Table 2.
HHV-6 Reactivation as a Risk Factor for Subsequent aGVHD (Group 1)
| Reference (Study Design) | Graft Source | No. of Patietns | Testing Method | Reactivation Percent (Frequency) | Median Day (Post-HCT) of HHV-6 Reactivation (Range) | Median Day of aGVHD Onset (Range) | HHV-6 Active Antivirals: Indication for Treatment | HR [95% Cl]; P (aGVHD grade) |
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| Definition of Active Infection | ||||||||
| Admiraal 2017 [17],∥ (retrospective cohort) | BM: 45% CB: 52% PBSC: 3% | 273 | qPCRp > 1000 copies/mL | 27 (74/273) | N/A | N/A | Foscarnet treatment: HHV-6 disease, eg, encephalitis or bone marrow suppression Ganciclovir or foscarnet: CMV reactivation Cidofovir: adenovirus reactivation | “HR3.47 [2.11–5.7]; P<.0001 (grades II-IV) “HR2.74 [1.22–6.15]; P=.018 (grades III-IV) |
| Cirrone 2016 [11] (prospective cohort) | CB: 100% | 92 | qPCRp >200 copiesjmL | 65.2 (60/92) | Day 26 (IQR, 19–33) | Day 42 (N/A) | Ganciclovir prophylaxis (administered pretransplant): CMV-seropositive donor andfor recipient | “HR3.00 [1.4–6.4]; P=.004 (grade N/A) |
| Aoki 2015 [18] (retrospective cohort) | BM: 73% CB: 27% | 236 | qPCRp > 125 copiesjmL | 58.5(138/236) | N/A | N/A | N/A | “HR 1.87 [1.13–3.09]; P=.01 (grades II-IV) |
| Verhoeven 2015 [19] (prospective cohort) | BM: 71% CB: 7% PBSC: 22% | 106 | qPCRp+s >25 copiesjmL | 48(51/106) | Day 20 (1–44) | N/A | Foscarnet, Ganciclovir, or cidofovir: Indication not specified, but reported that 6/51 patients received these antivirals during HHV-6 reactivation | “HR 14.2 [2.1–94.4]; P=.006 (grades II-IV) |
| Violago 2015 [13],* (prospective cohort) | BM: 49% CB: 21% PBSC: 30% | 100 | qPCRp > 1000 copiesjmL | 19% (19/100) | Day 42 (N/A) | N/A | Foscarnet or ganciclovir prophylaxis (administered post-transplant until day +100): patients at risk for CMV reactivation (received by 67% of cohort) Foscarnet, ganciclovir, or cidofovir treatment: CMV or adenovirus reactivation; HHV-6 reactivation at the discretion of clinicians | UP=.028* (grades II-IV) UHR2.323 [.897–6.015]; P=.083 (grades II-IV) “HR 1.951 [.737– 5.1262]; P= .178 (grades II-IV) |
| Gotoh 2014 [27],† (prospective cohort) | BM: 43% CB: 31% PBSC: 26% | 49 | qPCRp >20 copiesjmL | 53.1 (26/49) | All patients were tested for HHV-6 on day 30 | Day 31 (13–81) | Foscarnet or ganciclovir treatment: CMV reactivation | “HR 9.957 [2.68–37.06]; P<.001f (grades II-IV) |
| Olson 2014 [14] (retrospective cohort) | CB: 100% | 125 | qPCRp >100 copies/mL (high reactivation >10,000 copies/mL) | 94(117/125) | Day 20 (10–59) | N/A | Foscarnet treatment: CMV reactivation; HHV-6 reactivation at the discretion of clinicians (311125 treated); HHV-6 disease | “HR 1.41 [.86–2.31]; P=.17 (grades II-IV)# |
| de Pagter 2013 [20],§ (retrospective cohort) | BM/PBSC: 95% CB: 5% | 108 | qPCRp > 1,000 copiesjmL | 17(18/108) | Day 18 (0–35) | N/A | Foscarnet or valganciclovir treatment: CMV reactivation | UHR 7.4 [3.84–14.3]; P<.001 (grades II-IV) “HR6.07 [2.9–12.7]; P<.001 (grades II-IV) |
| Zerr2012 [22] (prospective cohort) | BM: 19% CB: 7% PBSC: 74% | 315 | qPCRp >25 copies/mL (high reactivation >1,000 copies/mL) | 35(111/315) | Day 20 (IQR, 15–28) | Day 27 (IQR, 19–41) | Foscarnet or ganciclovir CMV reactivation | “aHR2.39 [1.60–3.56]; P<.001 (grades II-IV)# |
| Tormo 2010[31],‡ (prospective cohort) | BM: 3% CB: 19% PBSC: 78% | 68 | qPCRp > 10 copiesjmL | 39.7 (27/68) | Day 20 (7–44) | N/A | Foscarnet, ganciclovir, or valganciclovir treatment: CMV reactivation | HR.9[.3–0.9];P = .6* (grades II-IV) |
| Wang 2008 [12] (prospective cohort) | BM: 8% | 72 | qpCRPBMC | 48.6 (35/72) | Day 21 (7–84) | Day 26 (9–73) | Ganciclovir prophylaxis (administered pretransplant): indication not specified | “HR8.9 [2.9–31.0]; P=.0006 (grades II-IV by day +30) “HR 6.1 [2.1–17.8]; P= .001 (grades II-IV by day +50) (.continued on next page) |
| BM+PBSC/BM +PBSC+CB: 81% | >10 copies/10 [6] cells | Foscarnet or ganciclovir treatment: CMV reactivation | MHR 4.8 [1.7–13.6]; P =.0028 (grades II-IV by day +100) | |||||
| de Pagter 2008 [24]∥¶ (prospective cohort) | BM: 64% CB: 26% PBSC: 10% | 58 | qPCRP >250 copies/mL (high reactivation >1000 copies/mL) | 67(39/58) | Day 16(0–120) | N/A | Foscarnet or ganciclovir treatment: CMV reactivation Foscarnet treatment: HHV-6 disease (3 of 58 treated) | UOR5.3 [1.1–28.0]; P =.049 (grades II-IV)# mOR 7.8 [1.2–50.1]; P =.032 (grades II-IV)# |
| Zerr 2005 [25] (prospective cohort) | BM: 81% CB: 1% PBSC: 18% | 110 | qPCRP >25 copies/mL | 47(52/110) | Day 23 (IQR, 19–28) | N/A | Foscarnet or ganciclovir treatment: CMV reactivation | UHR5.6 [1.6–19]; P = .01 (grades III-IV) MaHR4.9 [1.5–16]; P =.02 (grades III-IV) |
| Chan 1997 [32],¶(prospective cohort) | BM:100% | 61 | Nested PCRpbl+ p AnyHHV-6DNA detection | 28(17/61) | N/A | N/A | Ganciclovir prophylaxis (administered until day +120 post-transplant or engraftment): matched unrelated transplant recipients (7/61 patients) Ganciclovir treatment: CMV reactivation | UP=.61 (grade N/A)¶ |
U indicates univariate analysis; M, multivariate analysis; P, plasma; S, serum; PBL, peripheral blood leukocyte; BM, bone marrow; CB, cord blood; PBSC, peripheral blood stem cells.
Incidence of aGVHD in HHV-6–postitve patients vs. HHV-6–negative (P = .028).
HHV-6 testing was performed only on day +30 post-HCT. This study did provide an HR but tested for HHV-6B only on day +30 post-HCT. We judged this to be systematic HHV-6 testing so we included it in our systematic review. However, this method is not homogenous with the rest of the studies included in our meta-analysis (weekly or biweekly HHV-6 testing). Thus, we did not include Gotoh et al. [27] in our meta-analysis.
Cryopreserved specimens were used for analysis and availability of sufficient volume of plasma for PCR was a limiting factor that precluded analysis of a larger number of specimens (median 6 samples per patient [range, 3 to 11] by day +75).
There is some overlap between de Pagter 2013 (patients from UMC Utrecht and Erasmus MC from January 2004 to May 2008: median age at transplant 40 years [range 17–65]) and Admiraal 2017 (patients from UMC Utretcht from January 2004 to September 2014: median age at transplant 8.4 years [range, .1–22.7]). Based on this information, the overlap was judged to be small. Thus, both studies were included in the meta-analysis.
All patients from de Pagter et al. 2008 were included in Admiraal et al. 2017, so only Admiraal et al. 2017 was used for the meta-analysis.
Study was excluded from meta-analysis (ie, no HR was reported).
High reactivation(>1000 copies/mL for Zerr 2012, de Pagter 2008 or >10,000 copies/mL in Olson 2014) was used as the predictor for aGVHD.