly associated with VSSS. We also performed an exploratory analysis stratified by chemotherapy and SCT. First, we examined potential predictors of VSSS among the 46 children who had received nonmyeloablative chemotherapy before the episode. Among chemotherapy recipients, peak temperature (OR, 4.2; 95% CI, 0.9 to 18.8; P = .06) and inpatient status (OR, 11.7; 95% CI, 1.2 to 110.8; P = .03) remained predictive of VSSS. In addition, children with AML were more likely to have VSSS (OR, 1.3; 95% CI, 1.1 to 1.7; P = .04). Only one child undergoing chemotherapy received IVIG in the 4 weeks before the episode, and this child did not develop VSSS. The analysis was then repeated for the 38 children who had received SCT before the episode. Among patients undergoing SCT, peak temperature remained significantly related to VSSS (OR, 16.4; 95% CI, 1.8 to 148.9; P = .01). Only two children in this group were outpatients at the onset of the episode, and neither developed VSSS. In the SCT group, IVIG was significantly protective against VSSS. There were 29 children who received IVIG in the 4 weeks before the episode, and four (14%) developed VSSS. In contrast, there were nine children who did not receive IVIG, and five (56%) developed VSSS (OR, 0.1; 95% CI, 0.02 to 0.7; P = .02). There were four children who developed viridans streptococcal bacteremia without receiving chemotherapy within the 4 weeks before the episode, one of whom developed VSSS. This 2.5-year-old girl presented with septic shock and cardiac arrest at diagnosis of pre–B-cell acute lymphoblastic leukemia before the institution of chemotherapy. At the time, she had a WBC count of 8.8 x 109 cells/L, with 80% lymphoblasts and an absolute neutrophil count of 0. No other etiology for the sepsis syndrome was discovered other than a positive blood culture for a viridans group Streptococcus species. She recovered with antibiotic therapy and supportive care.
We found that VSSS occurred in 18% of episodes of viridans streptococcal bacteremia in children with cancer or patients undergoing SCT. Furthermore, peak temperature at presentation and inpatient status were significantly associated with the development of VSSS in these patients. It is important to stress that our study examined predictors of VSSS among those with viridans streptococcal bacteremia and not among children with febrile neutropenia in general. The pathogenesis of VSSS is not entirely clear but may be related to capillary endothelial damage resulting from the release of cytokines such as interleukin-6, interleukin-8, or tumor necrosis factor beta.21 Although a novel toxin has recently been described in a toxic shock–like syndrome caused by Streptococcus mitis in immunocompetent adults,22 no toxin has yet been implicated in the pathogenesis of VSSS in cancer patients. Our results differ somewhat from others who examined predictors of VSSS in other patient populations. For example, Marron et al20 determined that among adults with febrile neutropenia and viridans streptococcal bacteremia, severe oral mucositis, high-dose chemotherapy with cyclophosphamide, and allogeneic SCT were significantly associated with VSSS. In another report, Elting et al16 found that those with profound neutropenia and menstruating women were at higher risk of VSSS among adult cancer patients. A report of patients undergoing SCT that included both adults and children found that only age younger than 15 years was associated with VSSS.18 None of these reports examined peak temperature or inpatient status. We did not find that factors such as neutropenia, mucositis, or the presence of a CVL were related to VSSS. The absence of such an association may be specific to children or alternatively may be related to the limited power of our study. Although previous reports have not examined peak temperature or inpatient status as potential risk factors for VSSS, our findings are not unexpected, as they have both been associated with adverse outcomes in febrile neutropenic patients. Peak oral temperature greater than 39°C has been reported to be a predictor of significant bacterial infection in children with febrile neutropenia in a prospective study.23 Inpatient status is a well-known predictor of serious medical complications in adults with febrile neutropenia24-26 and has more recently been shown to be a risk factor for complications in children with febrile neutropenia.27 We did not find that the empiric addition of vancomycin affected the risk of VSSS. Because of the retrospective nature of our study, we cannot determine whether some children received empiric vancomycin because of subtle signs of VSSS at presentation, and thus we cannot draw conclusions in this regard. The existing literature regarding the effectiveness of empiric vancomycin in viridans streptococcal bacteremia is conflicting. For example, in one report of viridans streptococcal bacteremia among SCT patients, the use of a vancomycin-containing regimen before shock symptoms developed did not improve survival.18 Similarly, the European Organization for Research and Treatment of Cancer found that randomly allocated empiric vancomycin in febrile neutropenia did not affect mortality rates among patients with gram-positive infections.28 Conversely, Elting et al29 found that patients with viridans streptococcal bacteremia who did not receive vancomycin as part of their initial empirical regimen were more likely to die than patients who did receive it. In our series, the two children who died from VSSS had recurrent episodes of viridans streptococcal bacteremia, suggesting that they may have been predisposed to these infections. The prospective examination of genetic markers of susceptibility to viridans streptococcal infections, such as single nucleotide polymorphisms in genes related to innate immunity, may be of interest for future research. The results of the stratified analysis in chemotherapy recipients and patients undergoing SCT must be regarded as hypothesis generating. Nonetheless, it is interesting that the receipt of IVIG within 4 weeks of the episode seemed to be protective against VSSS in patients undergoing SCT. There is evidence that IVIG can reduce mortality in bacterial sepsis or septic shock.30 In addition, IVIG may improve outcome31 and survival32 in streptococcal toxic shock syndrome. If VSSS is pathophysiologically similar to group A streptococcal toxic shock syndrome, then IVIG may have a role in prevention or treatment. However, further research is warranted before conclusions can be drawn. In our series of 88 episodes of viridans streptococcal bacteremia, 80% underwent echocardiography and no cases of infective endocarditis were established. Our finding suggests that echocardiograms performed to examine for endocarditis could be reserved for those at higher risk, such as patients with congenital heart disease or those in whom endocarditis is clinically suspected. Our findings must be interpreted in light of our study's retrospective design and relatively small sample size. In addition, viridans streptococcal speciation is not routinely performed in our institution and was therefore unavailable to us. However, most reports have concluded that the particular species does not impact on the outcome or risk of VSSS in patients with viridans streptococcal bacteremia.18,20 We observed that VSSS occurred in 18% of our children with cancer or SCT patients with viridans streptococcal bacteremia. Children at high risk of viridans streptococcal bacteremia who present with high fever or who are inpatients when they develop fever merit careful observation and may benefit from interventions to prevent or attenuate VSSS. Further prospective research is required to identify effective interventions to improve outcomes in children who are at risk of developing VSSS.
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Pizzo PA, Ladisch S, Witebsky FG: Alpha-hemolytic streptococci: Clinical significance in the cancer patient. Med Pediatr Oncol 4:367-370, 1978[Medline] 2. Hoecker JL, Pickering LK, Groschel D, et al: Streptococcus salivarius sepsis in children with malignancies. J Pediatr 92:337-338, 1978[CrossRef][Medline] 3. Bochud PY, Eggiman P, Calandra T, et al: Bacteremia due to viridans streptococcus in neutropenic patients with cancer: Clinical spectrum and risk factors. Clin Infect Dis 18:25-31, 1994[Medline] 4. Henslee J, Bostrom B, Weisdorf D, et al: Streptococcal sepsis in bone marrow transplant patients. Lancet 1:393, 1984 5. Villablanca JG, Steiner M, Kersey J, et al: The clinical spectrum of infections with viridans streptococci in bone marrow transplant patients. Bone Marrow Transplant 5:387-393, 1990[Medline] 6. Martino R, Manteiga R, Sanchez I, et al: Viridans streptococcal shock syndrome during bone marrow transplantation. Acta Haematol 94:69-73, 1995[Medline] 7. Bilgrami S, Feingold JM, Dorsky D, et al: Streptococcus viridans bacteremia following autologous peripheral blood stem cell transplantation. Bone Marrow Transplant 21:591-595, 1998[CrossRef][Medline] 8. Hann I, Viscoli C, Paesmans M, et al: A comparison of outcome from febrile neutropenic episodes in children compared with adults: Results from four EORTC studies—International Antimicrobial Therapy Cooperative Group (IATCG) of the European Organization for Research and Treatment of Cancer (EORTC). Br J Haematol 99:580-588, 1997[CrossRef][Medline] 9. Martino R, Subira M, Manteiga R, et al: Viridans streptococcal bacteremia and viridans streptococcal shock syndrome in neutropenic patients: Comparison between children and adults receiving chemotherapy or undergoing bone marrow transplantation. Clin Infect Dis 20:476-477, 1995[Medline] 10. Bochud PY, Calandra T, Francioli P: Bacteremia due to viridans streptococci in neutropenic patients: A review. Am J Med 97:256-264, 1994[CrossRef][Medline] 11. Shenep JL: Viridans-group streptococcal infections in immunocompromised hosts. Int J Antimicrob Agents 14:129-135, 2000[CrossRef][Medline] 12. Rossetti F, Cesaro S, Putti MC, et al: High-dose cytosine arabinoside and viridans streptococcus sepsis in children with leukemia. Pediatr Hematol Oncol 12:387-392, 1995[Medline] 13. Engelhard D, Elishoov H, Or R, et al: Cytosine arabinoside as a major risk factor for Streptococcus viridans septicemia following bone marrow transplantation: A 5-year prospective study. Bone Marrow Transplant 16:565-570, 1995[Medline] 14. Persson L, Vikerfors T, Sjoberg L, et al: Increased incidence of bacteraemia due to viridans streptococci in an unselected population of patients with acute myeloid leukaemia. Scand J Infect Dis 32:615-621, 2000[CrossRef][Medline] 15. Kern W, Kurrle E, Schmeiser T: Streptococcal bacteremia in adult patients with leukemia undergoing aggressive chemotherapy: A review of 55 cases. Infection 18:138-145, 1990[CrossRef][Medline] 16. Elting LS, Bodey GP, Keefe BH: Septicemia and shock syndrome due to viridans streptococci: A case-control study of predisposing factors. Clin Infect Dis 14:1201-1207, 1992[Medline] 17. Paganini H, Staffolani V, Zubizarreta P, et al: Viridans streptococci bacteraemia in children with fever and neutropenia: A case-control study of predisposing factors. Eur J Cancer 39:1284-1289, 2003 18. Steiner M, Villablanca J, Kersey J, et al: Viridans streptococcal shock in bone marrow transplantation patients. Am J Hematol 42:354-358, 1993[Medline] 19. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Susceptibiltiy Testing (ed 6). Villanova, PA, National Committee for Clinical Laboratory Standards, 1995 20. Marron A, Carratala J, Gonzalez-Barca E, et al: Serious complications of bacteremia caused by Viridans streptococci in neutropenic patients with cancer. Clin Infect Dis 31:1126-1130, 2000[CrossRef][Medline] 21. Soto A, McWhinney PH, Kibbler CC, et al: Cytokine release and mitogenic activity in the viridans streptococcal shock syndrome. Cytokine 10:370-376, 1998[CrossRef][Medline]
22. Lu HZ, Weng XH, Zhu B, et al: Major outbreak of toxic shock-like syndrome caused by Streptococcus mitis. J Clin Microbiol 41:3051-3055, 2003
23. Klaassen RJ, Goodman TR, Pham B, et al: "Low-risk" prediction rule for pediatric oncology patients presenting with fever and neutropenia. J Clin Oncol 18:1012-1019, 2000
24. Klastersky J, Paesmans M, Rubenstein EB, et al: The Multinational Association for Supportive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 18:3038-3051, 2000
25. Talcott JA, Finberg R, Mayer RJ, et al: The medical course of cancer patients with fever and neutropenia: Clinical identification of a low-risk subgroup at presentation. Arch Intern Med 148:2561-2568, 1988 26. Talcott JA, Siegel RD, Finberg R, et al: Risk assessment in cancer patients with fever and neutropenia: A prospective, two-center validation of a prediction rule. J Clin Oncol 10:316-322, 1992[Abstract] 27. Alexander SW, Wade KC, Hibberd PL, et al: Evaluation of risk prediction criteria for episodes of febrile neutropenia in children with cancer. J Pediatr Hematol Oncol 24:38-42, 2002[CrossRef][Medline] 28. European Organization for Research and Treatment of Cancer (EORTC) International Antimicrobial Therapy Cooperative Group and the National Cancer Institute of Canada-Clinical Trials Group. Vancomycin added to empirical combination antibiotic therapy for fever in granulocytopenic cancer patients. J Infect Dis 163:951-958, 1991[Medline] 29. Elting LS, Rubenstein EB, Rolston KV, et al: Outcomes of bacteremia in patients with cancer and neutropenia: Observations from two decades of epidemiological and clinical trials. Clin Infect Dis 25:247-259, 1997[Medline] 30. Alejandria MM, Lansang MA, Dans LF, et al: Intravenous immunoglobulin for treating sepsis and septic shock. Cochrane Database Syst Rev CD001090, 2002 31. Darenberg J, Ihendyane N, Sjolin J, et al: Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: A European randomized, double-blind, placebo-controlled trial. Clin Infect Dis 37:333-340, 2003[CrossRef][Medline] 32. Kaul R, McGeer A, Norrby-Teglund A, et al: Intravenous immunoglobulin therapy for streptococcal toxic shock syndrome: A comparative observational study—The Canadian Streptococcal Study Group. Clin Infect Dis 28:800-807, 1999[Medline] Submitted September 22, 2003; accepted January 16, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
18 years) with a diagnosis of cancer or SCT patients. The primary outcome was VSSS, defined as hypotension requiring intravascular volume expansion or inotropic support and/or respiratory insufficiency necessitating assisted ventilation. 
7 days of parenteral antibiotics active against viridans group streptococci. Viridans group streptococci were identified by standard phenotypic methods. Antibiotic susceptibility testing was performed according to the National Committee for Clinical Laboratory Standards (NCCLS).
