Infectious Complications

Human herpes virus 6 infection is a hallmark of cord blood transplant in adults and may participate to delayed engraftment: a comparison with matched unrelated donors as stem cell source

Abstract

Occurrence of CMV, EBV and human herpes virus 6 (HHV6) infections and immune reconstitution were compared in 15 adult patients receiving a cord blood transplantation (CBT) and 40 patients who received an allogeneic transplantation from a matched unrelated donor (MUD). Herpes virus DNA quantifications in the blood (459 samples) were performed before and then monthly up to 9 months after transplant and the main lymphocytes populations were counted at 3, 6 and 9 months. Incidence of HHV6 infection was significantly higher in the CBT group (80 vs 42.5%; P<0.0001), with higher viral load (P<0.0001). In multivariate analysis, the use of a CBT and a myeloablative conditioning regimen were found to increase the risk of HHV6 infection (odds ratio (OR)=5.4, P=0.02 and OR=3.5, P=0.04, respectively). Incidences of CMV were similar between the two groups whereas MUD increased the risk of EBV infection, in univariate analysis only. HHV6 reactivation translated toward delayed neutrophils and plts engraftment in the two groups. MUD and CBT do not share the same immune reconstitution patterns, notably for B and CD8 lymphocytes and NK cells. There is a strong and specific relationship between HHV6 infection and the use of cord blood cells.

Introduction

Cord blood as a stem cell (SC) source is increasingly accepted as an alternative source of hematopoietic SCs for allogeneic SCT (allo-HSCT) in adult patients with hematological diseases, both in the myeloablative1, 2, 3, 4 and the reduced-intensity conditioning settings.5 However, despite these initial encouraging results, opportunistic infections remain a matter of concern after cord blood transplantation (CBT) as a consequence of delayed hematopoietic and immune reconstitution.1, 2, 3, 4, 6 Indeed, different studies documented a higher incidence of severe bacterial infections accountable for early mortality in adult patients receiving CBT.3, 7, 8 Data related to viral infections after CBT (especially for Herpesviridae) are still relatively scarce. For instance, some investigators described a similar incidence of CMV reactivation after CBT and allo-SCT transplantation using peripheral blood or BM SC.3, 6 In contrast, human herpes virus 6 (HHV6) reactivations appear to occur more frequently after CBT both in children9 and in adults.10, 11

This report aimed to analyze the incidence, features and outcome of CMV, EBV and HHV6 infections in 55 consecutive adult patients receiving unrelated CBT or allo-HSCT from HLA-matched unrelated donors (MUD).

Patients and methods

Study design

In all, 55 consecutive adult patients who received an unrelated allo-HSCT between January 2006 and November 2007 were retrospectively examined for three herpes viruses (CMV, EBV and HHV6) and for immune reconstitution. Allo-HSCT were performed using PBSCs from a MUD group (N=40) or with unrelated umbilical cord blood SCs (CBT group, N=15). Patients were treated in different institutional transplant protocols and gave informed consent. The transplant protocols were approved by the relevant ethical committees and the study was performed according to institutional guidelines.

Among the patients characteristics (Table 1), only the use of thymoglobulin and the number of cells infused differed significantly between the two groups. Administration of Valaciclovir (3 g per day) for prevention of HSV infection was carried out in all patients for at least 3 months after transplant. Foscavir (Astra Zeneca, Rueil-Malmaison, France) or Ganciclovir (Roche, Neuilly/Seine, France) were used pre-emptively in patients showing two successive CMV viral load >3 log/ml or in patients with documented CMV disease. Rituximab (Roche, Welwyn Garden City, UK) 375 mg/m2 per week for 4 weeks was used pre-emptively in patients showing two successive EBV positive PCR >3 log/ml or in patients with refractory chronic GVHD or EBV-associated lymphoma.

Table 1 Patients, disease and transplant characteristics (N=55)

Viral monitoring after allo-hematopoietic SCT and methods

CMV, EBV and HHV6 DNA quantification were performed in the blood of recipients before allo-HSCT, and then on a monthly basis up to 9 months after allo-HSCT. A total number of 459 samples (MUD group, n=335; CBT group, n=124) were evaluated and a median of 10 (range, 3–11) samples was analyzed per patient. In patients who experienced at least one episode of viral infection (see definition section), additional samples were also analyzed to initiate a prophylactic or a curative treatment. HHV6 DNA detections were also performed on all cord blood grafts before allo-HSCT.

Total nucleic acids were extracted from 200 μl EDTA of whole blood in recipients or of cord blood before transplant with a MagNAPure LC instrument and the MagNAPure LC DNA isolation kit (Roche Molecular Biochemicals, Mannheim, Germany) according to the manufacturer's recommendations and stored in a final volume of 100 μl at −20 °C until further analysis.

Herpes virus DNA quantifications were performed using in-house real-time PCR procedures, as described earlier.12, 13 Briefly, CMV (US6 gene), EBV (BNRF1gene) and HHV6 (U65–U66 gene) DNA were quantified on 5 μl DNA extracts and viral loads were expressed as the number of viral DNA copies/ml of blood. Detection limit of the three PCR ranged from 5 to 10 viral genome copies per assay and samples with viral loads over 2 log/ml of blood were considered as positive. The HHV6 PCR also allowed for discrimination between type A and type B. A nested qualitative PCR (detection limit at less than five copies per reaction) was also applied for the detection of HHV6 (U100 gene) on cord blood extracts.14

Definitions

An active infection was defined by at least one positive PCR with a viral load >3 log/ml of blood or two consecutive PCR with a viral load between 2 and 3 log/ml of blood. Herpes virus disease was defined as suggestive symptom from the affected organ, combined with the detection of the herpes virus by histology, isolation or immunochemistry. The presence of chromosomally integrated HHV6 (CI HHV6) was suspected when very high HHV6 DNA load (>6 log/ml) were observed before the graft (recipient with CI HHV6) or rapidly after the graft, at the time of engraftment (CI HHV6 from the donor).15, 16

Neutrophil and plt recoveries were defined as the first of 3 consecutive days during which the ANC in the blood was >0.5 × 109/l and the plt count was >2 × 109/l without transfusion support. Acute and chronic GVHD were graded according to the standard Seattle criteria.17, 18

Immune reconstitution

T, B and NK lymphocytes recovery in the blood was assessed for each patient at 3, 6 and 9 months post transplant. The CD3+, CD4+, CD8+ T cells, the CD19+ B cells and the CD56+ NK lymphocytes were quantified using standard flow cytometry. Igs were quantified (g/l) for each patient in the serum using a standard electrophoresis method.

Statistical analysis

Patients characteristics, transplant related events and the association of each viral infection with relevant variables were evaluated in a univariate analysis, using either the χ2 test or the two-tailed Fisher's exact test, for proportion, and the Wilcoxon test for quantitative data. Multivariable analysis was performed by means of logistic regression analysis, using the criteria to remove factors with P-values >0.05. Data obtained as of 1 September 2008, were included in this analysis. All data were computed using SAS 9.1 (SAS Institute Inc., SAS Campus Drive, Cary, NC, USA) and in all cases, the confidence interval was 95% and values of P<0.05 were considered significant.

Results

The main transplant-related events are summarized in Table 2.

Table 2 Transplant-related events

Herpes virus DNA detection

Among the whole cohort, 29 (53%), 29 (53%) and 22 (40%) patients experienced at least one positive PCR for HHV6, EBV and CMV respectively. In all, 19 (34.5%), 16 (29%) and 9 (16%) patients experienced one, two or the three herpesviruses infections. There was no significant link between the three viral infections. When analyzing the whole collection of 459 samples, percentage of positive samples were 14.1% for CMV, 16.3% for EBV and 26.8% for HHV6. All HHV6 stains were typed as B variant. The majority of HHV6 positive samples (102/123) showed a viral load >3 log/ml. Conversely, the majority of positive samples for EBV (55/75) and CMV (39/65) showed a viral load <3 log/ml.

Distribution of herpes viruses

Human herpes virus 6 infection

All cord blood grafts were tested HHV6 negative. HHV6 infections were more frequent after CBT (80% of patients (n=12/15) vs 42.5% (n=17/40), odd ratio (OR)=4.41, (1.32–22.21), P=0.01). Percentages of positive samples (59% in CBT (73/124) vs 15% (50/335), OR=8.16, (5.11–13.05), P<0.0001) and HHV6 viral loads were also significantly higher in CBT group (mean 3.98±0.86 log/ml, median 4.25 vs mean 3.19±0.82 log/ml, median 3.48, P< 0.0001). By univariate analysis, a myeloablative conditioning regimen (OR=3.57, (1.11–11.48), P=0.02), the use of MTX (OR=5.13, (1.41–18.66), P=0.009) and of TBI (OR=4.47, (1.23–16.28), P=0.01) were associated with an increased frequency of HHV6 infection while the risk decreased when using MMF (OR=0.31, (0.10–1.03), P=0.05) or ATG (OR=0.20, (0.05–0.72), P=0.004). Multivariate analysis identified CB as SCs source (OR=5.45, (1.24–22.99), P=0.02) and a myeloablative regimen (OR=3.52, (1.03–12.05), P=0.04) as the two independent parameters for increasing HHV6 infection.

CMV infection

Prevalence of active CMV infection, in patients at risk for CMV, did not differ among the two groups (CBT 60% vs MUD 79%, P=NS) and was not affected by the other parameters.

EBV infection

In univariate analysis, EBV infection was less frequent among CBT (27 vs 62%, OR=0.22, (0.06–0.81), P=0.01) whereas the use of ATG was found to increase EBV infection (67 vs 33%, OR=3.09, (0.99–10.91), P=0.04). However, the multivariate analysis showed no independent risk factor for EBV infection, especially the SC source.

Kinetics of infections

One patient and one donor were found with probable CI HHV6 15, 16 and the two relative recipients thus excluded from analysis. One patient in the CBT group has lost progressively his own CI HHV6 (at a level over 7 log/ml before the graft then around 2 log/ml at the end of the follow-up) whereas one patient in the MUD group acquired CI HHV6 from his donor, as shown by the rapid increase of viral load and its subsequent maintenance at a level over 6 log/ml (Figure 1).

Figure 1
figure1

Percentage of positive patients at each time of the follow-up according to the source of HSC. Number of patients analyzed for each group ranged from 15 cord blood transplantation (CBT)/39 matched unrelated donor (MUD) at month 0 to 7 CBT/18 MUD at month 9 for human herpes virus 6 (HHV6) and EBV, and from 5 CBT/24 MUD at month 0 to 3 CBT/10 MUD at month 9 for CMV (analysis restricted to patients at risk for CMV). Asterisks indicates significant differences (P<0.05).

Human herpes virus 6 infection started at a median of 36 days (range: 16–74) in CBT as compared with a median of 58 days (range: 24–100) in MUD (P=NS). In CBT, all HHV6 infected patients were still positive at the end of their follow-up as compared with only 41% in MUD (P<0.009). HHV6 viral load was significantly higher in CBT at month 7, 8 and 9 post transplant (Figure 2).

Figure 2
figure2

Comparison with human herpes virus 6 (HHV6) viral load intensity at each time of the follow-up, in cord blood transplantation (CBT) group and matched unrelated donor (MUD) group. Asterisks indicates significant differences (P< 0.05).

EBV infections started at a median of 25 days (range: 12–180), with no significant differences between MUD and CBT. Four patients were positive for EBV before the graft and became negative after transplant. Four patients were still EBV positive at the end of the follow-up (CBT n=1, MUD n=3, P=NS). EBV viral load did not differ significantly between the two groups.

CMV infection started at a median of 36 days (range: 14–78). One patient was positive before the graft and only one MUD patient was still CMV positive at the end of the follow-up. CMV viral load did not differ significantly between the two groups.

Consequences of viral infections

Considering the whole cohort, neutrophil and plt recoveries were significantly delayed in early (before the end of aplasia) HHV6 reactivating patients (median: 37.5 days vs 16.5 days; P=0.03; and median: 98.5 days vs 12.5 days; P=0.0001). For patients who engrafted in CBT (n=10), neutrophil and plt recoveries were also delayed in early reactivating patients (median: 40 days (n=4) vs median 24 days (n=6), P=0.05 and median: 115 days vs 44 days, P=0.09). In MUD who engrafted (n=39), HHV6 infection occurred after neutrophil recovery in all patients except two, whereas in patients showing early HHV6 infection (n=4), plt recovery was significantly delayed (median: 87 days vs 13 days, P=0.003). No significant clinical manifestations because of HHV6 were observed in the two groups, except in one MUD patient where an HHV6 encephalopathy was suspected. In addition, HHV6 was not found to increase the risk of failure, acute GVHD or death after transplant.

Rituximab was administered in 10 patients during the period of follow-up (MUD: EBV infections, n=7; chronic GVHD n=2; CBT: EBV associated lymphoma n=1). Seven (six MUD) patients received pre-emptive antiviral therapy for CMV infection (five of them remained HHV6 positive during therapy). Only one case of CMV disease (colitis and pneumopathy) in MUD was noted, because of a very resistant strain.

Immune Reconstitution

Comparison of immune reconstitution between the two groups is shown in Table 3.

Table 3 Kinetic of immune reconstitution after the transplantation, according to the source of graft

The number (1, 2 or 3) of herpes virus infections did not influence the pattern of immune reconstitution, except for the CD8+ lymphocytes count at 3 months, which was significantly higher among patients with at least one infection (median: 250 × 109/l vs 86 × 109/l, P=0.03). In univariate analysis, when considering the whole cohort: (1) EBV infection was associated with a significant decrease of the number of NK cells at 3 months (median: 117 109/l vs 212 109/l, P=0.04) and of the number of CD4+ lymphocytes at 9 months (median: 118 109/l vs 274 109/l, P=0.04); 2) HHV6 infection was associated with a significant increase of the number of NK cells at 3 months (median: 324 109/l vs 175.5 109/l, P=0.01) and a significant decrease of the number of CD8+ lymphocytes at 6 months (median: 147.5 109/l vs 477 109/l, P=0.02). Multivariate analysis found that only CB as source of graft was significantly associated with an increase of NK cells at 3 months (OR=10.29 (1.06–99.78), P=0.04).

Discussion

The aim of our study was to compare simultaneously the occurrence of three herpesviruses (CMV, EBV and HHV6) infections and the immune reconstitution in adult patients receiving allo-HSCT using cord blood or unrelated PBSCs as SC sources. The originality of our series, although limited by its retrospective design and the small number of cord blood patients, consisted in the evaluation, for a period up to 9 months post transplant, of two well-matched cohorts. Thus, simultaneous monitoring of herpes viruses in the setting of unrelated CBT have only been studied in children series19 but not in adults whereas immune reconstitution has been poorly studied in the setting of CBT.6

Our results showed only a significant association between HHV6 infection and CBT by multivariate analysis. For EBV and CMV, our study confirmed previous data, notably the increased risk of EBV infection in patients receiving ATG20 and the absence of influence of the graft source on CMV infection.21

Human herpes virus 6 was discovered in 1986 and two subtypes can be found, type A and type B. HHV6-B is extremely widespread in the population and infects almost all children within the first few years of life establishing latency after primary infection.22 As expected, none of the cord blood used in this study showed HHV6 positivity23 and all HHV6 infections were because of the type B virus.22 Thus, we postulate that HHV6 originates from the reactivation of endogenous HHV6. Compared with MUD, in which the results were in the range of most reported studies,22, 24, 25 CBT showed a significant by higher incidence and an higher median viral load of HHV6 infections and for a longer period of time after transplant. It was described earlier in three studies but with a short follow-up post transplant.9, 10, 11

Risk factors for developing HHV6 infection after allo-HSCT have been studied showing discordant results. Comparison of BM and PBSCs as SC source was shown to be26 or not to be27 a risk factor for HHV6 infection after allo-HSCT. Contrary to our results, the intensity of the conditioning regimen showed no influence in the series of Yamane et al.11 In contrast, transplants from unrelated and mismatched donors were shown to be the strongest factor to develop HHV6 infection after allo-HSCT in comparison with related transplant,9, 11, 27 maybe because of a higher prolonged immune deficiency and/or higher incidence of acute GVHD. In our series, both groups received transplants from unrelated donor and GVHD incidence was similar. Thus, in this particular setting, the use of unrelated CB as SC source shows the potential to independently worsen the risk of HHV6 after allo-transplant in adults. Characteristics of cord blood graft are the limited nucleated cell dose, the presence of immature T cells with impaired capacity for cytokine production and diminished lytic activity and the very low level of contamination with herpesviruses.28, 29, 30 Thus, the absence of specific primed HHV6T cells in CB may be one plausible explanation for this higher incidence of HHV6 infection. However, the absence of specific primed CMV or EBV T cells are the mark of CB graft as well. Then it is difficult to explain why HHV6 infections are linked to CBT and not CMV or EBV. It is more surprising for CMV than EBV because: (1) CMV and HHV6 are both member of the β-Herpesvirinae subfamily; (2) HHV6 has been described as a cofactor for CMV disease31 and (3) HHV6 and CMV share similar target cells such as monocytes and BM progenitors.32, 33 As a consequence, a yet unknown factor in the CB graft or some specific features during immune reconstitution would exacerbate the reactivation of HHV6, that do not influence CMV reactivation. One possible explanation has been suggested by analyzing quantitative expression of the HHV6 cell receptor CD46 on human CB, peripheral blood and G-CSF mobilized leukapheresis cells.34 Hematopoietic progenitor cells showed CD46 expression on their surface fulfilling the basic requirement for the susceptibility of HHV6 and more interestingly very significantly higher expression of CD46 was found on CB cells compared with G-CSF mobilized cells. CD46, a member of the regulator of complement fixation family, is known as a key immunologic regulator capable of bridging innate and adaptive immune responses. Then, the CD46 receptor and its higher expression in CB graft may be a key of the mechanism by which HHV6 can modulate immunity in its favor conducting to higher replication after CB transplant. This hypothesis is strengthened by the fact that CD46 is also a receptor for adenovirus, which is more frequent after CBT compared with other source of HSC.35

Another hypothesis to explore is the particular pattern of immune reconstitution after CBT. We have compared immune reconstitution between CB and PBSCs transplants showing that, at least during the first 6 months, B lymphocytes and NK cells count were higher among CBT patients, whereas the CD8 count was lower. As already described,29 we observed a B-cell ‘rebound’ at month 6, which may be explained by the fact that basically B lymphocytes are in excess in CB graft.32 Similarly, our study confirmed the rapid recovery of NK cells after CBT.29, 30, 36 It is of importance as NK cells are known to have potential effect on clinical outcomes in term of complications, GVHD or relapse.36 This cell type is also one of the targets of HHV6, in which it can undergo a complete multiplication cycle33 and thus may represent one of the source of the progeny viruses.

Human herpes virus 6 clinical relevance remains debated. In our study, along with others, we have already reported the main consequence of HHV6 infection was to delay neutrophil and plt recoveries, especially in early reactivating patients.25, 27, 37 Delayed engraftment is a well-known complication of cord blood transplant occurring at a higher incidence when compared with other source of SCs.1, 2, 3, 4, 6 The role of HHV6 in delayed engraftment raises logically the question of HHV6 prophylaxis in CB transplant. If anti-CD46 antibodies may be envisaged,38 other therapeutic agents are already available in prophylaxis such as ganciclovir or foscarnet.39

Finally, two cases consistent with chromosomally integrated HHV6 were also observed, which is in accordance with the prevalence of 0.2–0.8% observed in the general population.40, 41

In conclusion, our results show that after allo-HSCT, the pattern of HHV6 infection is dependent on the source of SCs. A specific relationship is suggested between HHV6 infection and the use of CB cells but larger studies are still needed, especially to better define the role of immune reconstitution.

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Correspondence to P Chevallier.

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Chevallier, P., Hebia-Fellah, I., Planche, L. et al. Human herpes virus 6 infection is a hallmark of cord blood transplant in adults and may participate to delayed engraftment: a comparison with matched unrelated donors as stem cell source. Bone Marrow Transplant 45, 1204–1211 (2010). https://doi.org/10.1038/bmt.2009.326

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Keywords

  • cord blood transplant
  • MUD
  • allo-HSCT
  • HHV6
  • CMV
  • EBV

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