J Hematol

Journal of Hematology, ISSN 1927-1212 print, 1927-1220 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Hematol and Elmer Press Inc

Journal website https://jh.elmerpub.com

Original Article

Volume 14, Number 1, February 2025, pages 1-13

Prevalence of Viral Infections and Serious Complications in Pediatric Hematopoietic Stem Cell Transplant Patients: A Ten-Year Single-Institution Retrospective Study

Figure 1. Distribution of infectious episodes by virus, along post-transplant phases (a), graft sources (b), age groups (c); and pie charts of distribution of viral infection episodes by age groups or graft sources (d). ADNV: adenovirus; BK virus: human polyoma virus 1; BM: bone marrow; CMV: cytomegalovirus; EBV: Epstein-Barr virus; GvHD: graft-versus-host disease; HHV6: human herpes virus 6; HSV: herpes simplex virus; PBSC: peripheral blood stem cell; pHSCT: pediatric hematopoietic stem cell transplant; UCB: umbilical cord blood; VZV: varicella-zoster virus.

Figure 2. Kaplan-Meier plots for the study population: overall survival (a), overall survival by sex (b), overall survival by graft sources (c), overall survival by age groups (d), overall survival by patient’s CMV status (e), and mortality by primary cause of death (f). CMV: cytomegalovirus.

**Table 1.** Demographics of Study Patients
Demographic variables	Age	P-value
Sex					0.1018
Female	12	22	4	12
Male	18	36	25	22
Ethnicity					0.6918
Hispanic	19	36	20	21
White	6	15	5	8
Middle Eastern	4	6	2	2
Asian	1	1	1	3
NOS	0	0	1	0
Primary disease					0.0093
Malignant	13	37	21	28
Non-malignant	17	21	8	6
Disease classification					3.6835 × 10^-5
Acute leukemia	9	35	13	24
MDS/MPL	1	1	0	0
Primary immunodeficiency	11	5	0	1
IDM	0	1	1	0
Histiocytic disorder	3	2	1	0
Chronic leukemia	0	6	6	5
Bone marrow failure	2	6	1	0
Hemoglobinopathy	4	2	6	1
PTLD	0	0	1	0
Lymphoma	0	1	0	3
Solid tumor	0	0	1	0
Disease status					0.2248
CR1	9	17	12	16
CR1/MRD⁺	1	2	0	0
CR2	1	15	6	11
CR2/MRD⁺	0	1	0	0
CR3	1	3	1	1
CR4	0	2	0	0
PR	3	2	0	0
Aplastic	0	1	0	0
Active disease	1	0	1	1
N/A	14	15	9	5
Cell source					0.03260
Cord	18	31	9	9
PBSC	0	5	2	4
Marrow	12	22	18	21
A total of 151 patients were distributed across four age groups. ^aOne patient was originally diagnosed and treated for juvenile myelomonocytic leukemia and later developed post-transplant lymphoproliferative disorder (PTLD). ^bOne patient was diagnosed and treated for histiocytic disorder and later developed chronic leukemia. Sex and ethnicity were self-reported, patients who declined to report were documented as not otherwise specified (NOS). Malignant diseases included acute leukemia, myelodysplastic syndrome/myeloproliferative disorder (MDS/MPL), chronic leukemia, lymphoma, and solid tumors. Non-malignant diseases included primary immunodeficiency, inborn disease of metabolism (IDM), histiocytic disorders, bone marrow failure, hemoglobinopathy, and platelet and other inherited disorders (PLD). With regard to disease status, complete response (CR) refers to no detectable evidence of malignancy on imaging and/or tissue samples. Partial response (PR) refers to a significant reduction in tumor burden, with minimal disease detectable on imaging and/or tissue samples. Mean residual disease positive (MRD⁺) refers to detectable disease based on molecular and/or tissue sampling. Both donor and recipient serologies were documented for CMV and HSV. GCV prophylaxis distribution described for the 81 recipient CMV⁺ cases. Rates of ganciclovir and acyclovir prophylaxis were documented in only the recipient seropositive CMV and HSV patient groups. P-values of χ² test are shown. CMV: cytomegalovirus; GCV: ganciclovir; HRD: haplo-related donor; HSV: herpes simplex virus; MRD: matched related donor; MUD: matched unrelated donor; PBSC: peripheral blood stem cell; TBI: total body irradiation.
Donor source					0.1809
MUD	24	37	18	16
MRD	6	17	8	15
HRD	0	4	3	3
Conditioning					0.0422
Conditioning, no TBI	24	31	16	16
TBI conditioning	6	27	13	18
CMV serology
Donor					0.2946
CMV^-	12	28	17	12
CMV⁺	17	30	12	22
Missing	1	0	0	0
Recipient					0.2473
CMV^-	12	28	17	12
CMV⁺	17	30	12	22
Equivocal	1	0	0	0
GCV prophylaxis					0.7643
Yes	13	24	11	18
No	4	6	1	4
HSV serology					0.3152
HSV^-	16	26	18	21
HSV⁺	14	32	11	13
VZV serology					0.7567
VZV⁺	3	14	5	6
VZV^-	3	3	3	3
Not tested	24	41	21	25
Acyclovir prophylaxis					0.5516
Yes	17	35	21	23
No	13	23	8	11

Table 1. Demographics of Study Patients

Demographic variables

Age

P-value

0 - 2 years old (n = 30)

2 - 12 years old (n = 58)^a

12 - 16 years old (n = 29)^b

16 - 21 years old (n = 34)

Sex

0.1018

Female

Male

Ethnicity

0.6918

Hispanic

White

Middle Eastern

Asian

NOS

Primary disease

0.0093

Malignant

Non-malignant

Disease classification

3.6835 × 10^-5

Acute leukemia

MDS/MPL

Primary immunodeficiency

IDM

Histiocytic disorder

Chronic leukemia

Bone marrow failure

Hemoglobinopathy

PTLD

Lymphoma

Solid tumor

Disease status

0.2248

CR1

CR1/MRD⁺

CR2

CR2/MRD⁺

CR3

CR4

Aplastic

Active disease

N/A

Cell source

0.03260

Cord

PBSC

Marrow

0 - 2 years old (n = 42)

2 - 12 years old (n = 76)^a

12 - 16 years old (n = 35)^b

16 - 21 years old (n = 40)

A total of 151 patients were distributed across four age groups. ^aOne patient was originally diagnosed and treated for juvenile myelomonocytic leukemia and later developed post-transplant lymphoproliferative disorder (PTLD). ^bOne patient was diagnosed and treated for histiocytic disorder and later developed chronic leukemia. Sex and ethnicity were self-reported, patients who declined to report were documented as not otherwise specified (NOS). Malignant diseases included acute leukemia, myelodysplastic syndrome/myeloproliferative disorder (MDS/MPL), chronic leukemia, lymphoma, and solid tumors. Non-malignant diseases included primary immunodeficiency, inborn disease of metabolism (IDM), histiocytic disorders, bone marrow failure, hemoglobinopathy, and platelet and other inherited disorders (PLD). With regard to disease status, complete response (CR) refers to no detectable evidence of malignancy on imaging and/or tissue samples. Partial response (PR) refers to a significant reduction in tumor burden, with minimal disease detectable on imaging and/or tissue samples. Mean residual disease positive (MRD⁺) refers to detectable disease based on molecular and/or tissue sampling. Both donor and recipient serologies were documented for CMV and HSV. GCV prophylaxis distribution described for the 81 recipient CMV⁺ cases. Rates of ganciclovir and acyclovir prophylaxis were documented in only the recipient seropositive CMV and HSV patient groups. P-values of χ² test are shown. CMV: cytomegalovirus; GCV: ganciclovir; HRD: haplo-related donor; HSV: herpes simplex virus; MRD: matched related donor; MUD: matched unrelated donor; PBSC: peripheral blood stem cell; TBI: total body irradiation.

Donor source

0.1809

MUD

MRD

HRD

Conditioning

0.0422

Conditioning, no TBI

TBI conditioning

CMV serology

Donor

0.2946

CMV^-

CMV⁺

Missing

Recipient

0.2473

CMV^-

CMV⁺

Equivocal

GCV prophylaxis

0.7643

Yes

HSV serology

0.3152

HSV^-

HSV⁺

VZV serology

0.7567

VZV⁺

VZV^-

Not tested

Acyclovir prophylaxis

0.5516

Yes

**Table 2.** CMV Viral Infections in the Post-Transplant Period
CMV serology	Infectious event (days post-transplant)
Patients were organized into four recipient (R) and donor (D) serology groups, with either seropositive or seronegative CMV results (+ or -). Incidence of CMV infection was divided into three post-transplant time periods (0 - 30, 31 - 100, and 101 - 730 days). Incidence of CMV disease in these recipient/donor serology groups was also documented. Three patients were excluded from this analysis, as they were missing CMV serology data or had equivocal serology result. P-value = 0.00192 across all groups. P-value = 0.6320 between R⁺/D^- infection and R⁺/D^- infection. P-value = 0.2875 between R⁺/D^- and R⁺/D^- CMV disease. CMV: cytomegalovirus.
R^-/D^- (n = 31)	0	0	0	0	0
R^-/D⁺ (n = 37)	3	1	2	0	0
R⁺/D^- (n = 30)	12	6	5	1	7
R⁺/D⁺ (n = 50)	22	5	15	2	7
Total	37	12	22	3	14

Table 2. CMV Viral Infections in the Post-Transplant Period

CMV serology

Infectious event (days post-transplant)

No. of infections

0 - 30

31 - 100

101 - 730

CMV disease

Patients were organized into four recipient (R) and donor (D) serology groups, with either seropositive or seronegative CMV results (+ or -). Incidence of CMV infection was divided into three post-transplant time periods (0 - 30, 31 - 100, and 101 - 730 days). Incidence of CMV disease in these recipient/donor serology groups was also documented. Three patients were excluded from this analysis, as they were missing CMV serology data or had equivocal serology result. P-value = 0.00192 across all groups. P-value = 0.6320 between R⁺/D^- infection and R⁺/D^- infection. P-value = 0.2875 between R⁺/D^- and R⁺/D^- CMV disease. CMV: cytomegalovirus.

R^-/D^- (n = 31)

R^-/D⁺ (n = 37)

R⁺/D^- (n = 30)

R⁺/D⁺ (n = 50)

Total

**Table 3.** HHV6 Infections in the Post-Transplant Period
HHV6 infections	Infectious event (days post-transplant)
Patients were grouped by cell source. Incidence of HHV6 divided into three post-transplant time periods (0 - 30, 31 - 100, and 101 - 730 days). Rates of all viral encephalitis (including HSV, VZV, HHV6, and ADNV) were also organized by cell source. P-value = 0.01479 for graft source and number of infections. ADNV: adenovirus; HHV6: human herpes virus 6; HSV: herpes simplex virus; PBSC: peripheral blood stem cell; VZV: varicella-zoster virus.
Cord	16	11	4	1	5
PBSC	0	0	0	0	0
Marrow	5	2	3	0	0
Total	21	13	7	1	5

Table 3. HHV6 Infections in the Post-Transplant Period

HHV6 infections

Infectious event (days post-transplant)

No. of infections

0 - 30

31 - 100

101 - 730

Encephalitis

Patients were grouped by cell source. Incidence of HHV6 divided into three post-transplant time periods (0 - 30, 31 - 100, and 101 - 730 days). Rates of all viral encephalitis (including HSV, VZV, HHV6, and ADNV) were also organized by cell source. P-value = 0.01479 for graft source and number of infections. ADNV: adenovirus; HHV6: human herpes virus 6; HSV: herpes simplex virus; PBSC: peripheral blood stem cell; VZV: varicella-zoster virus.

Cord

PBSC

Marrow

Total

**Table 4.** Descriptions and Outcomes of Patients Diagnosed With Viral Encephalitis
Patient (age in years)	Primary diagnosis	Cell source	Time from transplant (days)	Comorbidities	Outcomes (treatment/status/cause of death)
The characteristics, complications, and time course of eight patients diagnosed with viral encephalitis were described. The primary diagnosis details the disease indicated for HSCT. Time from transplant to diagnosis of encephalitis was categorized into three broad post-transplant periods. Common comorbidities of HSCT therapy, as well as disease-specific complications were also documented. The antiviral therapies used to treat encephalitis included acyclovir, ganciclovir, foscarnet, and cidofovir. Patient status was detailed as alive, recovered from encephalitis, deceased from encephalitis (E+ denoting number of days survived with encephalitis), and overall deceased date in the post-transplant period (D+ denoting number of days survived from transplant). Major causes of death in addition to encephalitis were also detailed. ^aOne patient was lost to follow-up and was confirmed to be deceased by an outside hospital. ADNV: adenovirus; AKI: acute kidney injury; ALL: acute lymphocytic leukemia; AML: acute myeloid leukemia; AMS: altered mental status; ARF: acute renal failure; BS: bacterial sepsis; CMV: cytomegalovirus; FS: fungal sepsis; GF: graft failure; GvHD: graft-versus-host disease; HHV6: human herpes virus 6; HSCT: hematopoietic stem cell transplant; HSV: herpes simplex virus; LTFU: lost to follow-up; UCB: umbilical cord blood; UTI: urinary tract infection; VRE: vancomycin-resistant enterococcus; VZV: varicella-zoster virus.
E1 (18)	ALL/HHV6	UCB	0 - 30	BK hemorrhagic cystitis, bacterial sepsis, fungal sepsis	Foscarnet, ganciclovir; deceased E+ 139; D+ 166; BS, FS, HHV6 encephalitis, BK
E2 (5)	AML/HHV6	UCB	0 - 30	HHV6 viremia, GvHD, ADNV enteritis	Foscarnet, ganciclovir; recovered from encephalitis; deceased D + 602; relapsed disease, BS.
E3 (20)	AML/ADNV	UCB	31 - 100	HHV6 viremia, GvHD, ADNV enteritis, VRE UTI	Cidofovir; deceased E+ 43; D+ 70; AMS, AKI, GvHD, HHV6
E4 (4)	AML/HHV6	UCB	0 - 30	HHV6 viremia, BK hemorrhagic cystitis, Klebsiella UTI	Ganciclovir; recovered from encephalitis; alive
E5 (8)	ALL/HHV6^a	UCB	0 - 30	ADNV enteritis, HSV viremia, Aspergillus pneumonia, C. diff colitis	Acyclovir; deceased E+ 39; D+ 64; FS, HHV6, ADNV, ARF
E6 (9)	AML/HHV6	UCB	0 - 30	Graft failure, fungal sepsis, HHV6, ADNV	Foscarnet, ganciclovir; deceased E+ 17; D+ 39; GF, FS, HHV6, ADNV, ARF
E7 (15)	AML/VZV^a	UCB	101 - 730	GvHD, CMV viremia, BK viremia, fungal sepsis, ADNV enteritis	Acyclovir; deceased date unknown; GF, LTFU

Table 4. Descriptions and Outcomes of Patients Diagnosed With Viral Encephalitis

Patient (age in years)

Primary diagnosis

Cell source

Time from transplant (days)

Comorbidities

Outcomes (treatment/status/cause of death)

The characteristics, complications, and time course of eight patients diagnosed with viral encephalitis were described. The primary diagnosis details the disease indicated for HSCT. Time from transplant to diagnosis of encephalitis was categorized into three broad post-transplant periods. Common comorbidities of HSCT therapy, as well as disease-specific complications were also documented. The antiviral therapies used to treat encephalitis included acyclovir, ganciclovir, foscarnet, and cidofovir. Patient status was detailed as alive, recovered from encephalitis, deceased from encephalitis (E+ denoting number of days survived with encephalitis), and overall deceased date in the post-transplant period (D+ denoting number of days survived from transplant). Major causes of death in addition to encephalitis were also detailed. ^aOne patient was lost to follow-up and was confirmed to be deceased by an outside hospital. ADNV: adenovirus; AKI: acute kidney injury; ALL: acute lymphocytic leukemia; AML: acute myeloid leukemia; AMS: altered mental status; ARF: acute renal failure; BS: bacterial sepsis; CMV: cytomegalovirus; FS: fungal sepsis; GF: graft failure; GvHD: graft-versus-host disease; HHV6: human herpes virus 6; HSCT: hematopoietic stem cell transplant; HSV: herpes simplex virus; LTFU: lost to follow-up; UCB: umbilical cord blood; UTI: urinary tract infection; VRE: vancomycin-resistant enterococcus; VZV: varicella-zoster virus.

E1 (18)

ALL/HHV6

UCB

0 - 30

BK hemorrhagic cystitis, bacterial sepsis, fungal sepsis

Foscarnet, ganciclovir; deceased E+ 139; D+ 166; BS, FS, HHV6 encephalitis, BK

E2 (5)

AML/HHV6

UCB

0 - 30

HHV6 viremia, GvHD, ADNV enteritis

Foscarnet, ganciclovir; recovered from encephalitis; deceased D + 602; relapsed disease, BS.

E3 (20)

AML/ADNV

UCB

31 - 100

HHV6 viremia, GvHD, ADNV enteritis, VRE UTI

Cidofovir; deceased E+ 43; D+ 70; AMS, AKI, GvHD, HHV6

E4 (4)

AML/HHV6

UCB

0 - 30

HHV6 viremia, BK hemorrhagic cystitis, Klebsiella UTI

Ganciclovir; recovered from encephalitis; alive

E5 (8)

ALL/HHV6^a

UCB

0 - 30

ADNV enteritis, HSV viremia, Aspergillus pneumonia, C. diff colitis

Acyclovir; deceased E+ 39; D+ 64; FS, HHV6, ADNV, ARF

E6 (9)

AML/HHV6

UCB

0 - 30

Graft failure, fungal sepsis, HHV6, ADNV

Foscarnet, ganciclovir; deceased E+ 17; D+ 39; GF, FS, HHV6, ADNV, ARF

E7 (15)

AML/VZV^a

UCB

101 - 730

GvHD, CMV viremia, BK viremia, fungal sepsis, ADNV enteritis

Acyclovir; deceased date unknown; GF, LTFU