Abstract
Background
Cord blood transplant (CBT) recipients have a high incidence of herpes zoster (HZ) in the context of short-term peritransplant antiviral prophylaxis. In 2009, international guidelines recommended HZ prophylaxis for at least 1 year after hematopoietic cell transplant. The impact of longer-term antiviral prophylaxis on HZ incidence after CBT is unknown.
Methods
We retrospectively analyzed varicella zoster virus (VZV)–seropositive CBT recipients who were transplanted between 2006 and 2016. We abstracted HZ events and other variables for up to 5 years post-CBT. We calculated the cumulative incidence of HZ and used Cox proportional hazards regression to identify variables associated with HZ.
Results
The study cohort consisted of 227 patients. Among 1-year survivors, 91% were still receiving prophylaxis, for a median duration of 20.6 months. HZ occurred in 44 patients (19%) at a median of 23.6 months. The cumulative incidence of HZ by 1 year after CBT was 1.8% (95% confidence interval [CI], .1%–4%), but increased to 26% (95% CI, 19%–33%) by 5 years. In a multivariable analysis, acute graft-vs-host disease was associated with increased risk, whereas antiviral prophylaxis was associated with reduced risk for HZ (adjusted hazard ratio, 0.19 [95% CI, .09–.4]). There was no association between CD4+ T-cell counts at 1 year post-CBT and subsequent risk for HZ.
Conclusions
We found a high incidence of HZ after CBT despite antiviral prophylaxis for > 1 year. Based on these findings, we suggest longer duration of prophylaxis for HZ after CBT. Compliance with antiviral prophylaxis, VZV-specific immune monitoring, and vaccination to mitigate HZ after CBT also require further study.
Keywords: hematopoietic cell transplant, cord blood, varicella zoster virus, prophylaxis, antiviral
Cord blood transplant (CBT) recipients have a high cumulative incidence of herpes zoster (HZ) despite longer-term antiviral prophylaxis. Antiviral prophylaxis during immunosuppression and for 3 or more years might reduce the incidence and complications of HZ after CBT.
Herpes zoster (HZ) due to reactivation of varicella zoster virus (VZV) is a frequent complication after autologous and allogeneic hematopoietic cell transplant (HCT) with a peak incidence during the first year post-HCT [1]. In immunosuppressed HCT recipients, VZV reactivation may result in disseminated infection with high morbidity [2, 3]. HZ may have additional complications in up to one-third of cases [4, 5]. Seo and colleagues reported an overall incidence of HZ of 25.6% in HCT recipients when anti-HZ prophylaxis was given only in the peri-HCT period, with most events occurring in the first year post-HCT [6].
Several risk factors for HZ have been identified and include older age, total body irradiation–based conditioning regimens, antithymocyte globulin–based graft-vs-host disease (GVHD) prophylaxis, and GVHD [7–10]. Historically, the duration of antiviral prophylaxis with acyclovir (ACV) or valacyclovir (VACV) was limited to a short, peri-HCT course; however, several groups demonstrated that a high risk of HZ persisted for months after HCT, suggesting the need to administer longer-term antiviral prophylaxis for at least 1 year post-HCT and while taking immunosuppressive medications [11–13]. In 2009, international guidelines for prevention of infection in HCT recipients recommended extended antiviral prophylaxis for a minimum of 1 year post-HCT among VZV-seropositive patients, and beyond 1 year for patients with chronic GVHD requiring immunosuppressants [14].
Cord blood is an alternative source for hematopoietic cells if no human leukocyte antigen–matched donor is available. Cord blood transplant (CBT) recipients have high infection rates in the early post-HCT period due to delayed engraftment and immune reconstitution [15]. In a cohort of 44 CBT recipients who received prophylactic ACV for only 35 days post-HCT, Tomonari and colleagues reported a cumulative incidence of HZ of 80% by 30 months, with 80% of events occurring in the first year [16]. Similar results were documented by others, suggesting an increased risk for HZ in CBT recipients compared to other HCT types [17]. In our study, we retrospectively analyzed the incidence of and risk factors for HZ over 5 years after CBT in patients who received longer-duration antiviral prophylaxis.
METHODS
Patients and Transplant Characteristics
All patients who underwent a CBT at the Fred Hutchinson Cancer Research Center between 2006 and 2016 were eligible for the study. Patients with negative or unknown VZV serostatus, patients who previously received VZV vaccine (Varivax) without a documented history of chickenpox or HZ, and patients with < 30 days of follow-up were excluded (Figure 1). Patients received either myeloablative or reduced-intensity conditioning regimens, with or without total body irradiation (Table 1). From 2006 to May 2008, HZ prophylaxis included either ACV 800 mg twice daily or VACV 500 mg twice daily. From June 2008 to 2016, patients who were cytomegalovirus (CMV) seropositive received intensified prophylaxis with VACV 2 g, 3 times daily, through day +100 [18]. From 2006 to 2009, institutional guidelines recommended HZ prophylaxis until immunosuppression withdrawal; after 2009, guidelines recommended HZ prophylaxis for at least 1 year and at least 8 months after immunosuppression withdrawal. Additionally, HZ prophylaxis was recommended in patients restarted on immunosuppressive therapies. The Fred Hutchinson Institutional Review Board approved the study, and informed consent was signed by all patients in accordance with the Declaration of Helsinki.
Figure 1.
Consolidated Standards of Reporting Trials (CONSORT) diagram. Fifty-nine patients who received Varivax were excluded a priori. Abbreviations: CBT, cord blood transplant; VZV, varicella zoster virus.
Table 1.
Clinical Characteristics of the Study Population
| Herpes Zoster Post-CBT, No. (%) | |||
|---|---|---|---|
| Patient Characteristic | Overall No. (%) | No | Yes |
| No.a | 227 | 183 (81) | 44 (19) |
| Age at CBT | |||
| Age, y, median (range) | 39.9 (0.6–73.1) | … | … |
| ≤18 | 32 (14) | 24 (75) | 8 (25) |
| 19–40 | 89 (40) | 66 (74) | 23 (26) |
| 41–60 | 75 (33) | 63 (84) | 12 (16) |
| >60 | 31 (14) | 30 (97) | 1 (3) |
| Sex | |||
| Female | 117 (57) | 92 (79) | 25 (21) |
| Male | 110 (43) | 91 (83) | 19 (17) |
| Ethnicity | |||
| White | 110 (48) | 90 (82) | 20 (18) |
| Nonwhite | 104 (46) | 82 (79) | 22 (21) |
| Unknown | 13 (6) | 11 (85) | 2 (15) |
| HZ pre-CBT | |||
| No | 27 (12) | 5 (19) | 22 (81) |
| Yes | 24 (11) | 19 (79) | 5 (21) |
| Unknown | 176 (78) | 142 (81) | 34 (19) |
| Patient CMV serostatus | |||
| Positive | 147 (65) | 115 (78) | 32 (22) |
| Negative | 80 (35) | 68 (85) | 12 (15) |
| Underlying disease | |||
| Acute leukemia | 170 (75) | 133 (78) | 37 (22) |
| Othersb | 57 (25) | 50 (88) | 7 (12) |
| Disease status at CBT | |||
| Active disease | 20 (9) | 17 (85) | 3 (15) |
| Remission | 172 (76) | 136 (79) | 36 (21) |
| Nonapplicable | 7 (3) | 6 (86) | 1 (14) |
| Unknown | 28 (12) | 24 (86) | 4 (14) |
| Type of CBT | |||
| Single CBT | 17 (7) | 12 (71) | 5 (29) |
| Double CBT | 210 (93) | 171 (81) | 39 (19) |
| Conditioning regimen | |||
| RICc | 51 (22) | 48 (94) | 3 (6) |
| MACc | 176 (78) | 135 (77) | 41 (23) |
| Use of TBI | |||
| No | 6 (3) | 6 (100) | 0 (0) |
| Low dose | 118 (52) | 99 (84) | 19 (16) |
| High dosed | 103 (45) | 78 (76) | 25 (24) |
| Relapse post-CBT | |||
| No | 176 (78) | 137 (78) | 39 (22) |
| Yes | 51 (22) | 46 (90) | 5 (10) |
| ATG use | |||
| No | 213 (94) | 170 (80) | 43 (20) |
| Yes | 14 (6) | 13 (93) | 1 (7) |
Abbreviations: ATG, antithymocyte globulin; CBT, cord blood transplant; CMV, cytomegalovirus; HZ, herpes zoster; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning; TBI, total body irradiation.
aThirty-two subjects were censored at the last available medical record date at a median of 39 months (interquartile range [IQR], 35.2–47.9 months). Thirteen patients were censored at the time of a second HCT for either disease relapse (n = 7) or graft failure (n = 6) at a median of 12.3 months (IQR, 2.5–26.2 months).
bOther diseases included myelodysplastic syndromes (n = 24), chronic myeloid leukemia (n = 8), Hodgkin and non-Hodgkin lymphomas (n = 7), chronic lymphocytic leukemia (n = 5), immunodeficiency disorders (n = 4), systemic sclerosis (n = 2), chronic myelomonocytic leukemia (n = 1), malignant histiocytosis (n = 2), myelofibrosis (n = 2), unknown (n = 1), thalassemia (n = 1).
cRIC regimens were all based on fludarabine, cyclophosphamide, and low-dose TBI. MAC regimens included high-dose TBI–based, treosulfan-based, busulfan-based, melphalan-based, and thiotepa-based regimens. The mortality rate was significantly higher (P < .001) in the RIC group compared to the MAC group.
dPatients who received high-dose TBI were given a total dose of 1320 cGy.
Data Collection
We reviewed clinical databases and medical records up to 5 years after CBT. Patients are routinely cared at our center for a minimum of 100 days post-HCT. Following discharge, the Fred Hutchinson Long-Term Follow-Up program collected additional data through standardized surveys and medical record requests. The occurrence of HZ and its treatment were specific questions on surveys. All reports of HZ in medical records or physician surveys were included; for HZ reported only in a patient survey, the event was included if there were no accompanying medical records or physician surveys. If the exact date of HZ diagnosis was not available, we used the midpoint between the date of last medical records without notation of HZ and the date of first notation of the event. Start and stop dates for antiviral prophylaxis, antiviral treatment and immunosuppressant medications were collected using a similar approach; if there was a discrepancy between medical records and patient surveys, data from medical records were used. If the stop date were not explicit, we used the last date it was mentioned or the date of death (if applicable; Supplementary Materials).
Definitions
Herpes zoster episodes presenting as a cutaneous rash involving ≤ 2 adjacent dermatomes without crossing the body’s midline were defined as localized; if the rash crossed the body’s midline, if > 2 cutaneous dermatomes were involved, or if there was microbiologically proven visceral involvement, the episode was defined as disseminated. We reviewed all medical records for microbiologic testing for VZV; if not performed, the diagnosis was based on the treating provider’s clinical assessment. Postherpetic neuralgia was captured if mentioned in medical records.
Statistical Analysis
The primary endpoint was the incidence of first HZ episode after CBT. We depicted the probability of developing HZ using a cumulative incidence curve with death and second HCT as competing risk events. We calculated the incidence rate of first HZ episodes per 1 person-year. We examined the associations between the primary predictor of interest, antiviral prophylaxis, and cause-specific hazards of HZ using Cox proportional hazard regression models, censored at time of death, subsequent HCT, or time of last available records. Another predictor of interest was CD4+ T-cell count by 1 year post-CBT. In addition, we also evaluated patient and clinical covariates that could be confounders. ACV/VACV prophylaxis, GVHD, disease relapse, and immunosuppressive treatments were included as time-dependent covariates. Care was taken to examine relationships between risk factors and potential confounders to consider potential causal pathways; no relationships of concern were identified. Variables with a P value < .2 in univariable analyses or of clinical interest were candidates for inclusion in the multivariable model. Variables were retained in the model if they remained significant or modified the effect of another variable by > 10%. Two-sided P values < .05 were considered statistically significant. SAS version 9.4 (TS1M3) for Windows (SAS Institute, Cary, North Carolina) was used for analyses.
RESULTS
Patient Characteristics
Patient and clinical characteristics are listed in Table 1. Between 2006 and 2016, our institution performed a total of 360 CBTs; 227 patients met study inclusion criteria (Figure 1). Compared to allogeneic HCT recipients with a non–cord blood source during the same time period, our cohort had more diagnoses of acute leukemia, fewer cases of nonmalignant diseases, and higher use of myeloablative conditioning regimens (Supplementary Table 1). Patients were followed for a median of 25.4 months post-CBT (interquartile range [IQR], 6.8–49.0 months). Death from any cause occurred in 113 (50%) patients at a median of 7.6 months post-CBT (IQR, 4.2–16.1 months). Among patients with 5 years of follow-up, questionnaires and/or medical records were available for a median of 5 years, suggesting good data capture during follow-up.
Herpes Zoster Events
Herpes zoster occurred in 44 (19%) patients at a median of 23.6 months post-CBT (IQR, 16.1–30.3 months). Forty-three events were documented in medical records and/or physician surveys; 1 was documented only in a patient survey. An exact diagnosis date was available in 29 of 44 (66%) episodes. A microbiologic diagnosis was confirmed in 5 cases (skin, n = 2; plasma, n = 2; and cerebrospinal fluid, n = 1). No patients had a recurrent HZ episode during the study period. Data for secondary prophylaxis were evident in most patients (25/44) for a median of 360 days (IQR, 206–608 days).
The cumulative incidence of HZ was 1.8% (95% confidence interval [CI], .1%–4%) at 1 year but reached 26% (95% CI, 19%–33%) at 5 years (Figure 2). The incidence rate of the first HZ episode after CBT per person-year was 0.08 (95% CI, .06%–.09%) over the 5 years of follow-up (Table 2). The cumulative incidence was similar in patients receiving CBT between 2006–2008 and 2009–2016 (Supplementary Figure 1).
Figure 2.
Cumulative incidence plot of time to herpes zoster (HZ) episode and mortality after cord blood transplant. In this plot, the lower curve shows the cumulative incidence of HZ, with death and subsequent hematopoietic cell transplant (HCT) treated as competing risk events. The upper curve shows the cumulative incidence of overall mortality in patients who did not develop HZ, and the middle section illustrates the proportion of individuals alive and free of HZ.
Table 2.
Incidence Rate for the First Episode of Herpes Zoster Over 5 Years After Cord Blood Transplant
| Incidence Rate (95% CI) per Person-year | ||
|---|---|---|
| First Year Post-CBT | Second Year Post-CBT | Overall Period |
| 0.02 (.01–.03) | 0.06 (.046–.08) | 0.08 (.06–.09) |
Abbreviations: CBT, cord blood transplant; CI, confidence interval.
There were only 4 HZ events in the first year post-CBT. Among patients who survived for at least 1 year after CBT (n = 148), 91% were still receiving prophylaxis for a median antiviral prophylaxis duration of 20.6 months post-CBT (IQR, 14.1–29.4 months; Table 3). Most patients were still receiving prophylaxis at the time of death, loss to follow-up, or second transplant when these events occurred within the first year post-CBT. Antiviral prophylaxis durations were similar for patients transplanted before and after 2009 (median, 18.0 months [IQR, 12.2–24.8 months] and 21.4 months [IQR, 14.9–29.8 months], respectively). The proportion of patients who were and were not receiving antiviral prophylaxis or immunosuppressive therapy after 1, 2, 3, or 4 years post-CBT, and the occurrence of HZ events up until each year of follow-up in each group, are shown in Table 3 and Supplementary Table 2, respectively.
Table 3.
Duration of Antiviral Prophylaxis and the Occurrence of Herpes Zoster Among 1-, 2-, 3-, and 4-Year Survivors After Cord Blood Transplant
| HZ Within the Indicated Time Period, No. (%)a | |||
|---|---|---|---|
| Follow-up After CBT | Overall No. (%) | No | Yes |
| >1-y follow-up | 148 | 144 | 4 |
| Still on antiviral prophylaxis | 134 (91) | 132 (92) | 2 (50) |
| Not on antiviral prophylaxis | 14 (9) | 12 (8) | 2 (50) |
| >2-y follow-up | 119 | 98 | 21 |
| Still on antiviral prophylaxis | 60 (50) | 53 (54) | 7 (33) |
| Not on antiviral prophylaxis | 59 (50) | 45 (46) | 14 (67) |
| >3-y follow-up | 92 | 67 | 25 |
| Still on antiviral prophylaxis | 29 (32) | 26 (39) | 3 (12) |
| Not on antiviral prophylaxis | 63 (68) | 41 (61) | 22 (88) |
| >4-y follow-up | 72 | 46 | 26 |
| Still on antiviral prophylaxis | 15 (21) | 12 (26) | 3 (12) |
| Not on antiviral prophylaxis | 57 (79) | 34 (74) | 23 (88) |
Patients are stratified based on duration of post-CBT follow-up, and then further stratified based on duration of antiviral prophylaxis. We report here the numbers of HZ events that occurred up to the indicated year. For instance, among the 119 patients who had at least 2 years of follow-up, 21 had HZ within the first 2 years. Not all patients and HZ events are captured in this table, as patients were excluded over time due to death, second transplant, or loss to follow-up. All patients and events are captured in the time-dependent Cox model analysis.
Abbreviations: CBT, cord blood transplant; HZ, herpes zoster.
aExact start and stop dates were available for 93% and 68% of instances, respectively.
Clinical Features and Treatment of HZ
Clinical features of HZ events are summarized in Table 4 and Supplementary Table 3. Disseminated HZ occurred in 5 of 44 cases (11%), all of which had extensive skin involvement with 1 case developing VZV myelitis and 1 case developing VZV gastritis and hepatitis. Disseminated HZ presented earlier (median, 15.8 months) than localized HZ (median, 23.7 months).
Table 4.
Clinical Characteristics of First Herpes Zoster Episodes
| Clinical Findings | No. (%) |
|---|---|
| HZ post-CBT | 44 (19.4) |
| Months to event, median (IQR)a | 23.6 (16.1–30.3) |
| Type of HZ episode | |
| Localized | 30 (68.2) |
| Disseminatedb | 5 (11.4) |
| Skin only | 3 (6.8) |
| Skin and visceralc | 2 (4.5) |
| Unknown | 9 (20.5) |
| Postherpetic neuralgiad | 14 (31.8) |
Abbreviations: CBT, cord blood transplant; HZ, herpes zoster; IQR, interquartile range.
aIn 15 of 44 cases, the date of HZ was extrapolated using the midpoint between the date of last medical records without notation of HZ and the date of first notation of the event. Among these 15 cases, the stop date of antiviral prophylaxis was estimated for 5 individuals, the type of HZ episode was unknown for 7 individuals, and treatment was unknown for 8 individuals.
bThe 2 disseminated cases with visceral involvement had a microbiologic diagnosis, whereas the remaining 3 cases with skin-only involvement were clinically diagnosed (Supplementary Table 3).
cVisceral involvement includes 1 case of myelitis and 1 case of gastritis/hepatitis.
dPostherpetic neuralgia was based on documentation in medical records. Criteria may have been heterogeneous, and this may be an underestimate.
Antiviral treatment for HZ consisted of high-dose ACV in 19 cases, VACV in 16 cases, and famciclovir in 1 case. The type of treatment was not reported for the remaining 8 cases. Hospitalization for antiviral treatment or pain management was documented in 11 patients. Treatment was administered for a median time of 9.5 days (range, 5–68 days), and all patients responded to the given treatment.
Postherpetic neuralgia was reported as a complication in 14 of 44 patients (32%; Table 4). There were no reports of bacterial superinfections. No patients died because of HZ.
Risk Factors for HZ
We evaluated the association of demographic and clinical characteristics with HZ (Table 5). In a multivariable analysis, development of acute GVHD grades II–IV was associated with a higher risk of HZ, although the difference did not reach statistical significance. Use of ACV/VACV prophylaxis was associated with a lower risk of HZ (adjusted hazard ratio, 0.19 [95% CI, .09–.4]). Recipient CMV serostatus was not associated with HZ. We also evaluated the association between absolute CD4+ T-cell counts at 1 year post-CBT and risk for subsequent HZ. Among 1-year survivors with available data (n = 117), there was no association between CD4+ T-cell count ≤ 200 cells/µL and risk for HZ.
Table 5.
Univariable and Multivariable Cox Regression Models of Time to First Herpes Zoster Episode After Cord Blood Transplant
| Covariate and Category | HR (95% CI) | P Value | aHR (95% CI) | P Value |
|---|---|---|---|---|
| Age, y | ||||
| ≤40 | 1 | … | ||
| >40 | 0.75 (.4–1.42) | .38 | … | |
| Race/ethnicity | ||||
| White | 1 | … | ||
| Nonwhite | 1.04 (.57–1.91) | .89 | … | |
| Unknown | 0.62 (.14–2.65) | .52 | … | |
| Sex | ||||
| Female | 1 | … | ||
| Male | 1.01 (.56–1.83) | .98 | … | |
| Type of CBT | ||||
| Single CBT | 1 | … | ||
| Double CBT | 0.8 (.32–2.04) | .65 | … | |
| Conditioning regimen | ||||
| RIC | 1 | 1 | ||
| MAC | 1.94 (.6–6.27) | .27 | 1.44 (.43–4.79) | .55 |
| Use of TBI | ||||
| None/low dose | 1 | … | ||
| High dose | 1.23 (.68–2.24) | .49 | … | |
| History of pre- CBT HZ | ||||
| No | 1 | … | ||
| Yes | 1.33 (.38–4.60) | .65 | … | |
| Patient CMV serostatus | ||||
| Negative | 1 | … | ||
| Positive | 1.34 (.69–2.60) | .39 | … | |
| Underlying diseases | ||||
| Othersa | 1 | 1 | ||
| Acute leukemia | 1.91 (.85–4.28) | .12 | 1.63 (.72–3.72) | .25 |
| Disease status at CBT | ||||
| Active disease | 1 | … | ||
| Remission | 1.26 (.39–4.11) | .69 | … | |
| Nonapplicable | 0.92 (.09–8.83) | .94 | … | |
| Unknown | 0.68 (.15–3.03) | .61 | … | |
| ATG use | ||||
| No | 1 | … | ||
| Yes | 0.73 (.10–5.35) | .76 | … | |
| Acute GVHDb | ||||
| Grade 0–I | 1 | 1 | ||
| Grade II-IV | 2.80 (.63–12.3) | .17 | 3.67 (.84–16.0) | .08 |
| Chronic GVHDb | ||||
| No | 1 | … | ||
| Yes | 1.79 (.24–13.1) | .56 | … | |
| Disease relapseb | ||||
| No | 1 | … | ||
| Yes | 0.37 (.05–2.68) | .32 | … | |
| Antiviral prophylaxisb | ||||
| No | 1 | 1 | ||
| Yes | 0.20 (.10–.42) | <.001 | 0.19 (.09–.4) | <.001 |
| Immunosuppressive therapyb,c | ||||
| No | 1 | … | ||
| Yes | 0.74 (.37–1.48) | .39 | … | |
| CD4+ T-cell count by 1 yd | ||||
| ≤200/µL | 1 | … | ||
| >200/µL | 2.26 (.69–7.39) | .18 | … | |
| Unknown | 2.19 (.55–8.77) | .27 | … |
Abbreviations: aHR, adjusted hazard ratio; ATG, antithymocyte globulin; CBT, cord blood transplant; CI, confidence interval; CMV, cytomegalovirus; GVHD, graft-vs-host disease; HR, hazard ratio; HZ, herpes zoster; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning; TBI, total body irradiation.
aOther diseases included myelodysplastic syndromes (n = 24), chronic myeloid leukemia (n = 8), Hodgkin and non-Hodgkin lymphomas (n = 7), chronic lymphocytic leukemia (n = 5), immunodeficiency disorders (n = 4), systemic sclerosis (n = 2), chronic myelomonocytic leukemia (n = 1), malignant histiocytosis (n = 2), myelofibrosis (n = 2), unknown (n = 1), and thalassemic syndrome (n = 1).
bAcute GVHD, chronic GVHD, hematologic relapse, antiviral prophylaxis, and immunosuppressive therapy were considered as time-dependent covariates.
cImmunosuppressive therapy included GVHD prophylaxis or treatment. GVHD prophylaxis included calcineurin inhibitors in all cases; GVHD treatments included steroids, rituximab, etanercept, mycophenolate mofetil, and daclizumab.
dCD4+ T-cell counts at 1 year after CBT were available in 117 individuals.
At the time of HZ, there was clear documentation that 31 of 44 (70%) patients were not receiving antiviral prophylaxis. Among these 31 patients, the median time between antiviral prophylaxis discontinuation and HZ was 4.5 months (IQR, 1.6–13.8 months). Of the remaining 13 possible breakthrough cases, 6 patients had clear documentation that they were still receiving antiviral prophylaxis; for 7 patients, the exact timing of antiviral prophylaxis discontinuation was unclear and was estimated from the available medical records.
Of the 44 patients with HZ, 14 (32%) were receiving immunosuppressive therapies when HZ occurred. Five of the 13 (38%) breakthrough events occurred when patients were receiving immunosuppressants consisting of steroids (n = 2), calcineurin inhibitors (n = 1), or both (n = 2).
We also analyzed adherence to our institutional guidelines instituted in 2009 to guide future strategies. Among 101 evaluable patients, only 43 of 101 (42.6%) received antiviral prophylaxis for HZ prevention in accordance with our guidelines (ie, antiviral prophylaxis for ≥1 year after CBT and at least 8 months after completing immunosuppression). HZ occurred in 10 of 43 patients (23.3%) receiving prophylaxis in accordance with the guidelines and in 20 of 58 patients (34.5%) not adherent to the guidelines. Patients who followed the guidelines continued prophylaxis for a median of 17.6 months (IQR, 13.2–25.7 months) after immunosuppressant withdrawal.
DISCUSSION
Despite the improvements achieved in the last decades in treating post-HCT complications, reactivation of VZV in HCT recipients remains a challenging issue that substantially affects transplant outcomes and quality of life [19, 20]. In this study, we retrospectively evaluated the incidence, clinical outcomes, and risk factors for HZ in a large cohort of pediatric and adult CBT recipients who received long-term antiviral prophylaxis. We found a protective effect of antiviral prophylaxis during its administration, but despite prophylaxis for a median of 20.6 months among 1-year survivors, there remained a high incidence of HZ in the years following its discontinuation.
The role of ACV/VACV in both preventing and treating HZ is a well-known success story [12, 13, 21, 22]. Despite this, HCT recipients still have markedly higher rates of HZ compared to the annual incidence of 0.5% among healthy individuals [1, 23, 24]. A study focusing on HZ within 3 years after CBT demonstrated a higher cumulative incidence of HZ in children after CBT (46%) compared to bone marrow transplant (31%) without VZV-specific prophylaxis [17]; another study reported a cumulative incidence of 80% by 30 months after CBT using prophylaxis up to day +35 [16]. The introduction of prophylaxis for 1 year or longer was demonstrated to be effective in preventing HZ after autologous and allogeneic HCT (Table 6) [13]. Kanda et al reported a decrease in the 1-year cumulative incidence of HZ from 33% to 10% when the antiviral prophylaxis was prolonged until the end of immunosuppressive therapy compared to a short peri-HCT course of ACV/VACV, and other groups have reported similar findings [11, 13]. Although there is theoretical concern for increased HZ after prophylaxis discontinuation as a rebound effect [25], other studies have demonstrated no association between prophylaxis administration and delayed VZV-specific T-cell immune reconstitution [12].
Table 6.
Cumulative Incidence of Herpes Zoster in Previous Studies That Used Long-term Antiviral Prophylaxis After Hematopoietic Cell Transplant
| Antiviral Prophylaxis | Type of HCT | Duration | Cumulative Incidence | Reference |
|---|---|---|---|---|
| Oral ACV | Allo-HCT | Until IST discontinuation (median time, 152 d) | 10% at 1 y | Kanda et al [11] |
| Oral ACV | Allo-HCT | Until IST discontinuation or CD4+ T-cell count >200/µLa | 35% at 5 y | Thomson et al [26] |
| Oral ACV | Allo-HCT | 1 y | 8% at 2 y | Boeckh et al [12] |
| Oral ACV/VACV | Auto-HCT (24%), allo-HCT (76%), including CBT (1%) | 1 y | 8.8% at 2 y | Erard et al [13] |
| Oral ACV/VACV | Auto-HCT (31%), allo-HCT (69%), including CBT (2%) | 1 y or 6 mo after IST discontinuationb | 4.5% at 2 y | Erard et al [13] |
| Oral VACV | Allo-HCT | 1 y | 18.5% at 2 y | Oshima et al [27] |
| Oral ACV | Allo-HCT, including CBT (7.8%) | 1 y | 18.5% at 2 y | Kawamura et al [28] |
| Oral ACV/VACV | Auto-HCT | 1 y | 21% at 5 y | Sahoo et al [29] |
Abbreviations: ACV, acyclovir; allo-HCT, allogeneic hematopoietic cell transplant; auto-HCT, autologous hematopoietic cell transplant; CBT, cord blood transplant; IST, immunosuppressive treatment; VACV, valacyclovir.
aIn this study, median time on ACV for those who reactivated varicella zoster virus was 418 days (range, 164–987 days), and 398 days (range, 116–959 days) for those who did not reactivate.
bIn this study, ACV was discontinued at 1 year post HCT or 6 months after IST withdrawal, whichever happened later.
After CBT, viral reactivation represents a marked challenge in the early and late posttransplant periods [18, 30–32]. This is likely because cord blood lymphocytes do not include pathogen-specific memory T cells and have more immature features compared to adult peripheral blood–derived lymphocytes [33, 34]. Studies have demonstrated an association between lower CD4+ T-cell counts and viral reactivation in other contexts [34, 35]. Interestingly, we found that having a CD4+ T-cell count > 200 cells/µL at 1 year post-CBT was not protective against HZ. Similarly, Thomson and colleagues showed that a strategy of discontinuing antiviral prophylaxis after allogeneic HCT based on CD4+ T-cell counts > 200 cells/µL was not associated with a reduced incidence of HZ, suggesting that absolute CD4+ T-cell counts may not be a prognostic biomarker [26]. However, CD4+ T-cell counts are nonspecific, and they may not reflect virus-specific immune recovery.
In this study, we demonstrated a low incidence of HZ in the first year after CBT (1.8%) during the period in which almost all patients were taking ACV/VACV. However, ACV/VACV prophylaxis use declined after the first year (in part due to institutional guidelines); in parallel, the incidence of HZ markedly increased in the second year after CBT (11%), reaching 26% by 5 years (Figure 2). The occurrence of reported PHN was high in our cohort (32%) compared to the rates reported in other studies of HCT recipients [16] and the general population [36]. Furthermore, 11% of patients with HZ in our cohort developed disseminated disease within 2 years of CBT, including 2 cases of visceral disease. Our findings are comparable to those reported in other studies using similar prophylaxis schedules in different HCT settings (Table 6) [11–13, 27, 28]. Interestingly, the cumulative incidence of HZ was similar after CBT compared to other types of HCT when longer-term antiviral prophylaxis regimens are implemented.
As expected, the use of antiviral prophylaxis was highly effective in reducing the development of HZ during its administration, explaining the very low rate of events in the first post-CBT year. However, the risk for HZ remained high for an extended time period post-CBT. Based on our findings, the lack of alternative prophylactic strategies at this time, and the safety of ACV/VACV, antiviral prophylaxis for more than a year should be considered in CBT recipients and particularly in the context of ongoing immunosuppression. For instance, antiviral prophylaxis for at least 3 years after CBT may have prevented > 75% of HZ episodes in our cohort, including most instances of disseminated HZ. Although the emergence of resistant VZV has been previously reported in HCT recipients, all 44 cases reported here responded to the administered acyclovir, valacyclovir, or famciclovir.
To put our findings in context and guide future prevention strategies, we examined the frequency of adherence to our institutional guidelines and found that only 42.6% of patients were fully adherent. Among them, 23.3% still experienced HZ. Additionally, we identified 13 cases of definite or possible breakthrough HZ among patients receiving antiviral prophylaxis, and 3 of these episodes developed disseminated disease. These data indicate the need to identify approaches to both increase adherence and develop better strategies for antiviral prophylaxis. These efforts should be focused in the highest-risk individuals, such as those with GVHD requiring immunosuppressive therapy. Additionally, development of assays to assess VZV-specific immune reconstitution could further guide risk stratification. Vaccination may provide a more durable approach to reduce HZ risk and could also overcome the challenge of lack of compliance with medications [37]. The HZ recombinant subunit vaccine was recently approved in immunocompetent older populations [38], and randomized, placebo-controlled, phase 3 studies using this and another inactivated vaccine demonstrated safety and a significant reduction of HZ after autologous HCT [39, 40]. Data on the safety and efficacy of the HZ recombinant subunit vaccine among allogeneic HCT recipients are needed prior to recommending its use in this context.
Our study has intrinsic limitations due to its retrospective nature. It is possible that we underestimated or overestimated HZ episodes due to missing data or misclassification, respectively. We note that most HZ cases were clinically diagnosed. We could not account for patients’ adherence to antiviral prophylaxis if not detailed in clinical notes. Given that last patient underwent transplantation in 2016, 5 years of follow-up were not available for all. Although we may have overestimated the number of breakthrough cases due to incomplete records, some of these might be explained by poor adherence to prophylaxis or drug malabsorption. Comparable rates of breakthroughs were reported in other studies [29, 41]. Despite these limitations, this is the first and largest study of HZ conducted in CBT recipients using longer-term antiviral prophylaxis with ACV/VACV, to the authors’ knowledge.
In conclusion, this study highlights that antiviral prophylaxis is protective against HZ after CBT. However, there remained a high incidence of HZ after its discontinuation, despite prolonged administration for ≥ 1 year. Longer prophylaxis might reduce the incidence and complications of HZ. Studies of the roles of VZV-specific immune monitoring and vaccines to mitigate HZ in high-risk CBT recipients will be important to refine prophylactic strategies.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Notes
Author contributions. E. X., F. M., M. B., and J. A. H. designed the study. E. X., J. A. H., L. E. K., S. G., L. C., R. B., B. M., and A. E. collected data. H. X., W. L., E. X., and J. A. H. analyzed the data. E. X. and J. A. H. wrote the manuscript. All the authors read and approved the final manuscript.
Acknowledgments. The authors acknowledge Chris Davis for help with data abstraction.
Financial support. This study was supported in part by the National Institute of Allergy and Infectious Diseases (grant number K23 AI119133 to J. A. H.) and the National Institutes of Health/National Cancer Institute (Cancer Center support grant P30 CA015704).
Potential conflicts of interest. J. A. H. has served as a consultant for Amplyx and Gilead Sciences and has received research support from Karius and Takeda (formerly Shire), all unrelated to this research. S. A. P. receives research funding from Global Life Technologies, participates in clinical trials for Chimerix, and serves on the Zoster Working Group of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices, all unrelated to this research project. M. B. has served as a consultant and received research support from Merck Research Laboratories, Chimerix, GlaxoSmithKline, and Gilead Sciences, all unrelated to this research. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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