The incidence of bacteremia following hemopoietic SCT (HSCT) changes over time from the procedure. The first 30 days have the highest incidence, both in autologous and allogeneic HSCT recipients. In the following periods, bacteremia is a frequent complication in allogeneic HSCT, especially from alternative donors. Gram-positive cocci represent the most frequent cause of single-agent bacteremia. Knowledge of epidemiology (incidence and etiology) of bacteremias following HSCT is pivotal for planning management strategies (prevention, diagnosis and therapy) that must be distinct in the different post-transplant period.
The risk of developing bacteremia varies in the different phases following transplantation, pre-engraftment (day 0–30), early post-engraftment (day 31–100) and late post-engraftment (after day 100).
Incidence of bacteremia and risk factors after HSCT
In the pre-engraftment period, neutropenia and mucositis probably represent the most important risk factors4, 5, 6 both in autologous and allogeneic HSCT recipients. A retrospective analysis of the incidence of bacteremia following autologous HSCT in children with high-risk neuroblastoma7 showed that 34% of the procedures were complicated by bacteremia with a rate of 0.43 episodes/100 days of follow-up, but the incidence decreased in the different protocols, probably because of changes in the conditioning regimens. In another retrospective study on the incidence and timing of bacteremia in children undergoing autologous or allogeneic HSCT, this complication was diagnosed in 24% of the autologous HSCT with a rate of 0.11 episodes/100 patient-day at risk.2 The majority of the episodes (90%) were observed in the presence of neutropenia, especially in the first 30 days after the procedure (when 96% of bacteremias diagnosed in neutropenic patients were observed). In allogeneic HSCT, the proportion of bacteremic episodes (32%) and the rate (0.17 episodes/100 patient-days at risk) were higher than after autologous HSCT. However, only 45% of the episodes were diagnosed in the presence of neutropenia, even if the majority of them (76%) were still observed during the pre-engraftment period. However, in a prospective 3-year study on the incidence of fever during neutropenic episodes, performed at Gaslini Children's Hospital, Genoa, Italy, we observed that the proportion of febrile episodes and bacteremias observed in the first 30 days after the procedure was similar in the two types of transplants (Table 1), underlying the role of neutropenia and mucositis as the most important risk factors, independent of the HSCT source. The type of donor (familiar or non-familiar) or the degree of HLA matching (fully or partially) may represent other risk factors for the development of bacteremia after allogeneic HSCT.3, 8, 9, 10, 11 In a retrospective study on the epidemiology of bacteremias in 267 allogeneic HSCTs performed at Gaslini Children's Hospital that compared the incidence of bacteremias stratifying patients according to the type of donor (matched related donor (MRD) or any type of alternative donor (AD)), children receiving transplant from AD had a fourfold higher risk (95% CI 2.7–6.2) of developing bacteremia, compared with recipients of MRD-HSCT. The incidence was higher during the first 30 days after HSCT and especially during the first 20 days, when all episodes occurred in the presence of neutropenia (Figure 1), with a significant difference between AD- and MRD-HSCT recipients.
In the post-engraftment period, bacteremia represents a major problem mainly for allogeneic HSCT recipients,2 because of the presence of many other risk factors. The presence and severity of GvHD and its management (including the use of MoAbs), neutropenia due to poor bone marrow take or transplant rejection, drugs administered for treatment of complications, the presence of functional asplenia, all factors that may be present at the same time or in sequence in the same patient, may further increase the risk of late-onset bacteremias.5 In the aforementioned retrospective analysis of bacteremias in 267 pediatric allogeneic HSCTs, we also observed that in the post-engraftment periods the incidence of bacteremias was higher in AD-HSCT recipients. The incidence of this complication decreased over time, but became similar in the two HSCT groups only after 1 year from the procedure (Figure 2).
A last comment must be made on the role of indwelling central venous catheter (CVC). The presence of these devices represents an important risk factor for the development of bacteremia in cancer patients.12 An HSCT procedure and the use of double lumen CVCs, ordinarily implanted in allogeneic HSCT recipients, have been demonstrated to be independent risk factors for the development of catheter-related infections in children.13 The higher number of catheter manipulations required even for simple maintenance and the number of treatments (and CVC manipulations) needed for GvHD management are probably the main reasons for these observations.2, 12
Etiology of bacteremias
Gram-positive cocci represent the most frequent cause of bacteremia in autologous and allogeneic HSCTs,2, 5, 7, 10 representing nearly two-third of pathogens isolated in single-agent bacteremias. Gram negatives cause nearly 25% of single-agent episodes, but are also frequently isolated in many polymicorbial infections, especially if CVC related.14, 15 The clinical pictures and complications observed in children with these infections are similar to those observed in adults with similar conditions and more, in general, in all cancer patients.16 The only peculiar condition is probably represented by the high incidence of Streptococcus pneumoniae bacteremia observed in late phases after allogeneic HSCT,17 probably related to the presence of functional asplenia in the presence of chronic GvHD.14, 17 However, it must be remembered that local epidemiological factors may play an important role, especially for the presence of peculiar pathogens and antibiotic-resistant patterns.
Practical consequences of epidemiological studies
The knowledge of epidemiology (proportion, rates and etiology) of bacteremia after HSCT has important implications for the patients’ management. The high rate of bacteremias observed during the pre-engraftment neutropenic period (a high number of events in a short period of time) probably justifies the proposal of antibacterial prophylaxis tailored to local epidemiology in this period, even if this procedure has been studied only after autologous18 and not after allogeneic HSCT,19 and no study is available for children. On the other hand, in the following periods, there is a significant number of events, stretched over a long period of time, and this leads to a low rate of infection. As a consequence, during these periods, antibacterial prophylaxis should not be administered, although an empirical therapy for any febrile episode is justifiable, also in the absence of granulocytopenia.14 In any case, management strategies must be implemented taking into account local epidemiological factors, the type of the most frequently isolated pathogens and their susceptibility to antibiotics. The only exception to this strategy may be represented by the prevention of bacteremia due to S. pneumoniae by means of long-term prophylaxis in the presence of functional asplenia or severe chronic GvHD.20 However, this strategy may not be feasible because of the problems with compliance and antibacterial resistance. In these settings, the administration of empirical therapy in any illness, suggestive of the presence of an infection14, 20 and a vaccination program against S. pneumoniae (and other encapsulated bacteria),21 may represent the best choice for patients with prolonged risk.
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Benjamin DK, Miller WC, Bayliff S, Martel L, Alexander KA, Martin PL et al. Infections diagnosed in the first year after pediatric stem cell transplantation. Pediatr Infect Dis J 2002; 21: 227–234.
Sonis ST, Oster G, Fuchs H, Bellm L, Bradford WZ, Edelsberg J et al. Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation. J Clin Oncol 2001; 19: 2201–2205.
Sepkowitz KA . Risk and epidemiology of infections after allogeneic hemopoietic stem cell transplantation. In: Bowden RA, Ljungman P, Paya CV, (eds). Transplant Infections. Lippincott Willians & Wilkins: Philadelphia, 2003, pp 31–38.
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Barker JN, Hough RE, van Burik JA, DeFor TE, MacMillan ML, O’Brien MR et al. Serious infections after unrelated donor transplantation in 136 children: impact of stem cell source. Biol Blood Marrow Transplant 2005; 11: 362–370.
Nagatoshi Y, Kawano Y, Okamura J . Comparison of the outcomes of allogeneic bone marrow transplantation from partially mismatched related donors, matched sibling donors, and matched unrelated donors in Japanese pediatric patients: a single center result. Pediatr Transplant 2004; 8: 260–266.
Nucci M, Andrade F, Vigorito A, Trabasso P, Aranha JF, Maiolino A et al. Infectious complications in patients randomized to receive allogeneic bone marrow or peripheral blood transplantation. Transpl Infect Dis 2003; 5: 167–173.
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Castagnola E, Molinari AC, Fratino G, Viscoli C . Conditions associated with infections of indwelling central venous catheters in cancer patients: a summary. Br J Haematol 2003; 121: 233–239.
Fratino G, Molinari AC, Parodi S, Longo S, Saracco P, Castagnola E et al. Central venous catheter-related complications in children with oncological/hematological diseases: an observational study of 418 devices. Ann Oncol 2005; 16: 648–654.
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Engelhard D, Cordonnier C, Shaw PJ, Parkalli T, Guenther C, Martino R et al. Early and late invasive pneumococcal infection following stem cell transplantation: a European Bone Marrow Transplantation survey. Br J Haematol 2002; 117: 444–450.
Bucaneve G, Micozzi A, Menichetti F, Martino P, Dionisi MS, Martinelli G et al. Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. N Engl J Med 2005; 353: 977–987.
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Conflict of interest
None of the authors declared any financial interests.
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