Infection

What is the clinical significance of positive blood cultures with Aspergillus sp in hematopoietic stem cell transplant recipients? A 23 year experience

Summary:

Hematopoietic stem cell (HSC) transplantation is the most frequent underlying predisposing condition to invasive aspergillosis. However, the significance of positive blood culture with Aspergillus sp in this particular population remains uncertain. We retrospectively reviewed all blood cultures performed in 1453 patients who received HSC transplant at our institution between 1980 and 2002. We identified 19 patients with positive blood cultures with Aspergillus sp. Only one of these patients had clinical, histologic or microbiologic evidence of invasive aspergillosis. Thus, even in a population at highest risk for invasive aspergillosis, positive blood cultures with Aspergillus sp remain unusual, and cannot be readily associated with invasive aspergillosis. A case by case assessment by treating physicians of the clinical and radiologic parameters should be systematically made to establish the significance of aspergillemia. Single bottle positivity, obtained with the lysis-centrifugation blood culture system, is a common indicator of pseudoaspergillemia.

Main

The significance of positive blood cultures with Aspergillus sp varies according to the patient population. In a single-cancer center study, positive blood cultures with Aspergillus sp represented pseudofungemia in all 12 patients with solid tumors, whereas definite or probable aspergillemia was observed in 12 of 24 patients with hematological malignancies.1 In patients with deep-seated pulmonary aspergillosis, true aspergillemia was observed in 10.1% of 89 patients.2 HSC transplantation is the most important underlying predisposing condition to invasive aspergillosis.3 To our knowledge, no study has yet examined the significance of positive blood cultures with Aspergillus sp in this very high-risk population of patients. We report a 23-year single-center retrospective study of positive blood cultures for Aspergillus sp documented in HSC transplant recipients.

Patients and methods

Blood culture records of all patients who underwent an HSC transplantation at Hôpital Maisonneuve-Rosemont (HMR) between April 1980 and December 2002 were reviewed. Over this period, three different blood culture systems have been sequentially used in our microbiology laboratory: a conventional broth manual system from 1980 to 1985, a lysis centrifugation blood culture system (Isolator™ system) from 1985 to 1996, and an automated blood culture system (BacT/Alert™ system) thereafter. Medical records of recipients with Aspergillus sp positive blood cultures were reviewed to determine the clinical significance of these positive blood cultures. Aspergillus sp fungemia was classified as definite, probable or pseudofungemia according to previously proposed criteria.4 Definite Aspergillus sp fungemia was defined as the presence of Aspergillus sp in blood plus histologic or microbiologic evidence of Aspergillus sp in infected tissue; probable aspergillemia was defined as the presence of Aspergillus sp in blood with clinical signs and symptoms compatible with disseminated aspergillosis, but no histopathologic evidence of invasive aspergillosis and pseudofungemia was defined as the presence of Aspergillus sp in blood without compatible signs and symptoms, imaging, culture, or histologic evidence of invasive aspergillosis.

Results

From April 1980 to December 2002, 1453 patients were transplanted at HMR. A total of 939 different episodes of bloodstream infections in 525 (36%) recipients were documented. Of these 525 patients, 377 were allogeneic and 148 autologous transplant. Aspergillemia was observed 23 times in 21 patients. Patients 1 and 10 each had two separate episodes at 3- and 2-month intervals, respectively (Table 1). Median time between the HSC transplantation and positive blood culture with Aspergillus sp was 29 days (range 4–537 days). Aspergillus sp was recovered from a single bottle collected in different sets of blood cultures for all patients. All aspergillemic episodes were observed during the period when the lysis centrifugation blood culture system was used. Aspergillus fumigatus was identified in 11 patients, Aspergillus niger in two patients and nonspeciated Aspergillus in eight patients. Medical records of 19 recipients were available for review. Six patients were on Amphotericin B prophylaxis or treatment at the time of their blood sampling (Table 1). No other anti-aspergillus antifungal drugs were used in any of our patients. Only two patients (patient 17 and 18) died within 30 days following their aspergillemia. Patient 17 had a broncho-pulmonary-obliterans pneumonitis and an intestinal graft-versus-host-disease (GVHD) with severe electrolytic disorders. She died 10 days after her single positive blood culture bottle with Aspergillus. A post-mortem examination revealed diffuse multiorgan lymphomatous infiltrations with no signs of aspergillosis. Patient 18 had compatible pulmonary infiltrates with clinical signs and symptoms and evolution suggestive of a probable invasive aspergillosis. Despite systemic antifungal therapy, this patient suffering from chronic GVHD died 10 days later. An autopsy was not granted. Of the remaining 17 patients, only four received Amphotericin B, mostly for persisting febrile neutropenia, during 5–19 days following the positive blood culture with Aspergillus. These patients along with those untreated patients, had neither clinical nor radiological signs and symptoms compatible with invasive aspergillosis, and therefore their positive blood cultures were categorized as pseudofungemia.

Table 1 Clinical characteristics and significance of positive blood cultures with Aspergillus sp in 19 HSCT recipients

Discussion

In our homogeneous high-risk population of HSC transplant recipients, our results confirm that positive blood cultures with Aspergillus sp are rare and usually clinically insignificant, despite the propensity of Aspergillus to invade the vascular compartment in these immunocompromised hosts. Aspergillus fungemia represented 17% of all fungemias (23 out of 131 cases) observed in our hospital's HSC recipient population during this study's 23-year surveillance period. By comparison, in a similar single-center study conducted over a 17-year period, Aspergillus fungemia accounted for 4% of all fungemias. These, however, were compiled only in non-HSC transplant patients with hematological malignancies.2

Only one of our 19 evaluated patients with positive blood cultures with Aspergillus sp was likely a true fungemia. During our 23-year study period, the incidence of invasive aspergillosis in our HSC recipients remained stable, ranging from 3.8 to 5.4%. Interestingly, all our aspergillemia occurred during the 11-year period when a lysis–centrifugation blood culture system was in use in our microbiology laboratory. During those years, over 23 000 blood cultures were processed with the lysis–centrifugation system. Of these, 0.2% grew a filamentous fungus, most commonly an Aspergillus sp. Despite the fact that all those blood cultures were processed in a laminar air-flow facility, an airborne contamination likely could not be completely avoided. Automated blood culture systems are now commonly used in hospital microbiology laboratories. The adequacy of these systems to recover fungal pathogens from blood cultures has been questioned, and the superiority of the lysis–centrifugation blood culture system has been underlined.5 However, routine procurement of blood cultures with the latter system in febrile neutropenic patients with acute leukemia has shown no advantage over an automated system to detect fungal and bacterial blood pathogens, and has been associated with high degree of contamination.6 Large studies have been conducted with modern automated blood culture systems, but recovery of Aspergillus sp is not documented.7,8,9,10 We have experimentally inoculated as little as one to 10 conidia into blood culture bottles of our current colorimetric automated blood culture system (BacT/Alert™), and systematically detected growth after only 24 h of incubation, hence establishing the ability of the system to support and detect the growth of Aspergillus sp. Vascular invasion characterizes invasive aspergillosis. Aspergillus hyphae are endocytosed by the blood vessel endothelial cells causing progressive endothelial cell injury and thrombosis. Vascular endothelial cells exposed in vitro to killed Aspergillus hyphae continue to cause cell injury and invasion.11 It is likely that the viability of the endocytosed Aspergillus hyphae is considerably impaired, which therefore reduces the potential to recover them through blood cultures.

In conclusion, even in the population of patients with the highest risk for invasive aspergillosis, that is, HSC transplant recipients, positive blood cultures with Aspergillus sp are rare, usually represent pseudofungemia and cannot be readily associated with invasive aspergillosis. Clinical and radiologic assessment of the patients’conditions, number of positive blood cultures and awareness of the type of blood culture system used in the institution should be systematically considered by treating physicians in order to establish the clinical significance of aspergillemia in HSC recipients. Single bottle positivity, obtained with the lysis–centrifugation blood culture system is a common indicator of pseudoaspergillemia.

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Acknowledgements

We thank Catherine Guilbault and Michèle Joseph for their help in retrieving the patients’ data.

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Correspondence to M Laverdière.

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Simoneau, E., Kelly, M., Labbe, A. et al. What is the clinical significance of positive blood cultures with Aspergillus sp in hematopoietic stem cell transplant recipients? A 23 year experience. Bone Marrow Transplant 35, 303–306 (2005). https://doi.org/10.1038/sj.bmt.1704793

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Keywords

  • Aspergillus
  • hematopoietic stem cell (HSC) transplantation
  • bloodstream infections
  • aspergillemia

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