Central nervous system infection following allogeneic hematopoietic stem cell transplantation

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ORIGINAL RESEARCH REPORT

Central nervous system infection following

allogeneic hematopoietic stem cell

transplantation

Ryo Hanajiri, Takeshi Kobayashi, Kosuke Yoshioka, Daisuke Watanabe,

Kyoko Watakabe, Yutaka Murata, Takeshi Hagino, Yasushi Seno,

Yuho Najima, Aiko Igarashi, Noriko Doki, Kazuhiko Kakihana,

Hisashi Sakamaki, Kazuteru Ohashi

*

Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan

Received 11 October 2015; accepted 29 August 2016

KEYWORDS

Allogeneic hematopoietic stem cell transplantation; Central nervous system infections;

Human herpesvirus 6

Abstract

Objective/background: Here, we described the clinical characteristics and outcomes of cen-tral nervous system (CNS) infections occurring after allogeneic hematopoietic stem cell trans-plantation (allo-HSCT) in a single institution over the previous 6 years.

Methods: Charts of 353 consecutive allogeneic transplant recipients were retrospectively reviewed for CNS infection.

Results: A total of 17 cases of CNS infection were identified at a median of 38 days (range, 10– 1028 days) after allo-HSCT. Causative pathogens were human herpesvirus-6 (n = 6), enterococ-cus (n = 2), staphylococenterococ-cus (n = 2), streptococenterococ-cus (n = 2), varicella zoster virus (n = 1), cytome-galovirus (n = 1), John Cunningham virus (n = 1), adenovirus (n = 1), and Toxoplasma gondii (n = 1). The cumulative incidence of CNS infection was 4.1% at 1 year and 5.5% at 5 years. Conclusion: Multivariate analysis revealed that high-risk disease status was a risk factor for developing CNS infection (p = .02), and that overall survival at 3 years after allo-HSCT was 33% in patients with CNS infection and 53% in those without CNS infection (p = .04).

Ó 2016 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

http://dx.doi.org/10.1016/j.hemonc.2016.08.008

1658-3876/Ó 2016 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

* Corresponding author at: Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan.

E-mail address:k.ohashi@cick.jp(K. Ohashi).

Hematol Oncol Stem Cell Ther (2016) xxx, xxx– xxx

A v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m

ScienceDirect

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / h e m o n c

Please cite this article in press as: Hanajiri R et al., Central nervous system infection following allogeneic hematopoietic stem cell transplan-tation ...,Hematol Oncol Stem Cell Ther (2016),http://dx.doi.org/10.1016/j.hemonc.2016.08.008

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Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients are at a high risk for several central ner-vous system (CNS) complications [1]. These complications arise either from the primary disease for which the patient is undergoing allo-HSCT or as a consequence of immunosup-pressive treatments, infection, or hemorrhage that may develop following allo-HSCT[2–4]. Although CNS infection usually results in a dismal outcome, early diagnosis and immediate treatment intervention may improve prognosis [5,6]. The incidence of CNS infection ranges from 0.8% to 15%[7–14], and various causative pathogens, including bac-teria [15], fungi [9,14], viruses [7,16–20], and protozoa [21], have been identified, but the full spectrum of patho-gens is not known. Multiple factors, including severe graft-versus-host disease (GVHD) or use of high doses of an immunosuppressive drug, such as alemtuzumab, were iden-tified as risk factors for CNS infection. However, little is known about the precise clinical characteristics of CNS infection, as clinical manifestations may be difficult to dis-tinguish from other conditions that cause neurological symptoms[8,11–13,22,23]. This study described the clinical course of 17 cases of CNS infection among 353 allogeneic transplant recipients over the previous 6 years at a single institution and reviewed their clinical outcomes.

Materials and methods

Patient demographics

We retrospectively reviewed 353 patients (210 men and 143 women; median age, 43 years; range, 16–73 years) with various diseases who underwent allo-HSCT at our institu-tion. Between January 2005 and December 2011, 261 patients underwent bone marrow transplantation (82 related, 179 unrelated), 48 underwent related peripheral-blood stem cell transplantation, and 44 patients underwent unrelated cord-blood stem cell transplantation. Clinical characteristics of patients are summarized inTable 1.

Transplantation procedure

Preparative treatment was performed according to the pri-mary disease and type of transplant. Generally, patients with lymphoid malignancy were conditioned using a total body irradiation (TBI)-containing regimen (12 Gy) that included cyclophosphamide (CY) at 120 mg/kg with or with-out cytarabine at 8 g/m2. Conversely, patients with myeloid malignancy were conditioned using a non-TBI-containing regimen that included oral busulfan (BU) at 16 mg/kg or intravenous BU at 12.8 mg/kg and CY at 120 mg/kg. Plasma concentrations of BU were not monitored. Patients with severe aplastic anemia were also conditioned using a total lymphoid irradiation-containing regimen. Reduced-intensity conditioning regimens consisted of fludarabine-based regimens with or without low-dose TBI. Cyclosporine or tacrolimus plus short-term methotrexate were used for prophylaxis. Tacrolimus was used in cases of unrelated or mismatched transplantation. Acute and chronic GVHD were

diagnosed and graded according to previously established criteria. Tosufloxacin and fluconazole were orally adminis-tered 14 days before allo-HSCT for prophylaxis against bac-terial and fungal infection, respectively. For patients with a high risk of invasive fungal infections, voriconazole was administered instead of fluconazole. Trimethoprim and sul-famethoxazole were administered to prevent Pneumocystis pneumonia. Acyclovir was administered to prevent herpes simplex virus infection until the end of administration of immunosuppressive drugs. Cytomegalovirus (CMV) disease monitoring using an antigenemia assay for pre-emptive gan-ciclovir therapy was performed.

Diagnostic procedure for CNS infection and statistical analysis

According to the standard operating procedure at our insti-tution, symptomatic patients with an altered mental status or convulsions, particularly those without any other identi-fied causes of neurological dysfunction, such as hemorrhage [4], metabolic disorder, or drug toxicity, were classified as possibly having CNS infection. These patients immediately underwent cerebrospinal fluid (CSF) examination with stan-dard culturing, staining for bacterial, viral, and protozoan pathogens, and polymerase chain reaction (PCR) testing for human herpesvirus virus 6 (HHV-6), varicella zoster virus (VZV), herpes simplex virus, CMV, and adenovirus. When progressive multifocal leukoencephalopathy was consid-ered, PCR for John Cunningham (JC) virus in the CSF was employed.

Descriptive statistics were provided for patient-baseline characteristics. Patient-, disease-, and transplant-related variables were compared using Fisher’s exact test for cate-gorical variables and the Mann-Whitney U test for continu-ous variables. The probability of CNS infection was calculated using the cumulative incidence-function method and considering death without CNS infection as a competing event. To evaluate the association between pretransplant clinical factors and CNS infection, a logistic regression model was used. Overall survival (OS) was calculated using the Kaplan-Meier method and compared with the log-rank test. OS was calculated from transplantation to death regardless of cause. Multivariate analyses were performed using the Cox proportional-hazards model. The following covariates were included in the multivariate analysis: age, sex, disease risk, stem cell source, donor type, conditioning regimen, GVHD prophylaxis, and the development of CNS infection. Variables with p < .10 in the univariate analyses were subjected to multivariate analysis. Development of CNS infection was treated as a time-dependent covariate. All p-values were two-sided, and a p < .05 was considered statistically significant.

Results

Clinical features of CNS infection following allo-HSCT

The charts of 353 allo-HSCT recipients were retrospectively reviewed for CNS infection.Table 1summarizes the

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charac-teristics of these 353 patients. Of these patients, 17 eventu-ally developed CNS infection at a median of 38 days (range, 10–1028 days) after allo-HSCT. The median age at the time of CNS infection was 43 years (range, 25–64 years), and nine patients were men (53%). Most patients underwent unre-lated HSCT with a myeloablative-conditioning regimen (Table 1). No patients with CNS infections received anti-thymocyte globulin as a conditioning regimen. The cumula-tive incidence of CNS infection was 4.1% at 1 year and 5.5% at 5 years after allo-HSCT. High-risk-disease status was a significant clinical factor for CNS infection according to uni-variate analysis (p = .01), and this factor remained signifi-cant according to multivariate analysis (relative risk = 4.56; 95% confidence interval, 1.28–16.2; p = .02). The 5-year cumulative incidence of CNS infection in patients with high-risk-disease status was 8.8%, whereas the inci-dence was 1.8% in patients with low-risk-disease status (Fig. 1).

Of the 17 patients who developed CNS infection (Table 2), the types of CNS infection were meningitis (n = 5), encephalitis (n = 3), meningoencephalitis (n = 6), brain abscess (n = 2), and progressive multifocal leukoen-cephalopathy (n = 1). The causative pathogens were HHV-6 (n = 6), enterococcus (n = 2), staphylococcus (n = 2), strep-tococcus (n = 2), VZV (n = 1), CMV (n = 1), JC virus (n = 1),

Table 1 Patient characteristics.

Variable No CNS infection (n = 336) CNS infection present (n = 17) p

Age (y) Median 48 43 .51

Range 16–73 25–64

Sex Male 201 9 .62

Female 135 8

Primary disease AML 151 8 .60

ALL 70 6 MDS 48 1 CML 27 1 SAA 18 0 ML 14 0 Others 8 1

Disease riska Low 169 3 .01

High 167 14

Stem cell source BM 250 11 .09

PBSC 47 1

CB 39 5

Donor type Related 93 3 .58

Unrelated 243 14

Conditioning regimen Myeloablative 268 16 .21

Reduced intensity 68 1

GVHD prophylaxis CyA based 164 6 .33

FK based 172 11

Note. ALL = acute lymphoid leukemia; AML = acute myeloid leukemia; BM = bone marrow; CB = cord blood; CML = chronic myeloid leu-kemia; CNS = central nervous system; CyA = cyclosporine; FK = tacrolimus; GVHD = graft-versus-host disease; MDS = myelodysplastic syndrome; ML = malignant lymphoma; PBSC = peripheral blood stem cell; SAA = severe aplastic anemia.

aDisease risk was classified into two categories: high risk included acute leukemia not in remission, myelodysplastic syndrome with excess blast count, or chronic myelomonocytic leukemia and the others were classified as low risk.

Years after transplantation

Cumulative incidence of CNS infection 1.0 0.8 0.6 0.4 0.2 0 0 1 2 3 4 5 6 Low risk High risk

Figure 1 Cumulative incidence of the development of CNS infection following allo-HSCT. The incidences for patients with high-risk-disease status versus those with low-risk-disease status are shown. Note. Allo-HSCT = allogeneic hematopoietic stem cell transplantation; CNS = central nervous system.

CNS infection following allogeneic HSCT 3

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Table 2 Clinical characteristics and outcomes of CNS infection.

Case Age (y) Sex Primary disease Stem cell source Conditioning GVHD prophylaxis Clinical findings

Type of CNS infection Causative pathogen Onset (day after transplantation) Prior steroid use Altered mental status Convulsions

1 55 F CML UBM CA+CY+TBI CyA+sMTX Meningoencephalitis HHV-6 Day 49 Yes Yes No

2 51 F MDS RBM BU+CY FK+sMTX Meningoencephalitis HHV-6 Day 36 Yes Yes No

3 42 M ATL CB CA+CY+TBI FK+sMTX Meningoencephalitis HHV-6 Day 27 No Yes No

4 48 M AML CB CA+CY+TBI FK+sMTX Meningoencephalitis HHV-6 Day 25 No Yes No

5 64 M ALL UBM Flu+Mel+TBI FK+sMTX Meningoencephalitis HHV-6 Day 19 No Yes No

6 34 M AML UBM BU+CY FK+sMTX Meningoencephalitis HHV-6 Day 21 Yes Yes Yes

7 34 F ALL UBM CY+TBI FK+sMTX Meningitis VZV Day 509 Yes No No

8 58 M ALL UBM CA+CY+TBI FK+sMTX Encephalitis CMV Day 38 Yes Yes No

9 55 F AML UBM BU+CY FK+sMTX PML JCV Day 1028 No Yes No

10 39 M ALL RPB CY+TBI CyA+sMTX Encephalitis ADV Day 121 Yes Yes No

11 58 F AML RBM BU+CY FK+sMTX Encephalitis Toxoplasma Day 101 Yes Yes No

12 37 M ALL CB CA+CY+TBI FK+sMTX Meningitis Enterococcus Day 13 Yes No No

13 45 F AML CB CA+CY+TBI CyA+sMTX Meningitis Enterococcus Day 11 No No No

14 50 F AML UBM BU+CY FK+sMTX Brain abscess S capitis Day 843 No Yes No

15 55 F ALL UBM CA+CY+TBI CyA+sMTX Brain abscess S capitis Day 150 Yes Yes No

16 25 M AML RBM BU+CY CyA+sMTX Meningitis S pneumonia Day 307 Yes Yes No

17 31 M AML CB CA+CY+TBI CyA+MMF Meningitis S haemolyticus Day 10 No Yes No

Case Laboratory findings Radiologic findings Treatment outcomes

WBC (/lL) Platelets (/lL) CSF Brain CT Brain MRI (abnormal lesions) Treatment modality Response Survival status at the last follow-up (days after onset of CNS infection)

Cause of death Cell count (mm3

) Protein (mg/dL)

1 3600 2.2 3 57.0 Normal Left medial temporal lobe DHPG? Foscarnet Improved Dead (234) Unknown

2 1100 2.2 41 59.0 Normal Medial temporal lobe DHPG? Foscarnet Improved but persistent memory impairment Alive (1737+) NA

3 2600 1.9 0 37.9 Normal Normal DHPG? Foscarnet No response Dead (78) Sepsis

4 50 0.8 0 0.0 ND Normal Foscarnet Improved but persistent disorientation Dead (81) Disease progression

5 2300 2.6 1 76.5 ND Normal Foscarnet Improved Dead (41) Pneumonia

6 3900 1.5 3 23.0 Normal Medial temporal lobe Foscarnet Persistent disturbance of consciousness Dead (141) Pneumonia

7 8300 11.0 283 125.4 Normal Normal ACV Improved Alive (1055+) NA

8 6100 2.6 364 362.0 ND ND Foscarnet Improved with exacerbation Dead (41) CNS infection

9 6100 15.2 2 26.0 ND Cerebellum Mefloquine No response Dead (107) CNS infection

10 2800 3.2 2 216.0 ND ND ND NA Dead (11) CNS infection

11 700 4.2 1 63.0 Normal Basal ganglia ST No response Dead (10) CNS infection

12 10 0.6 4 40.1 Normal ND VCM? LZD No response Dead (14) CNS infection

13 20 2.6 0 20.4 Normal Meningeal enhancement VCM? LZD Improved but persistent memory impairment Alive (1258+) NA

14 6900 6.0 ND ND ND Frontal lobe MEPM+VCM No response Alive (16+) NA

15 5100 2.3 61 138.3 ND Right frontal lobe VCM Improved Alive (475+) NA

16 12,600 12.3 4208 62.4 Normal Sinusitis CTRX+VCM Improved Alive (1284+) NA

17 30 1.1 7 41.0 ND Normal VCM No response Dead (15) CNS infection

Note. ACV = acyclovir; ADV = adenovirus; ALL = acute lymphoid leukemia; AML = acute myeloid leukemia; ATL = adult T cell leukemia; BU = busulfan; CA = cytarabine; CB = cord blood; CML = chronic myeloid leukemia; CMV = cytomegalovirus; CNS = central nervous system; CSF = cerebrospinal fluid; CT = computed tomography; CTRX = ceftriaxone; CY = cyclophosphamide; CyA = cyclosporine; DHPG = ganciclovir; F = female; FK = tacrolimus; GVHD = graft-versus-host disease; HHV-6 = human herpesvirus 6; JCV = John Cunningham virus; LZD = linezolid; M = male; MDS = myelodysplastic syndrome; MEPM = meropenem; MMF = mycophenolate mofetil; MRI = magnetic resonance imaging; NA = not applicable; ND = not done; PML = progressive multifocal leukoencephalopathy; RBM = related bone marrow; RPB = related peripheral blood stem cell; sMTX = short-term methotrexate; ST = trimethoprim/sulfamethoxazole; TBI = total body irradiation; UBM = unrelated bone marrow; VCM = vancomycin; VZV = varicella zoster virus; WBC = white blood cell; S capitis = Staphylococcus capitis; S haemolyticus = Staphylococcus

haemolyticus; S pneumonia = Streptococcus pneumoniae. R.Hanajiri

et al. cite this article in press as: Hanajiri R et al., Central nervous system infection following allogeneic hematopoiet ic stem cell transpla n-..., Hematol Oncol Stem Cell Ther (2016), http://dx.d oi.org/10.1 016/j.hemon c.2016.08.00 8

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adenovirus (n = 1), and Toxoplasma gondii (n = 1). All 10 cases of viral infections were diagnosed with a PCR assay of CSF, and the six cases of bacterial infections were diag-nosed with bacterial culture of CSF or abscess. Toxoplasmo-sis was diagnosed following a brain autopsy. At the onset of CNS infection, 10 patients (59%) were receiving steroids for GVHD treatment. Fourteen patients (82%) developed an altered mental status, and one patient developed convul-sions. Seven patients (41%) showed fever (>38°C), and high blood pressure (systolic blood pressure > 160 mmHg or dias-tolic blood pressure > 90 mmHg) was observed in five patients. Engraftment had been achieved in 12 patients (71%) at the onset of CNS infection. Lumbar puncture was performed in 16 patients, and cell counts were elevated in five of these patients (31%). Median cell counts were 3 mm 3(range, 0–4208 mm 3), and protein levels were ele-vated in nine patients (53%). Cranial computed tomography was performed in nine patients, but the results were essen-tially normal in all of the patients. Magnetic resonance imaging was performed in 14 patients, and nine patients (64%) displayed abnormal findings (Table 2). Abnormalities in the medial temporal lobe were observed in three of the six patients with HHV-6 infection. The median onset time of HHV-6 infection seemed to be earlier as compared with that of other CNS infections, although the difference was not statistically significant (26 days vs. 121 days; p = .18). (seeTable 3)

Treatment and outcome

A summary of treatments for CNS infection is presented in Table 2. The probability of an overall response was 53%; however, minor neurological symptoms remained in four patients (data not shown). Foscarnet was administered to all six patients with HHV-6 infection. Of these patients, two improved completely, but the remaining four improved with minor neurological symptoms or did not respond to the treatment. We were able to analyze sequential HHV-6 PCR values in three patients (Cases 1, 2, and 6), and in each patient, HHV-6 copy number in CSF decreased after initia-tion of foscarnet treatment (Case 1: HHV-6 PCR positive to negative; Case 2: 3000 copies/mL to undetectable; and Case 6: from 77,000 copies/mL to 150 copies/mL). For VZV meningitis (Case 7), CMV encephalitis (Case 8), and progres-sive multifocal leukoencephalopathy due to JC virus (Case 9), acyclovir, foscarnet, and mefloquine were administered, respectively. The patient with toxoplasmosis (Case 11) developed respiratory failure with diffuse bilateral infil-trates at the onset. Pneumocystis pneumonia was initially suspected, and, therefore, sulfamethoxazole-trimethoprim was administered. At autopsy, the brain of the patient showed widespread necrotizing tissue in the caudate

nucleus, basal ganglia, thalamus, hippocampus, cerebrum, cerebellum, midbrain, and pons, with abundant Toxoplasma gondii cysts and free tachyzoites (trophozoites). Toxo-plasma cysts were also visualized in the lung, thyroid, stom-ach, uterus, ovary, and peritoneum. For the six patients with bacterial meningitis, a bulk dose of antibiotics was intravenously administered. Two patients responded com-pletely, and one patient improved with persistent memory impairment.

As shown inFig. 2, OS in patients with CNS infection was significantly inferior to that observed in those without CNS infection (33% vs. 53% at 3 years; p = .04). Only six patients were alive at a median follow-up of 39 months (range, 1–58 months) after diagnosis of CNS infection. The median OS after the onset of CNS infection as determined using the Kaplan-Meier method was only 107 days. Only four patients simultaneously developed systemic infection documented by blood culture or autopsy. Causative pathogens for sys-temic infection were enterococcus (Cases 12 and 13), Strep-tococcus pneumoniae (Case 16), and Toxoplasma gondii (Case 11). The main cause of death was CNS infection in six patients, other infections in three patients, and disease progression in two patients (Table 2).

Discussion

In our series, 4.8% of allo-HSCT recipients developed CNS infection at a median of 38 days after transplantation. The incidence of CNS infection varies from 0.8% to 15%

Table 3 Multivariate analysis of adverse factors for overall survival.

Factors RR 95% CI p

CNS infection (yes vs. no) 2.27 1.20–4.28 .01

Disease risk (high vs. low) 2.57 1.80–3.68 <.01

Donor type (unrelated vs. related) 1.86 1.24–2.77 <.01

Note. CI = confidence interval; CNS = central nervous system; RR = relative risk.

Overall survival

Years after transplantation

1.0 0.8 0.6 0.4 0.2 0 0 1 2 3 4 5 6 No CNS infection CNS infection

Figure 2 OS following allo-HSCT for patients with and without CNS infection. Note. Allo-HSCT = allogeneic hematopoi-etic stem cell transplantation; CNS = central nervous system; OS = overall survival.

CNS infection following allogeneic HSCT 5

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[7–14], with the discrepancy in these incidences possibly due to differences in study design, patient population of the studies, definition of CNS infection, or prophylactic strategies for infections. In a retrospective study of 2628 patients undergoing allo-HSCT, Schmidt-Hieber et al. [7] reported that the incidence of viral encephalitis was 1.2%, a result comparable with ours. Regarding the risk factors for CNS infection, in a retrospective study of 655 patients who underwent allogeneic or autologous transplantation, Maschke et al.[11] revealed that severe GVHD or the use of high doses of immunosuppressive drugs may induce a risk for developing toxoplasma encephalitis. In our study, a high-risk-disease status was an independent risk factor for CNS infection, which may be attributed to the immunosuppres-sive status due to multiple courses of intenimmunosuppres-sive chemother-apy before transplantation. The prognosis of patients with CNS infection after allo-HSCT is extremely poor. Schmidt-Hieber et al. [7] reported that the median survival after the onset of viral encephalitis was only 94 days, with higher mortality in patients with rather than those without viral encephalitis. In our study, the median OS after the onset of CNS infection was 107 days, and OS at 3 years after allo-HSCT was 33%, similar to a report by Maschke et al. [11] Although in four cases it appeared that CNS disease was secondary to a systemic infection, most of the patients developed sole manifestation of the pathogen. Therefore, the worse 3-year OS observed among patients with CNS infections was a direct consequence of CNS infection.

Among our 17 cases of CNS infection, viruses accounted for 58%, bacteria for 36%, and protozoa for 6%; however, no fungal CNS infection was observed in our series. Maschke et al.[11]reported that cerebral aspergillosis was the sec-ond most common CNS infection post-transplantation. In another autopsy series of 180 transplant recipients, 27 patients had an infection in the brain parenchyma, and fungi were isolated in up to 60% of their cases[10]. The discrep-ancy in the causative pathogens may be due to differences in prophylactic strategies or the choice of diagnostic modal-ities for CNS infection.

Regarding HHV-6 meningoencephalitis, although all six patients received foscarnet relatively early in their clinical courses, only two showed good cognitive recovery, and four continued to have memory impairment or disorientation. Moreover, most patients died during follow-up, although no patients died of HHV-6 meningoencephalitis, similar to previous reports showing that >50% of patients with HHV-6 meningoencephalitis died of encephalitis-unrelated causes, such as GVHD and other infections[24,25]. Although inci-dental positivity of CSF PCR for HHV-6 in chromosomally integrated HHV-6 (ciHHV-6) patients with CSF pleocytosis may result in erroneous diagnosis of HHV-6 meningoen-cephalitis[26], considering that all six patients developed typical clinical features of HHV-6 meningoencephalitis, the possibility of misdiagnosis due to ciHHV-6 seems unlikely.

We also focused on the initial clinical findings of CNS infection; however, not surprisingly, we found no specific features in our series. Although most patients presented with altered mental status as the initial manifestation, <50% of patients developed fever (>38°C), and convulsions were observed in only one patient with HHV-6 infection. In a retrospective study of 1461 allo-HSCT cases, CNS infec-tion was documented in 14 (17.7%) out of 79 patients with

convulsions [27]. Thus, the initial manifestation of CNS infection may be very similar to that of other disorders, such as cerebrovascular disease, metabolic disorder, and drug toxicity[5,10,23,25]. Therefore, a positive diagnostic strategy, including PCR testing of CSF for virus infection and magnetic resonance imaging rather than computer tomography, may be needed to reach an accurate diagnosis, although not all positive cultures or PCR-testing results are reflective of the true infection and results should be inter-preted with caution.

This study had a limitation due to its retrospective nat-ure. Additionally, we may have overlooked some patients with CNS infection, despite detailed database analysis and extensive chart review. Nevertheless, our aim was to review the clinical outcomes of 353 allogeneic transplant patients after CNS infection over a 6-year period and to provide use-ful insights into this phenomenon.

Conflicts of interest

There are no competing financial interests.

Acknowledgment

We would like to thank the nursing staff of Tokyo Metropoli-tan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan for their excellent patient care.

References

[1]Antonini G, Ceschin V, Morino S, Fiorelli M, Gragnani F, Mengarelli A, et al. Early neurologic complications following allogeneic b marrow transplant for leukemia: a prospective study. Neurology 1998;50:1441–5.

[2]Iguchi A, Kobayashi R, Yoshida M, Kaneda M, Watanabe N, Cho Y, et al. Neurological complications after stem cell transplan-tation in childhood. Bone Marrow Transplant. 1999;24:647–52. [3]Bleggi-Torres LF, de Medeiros BC, Neto JZ, Loddo G, Pasquini R, et al. Neuropathological findings after bone marrow trans-plantation: an autopsy study of 180 cases. Bone Marrow Transplant 2000;25:301–7.

[4]Najima Y, Ohashi K, Miyazawa M, Nakano M, Kobayashi T, Yamashita T, et al. Intracranial hemorrhage following allo-geneic hematopoietic stem cell transplantation. Am J Hematol 2009;84:298–301.

[5]Schmidt-Hieber M, Zweigner J, Uharek L, Blau IW, Thiel E. Central nervous system infections in immunocompromised patients: update on diagnostics and therapy. Leuk Lymphoma 2009;50:24–36.

[6]Singh N, Husain S. Infections of the central nervous system in transplant recipients. Transpl Infect Dis 2000;2:101–11. [7]Schmidt-Hieber M, Schwender J, Heinz WJ, Zabelina T, Ku¨hl

JS, Mousset S, et al. Viral encephalitis after allogeneic stem cell transplantation: a rare complication with distinct charac-teristics of different causative agents. Haematologica 2009;96:142–9.

[8]Sostak P, Padovan CS, Yousry TA, Ledderose G, Kolb HJ, Straube A. Prospective evaluation of neurological complica-tions after allogeneic bone marrow transplantation. Neurology 2003;60:842–8.

[9]Jantunen E, Volin L, Salonen O, Piilonen A, Parkkali T, Anttila VJ, et al. Central nervous system aspergillosis in allogeneic

(7)

stem cell transplant recipients. Bone Marrow Transplant 2003;31:191–6.

[10]de Medeiros BC, de Medeiros CR, Werner B, Neto JZ, Loddo G, Pasquini R, et al. Central nervous system infections following bone marrow transplantation: an autopsy report of 27 cases. J Hematother Stem Cell Res 2000;9:535–40.

[11]Maschke M, Dietrich U, Prumbaum M, Kastrup O, Turowski B, Schaefer UW, et al. Opportunistic CNS infection after bone marrow transplantation. Bone Marrow Transplant 1999;23:1167–76.

[12]Barba P, Pinana JL, Valcarcel D, Querol L, Martino R, Sureda A, et al. Early and late neurological complications after reduced-intensity conditioning allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2009;15:1439–46.

[13]Weber C, Schaper J, Tibussek D, Adams O, Mackenzie CR, Dilloo D, et al. Diagnostic and therapeutic implications of neurological complications following paediatric haematopoi-etic stem cell transplantation. Bone Marrow Transplant 2008;41:253–9.

[14]Teive H, Carsten AL, Iwamoto FM, Almeida SM, Munhoz RP, Werneck LC, et al. Fungal encephalitis following bone marrow transplantation: clinical findings and prognosis. J Postgrad Med 2008;54:203–5.

[15]Campos A, Vaz CP, Campilho F, Morais A, Guimara˜es MA, Lopes C, et al. Central nervous system (CNS) tuberculosis following allogeneic stem cell transplantation. Bone Marrow Transplant 2000;25:567–9.

[16]Suzuki J, Ashizawa M, Okuda S, Wada H, Sakamoto K, Terasako K, et al. Varicella zoster virus meningoencephalitis after allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis 2012;14:E7–E12.

[17]Frange P, Peffault de Latour R, Boddaert N, Oualha M, Avettand-Fenoel V, et al. Adenoviral infection presenting as an isolated central nervous system disease without detectable viremia in two children after stem cell transplantation. J Clin Microbiol 2011;49:2361–4.

[18]Romee R, Brunstein CG, Weisdorf DJ, Majhail NS. Herpes simplex virus encephalitis after allogeneic transplantation: an instructive case. Bone Marrow Transplant 2010;45:776–8.

[19]Reddy SM, Winston DJ, Territo MC, Schiller GJ. CMV central nervous system disease in stem-cell transplant recipients: an increasing complication of drug-resistant CMV infection and protracted immunodeficiency. Bone Marrow Transplant 2010;45:979–84.

[20]Kishida S, Tanaka K. Mefloquine treatment in a patient suffering from progressive multifocal leukoencephalopathy after umbilical cord blood transplant. Intern Med 2010;49:2509–13.

[21]Mulanovich VE, Ahmed SI, Ozturk T, Khokhar FA, Kontoyiannis DP, de Lima M. Toxoplasmosis in allo-SCT patients: risk factors and outcomes at a transplantation center with a low incidence. Bone Marrow Transplant 2011;46:273–7.

[22]Narimatsu H, Miyamura K, Iida H, Hamaguchi M, Uchida T, Morishita Y, et al. Early central nervous complications after umbilical cord blood transplantation for adults. Biol Blood Marrow Transplant 2009;15:92–100.

[23]Kishi Y, Miyakoshi S, Kami M, Ikeda M, Katayama Y, Murashige N, et al. Early central nervous system complications after reduced-intensity stem cell transplantation. Biol Blood Marrow Transplant 2004;10:561–8.

[24]Sakai R, Kanamori H, Motohashi K, Yamamoto W, Matsuura S, Fujita A, et al. Long-term outcome of human herpesvirus-6 encephalitis after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2011;17:1389–94.

[25]Fujimaki K, Mori T, Kida A, Tanaka M, Kawai N, Matsushima T, et al. Human herpesvirus 6 meningoencephalitis in allogeneic hematopoietic stem cell transplant recipients. Int J Hematol 2006;84:432–7.

[26]Pellett PE, Ablashi DV, Ambros PF, Agut H, Caserta MT, Descamps V, et al. Chromosomally integrated human her-pesvirus 6: questions and answers. Rev Med Virol 2012;22:144–55, 7.

[27]Zhang XH, Xu LP, Liu DH, Chen H, Han W, Chen YH, et al. Epileptic seizures in patients following allogeneic hematopoi-etic stem cell transplantation: a retrospective analysis of incidence, risk factors, and survival rates. Clin Transplant 2012;27:80–9.

CNS infection following allogeneic HSCT 7

Please cite this article in press as: Hanajiri R et al., Central nervous system infection following allogeneic hematopoietic stem cell transplan-tation ...,Hematol Oncol Stem Cell Ther (2016),http://dx.doi.org/10.1016/j.hemonc.2016.08.008

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References

  1. (http://creativecommons.org/licenses/by-nc-nd/4.0/
  2. http://creativecommons.org/licenses/by-nc-nd/4.0/
  3. http://dx.doi.org/10.1016/j.hemonc.2016.08.008
  4. w w w . s c i e n c e d i r e c t . c o m
  5. w w w . e l s e v i e r . c o m / l o c a t e / h e m o n c
  6. Antonini G, Ceschin V, Morino S, Fiorelli M, Gragnani F,Mengarelli A, et al. Early neurologic complications following
  7. Iguchi A, Kobayashi R, Yoshida M, Kaneda M, Watanabe N, ChoY, et al. Neurological complications after stem cell
  8. Bleggi-Torres LF, de Medeiros BC, Neto JZ, Loddo G, PasquiniR, et al. Neuropathological findings after bone marrow
  9. Najima Y, Ohashi K, Miyazawa M, Nakano M, Kobayashi T,Yamashita T, et al. Intracranial hemorrhage following
  10. Schmidt-Hieber M, Zweigner J, Uharek L, Blau IW, Thiel E.Central nervous system infections in immunocompromised
  11. Singh N, Husain S. Infections of the central nervous system intransplant recipients. Transpl Infect Dis 2000;2:101–11
  12. 2009;96:142–9
  13. Sostak P, Padovan CS, Yousry TA, Ledderose G, Kolb HJ,Straube A. Prospective evaluation of neurological
  14. Jantunen E, Volin L, Salonen O, Piilonen A, Parkkali T, AnttilaVJ, et al. Central nervous system aspergillosis in allogeneic
  15. de Medeiros BC, de Medeiros CR, Werner B, Neto JZ, Loddo G,Pasquini R, et al. Central nervous system infections following
  16. Maschke M, Dietrich U, Prumbaum M, Kastrup O, Turowski B,Schaefer UW, et al. Opportunistic CNS infection after bone
  17. Barba P, Pinana JL, Valcarcel D, Querol L, Martino R, Sureda A,et al. Early and late neurological complications after
  18. 2008;41:253–9
  19. Teive H, Carsten AL, Iwamoto FM, Almeida SM, Munhoz RP,Werneck LC, et al. Fungal encephalitis following bone marrow
  20. 2000;25:567–9
  21. Suzuki J, Ashizawa M, Okuda S, Wada H, Sakamoto K, TerasakoK, et al. Varicella zoster virus meningoencephalitis after
  22. Frange P, Peffault de Latour R, Boddaert N, Oualha M,Avettand-Fenoel V, et al. Adenoviral infection presenting as
  23. Romee R, Brunstein CG, Weisdorf DJ, Majhail NS. Herpessimplex virus encephalitis after allogeneic transplantation: an
  24. 2010;45:979–84
  25. Kishida S, Tanaka K. Mefloquine treatment in a patientsuffering from progressive multifocal leukoencephalopathy
  26. Mulanovich VE, Ahmed SI, Ozturk T, Khokhar FA, KontoyiannisDP, de Lima M. Toxoplasmosis in allo-SCT patients: risk factors
  27. Narimatsu H, Miyamura K, Iida H, Hamaguchi M, Uchida T,Morishita Y, et al. Early central nervous complications after
  28. Kishi Y, Miyakoshi S, Kami M, Ikeda M, Katayama Y, MurashigeN, et al. Early central nervous system complications after
  29. Sakai R, Kanamori H, Motohashi K, Yamamoto W, Matsuura S,Fujita A, et al. Long-term outcome of human herpesvirus-6
  30. Fujimaki K, Mori T, Kida A, Tanaka M, Kawai N, Matsushima T,et al. Human herpesvirus 6 meningoencephalitis in allogeneic
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