Table 3.
Studies in Which Directionality of Analysis Was Not Articulated (Group 3)
| Reference (Study Design) | Graft Source | No. of Patients | Testing Method | Reactivation Percent (Frequency) | Médian Day of HHV-6 Réactivation (Range) | Médian Day of aGVHD Onset (Range) | HHV-6 Active Antivirals: Indication for Treatment | HR[95% Cl]; P(aGVHD Grade) |
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| Definition of Active Infection | ||||||||
| Quintela 2016 [33]* (case control) | BM: 42% CB:16% PBSC: 42% | 366 | qPCRWB >2 consecutive positive qPCR results (>3 logio copies/mL) | 20.5 (75/366) 13.9 (51/366)* | N/A | N/A | Foscarnet, ganciclovir, or cidofovir: CMV and/or HHV-6 infection (46/366 patients were treated) | P=.52 (all grades) |
| Inazawa2015 [26](prospective cohort)† | BM: 57% CB:37% PBSC: 6% | 105 | Qualitative PCRWB >50 copies | 60(63/105) | N/A | N/A | N/A | UP = .046† (all grades) UP = .005† (stage of skin GVHD) |
| Mutlu 2014 [28],¶ (prospective cohort) | BM:100% | 15 | qPCRWB >250 copies/mL | 53 (8/15) | Day 14 (6–23) | N/A | N/A | UP = .001 (grade 4)¶ |
| Ogata 2013 [34] (prospective cohort) | BM/PBSC: 29% BM: 44% CB:27% | 230 | qPCRp >50 copies/mL | 72.2 (166/230) | N/A | N/A | Ganciclovir treatment: CMV reactivation Foscarnet, Ganciclovir, or valganciclovir: HHV-6 reactivation at the discretion of clinicians | UP = .0003 (any reactivation) (grades II-IV) UP = .02 (> 10,000 copies/mL) (grades II-IV) |
| Jeulin 2013 [29] (retrospective cohort) | BM: 47% CB:20% PBSC: 33% BM+PBSC: .5% | 220 | Qualitative PCR & qPCRWB >2500 copies/mL | 20(44/220) | N/A | N/A | Foscarnet, ganciclovir, or cidofovir treatment: CMV or HHV-6 (persistent with clinical signs) reactivation | UP = .0028 (all grades) |
| Kullberg-Lindh 2011 [35];¶ (retrospective cohort) | BM: 66% CB: 2% PBSC: 32% | 47 | qPCRs >200–400 gEq/mL | 27.7(13/47) | N/A | N/A | Foscarnet or ganciclovir treatment: CMV reactivation | UP = .16 (all grades) MP = .38 (all grades )¶ |
| Betts 2011 [36] ‡ (prospective cohort) | BM: 34% CB:66% | 82 | qPCRWB >500 copies/mL (high level viremia >25,000 copies/mL) | 56.1 (46/82) | Day 23 (range 10–168) | N/A | Foscarnet, ganciclovir, valganciclovir or cidofovir treatment: CMV reactivation, and/or HHV-6 reactivation with clinical complications | UP = .12 (grades II-IV) UP = .55* (grades II-IV) |
| Chevallier 2010 [37] (retrospective cohort) | BM: 73% CB:27% | 55 | qPCRp >1 PCR >31og/mL or >2 consecutive PCRs between 2–31og/mL | 52.7 (29/55) | CB: Day 36 (16–74) BM: Day 58 (24–100) | N/A | Foscarnet or ganciclovir treatment: CMV reactivation or disease | P=NS (grades II-IV) |
| Yamane 2007 [38] (prospective cohort) | BM/PBSC: 24% BM: 48% CB:28% | 46 | qPCRp >200 copies/mL | 47.8 (22/46) | Week 3 (week 2-week 5) | N/A | Foscarnet or ganciclovir treatment: CMV reactivation | UP = .269 (grades II-IV) |
| Ogata 2006 [39] (prospective cohort) | BM: 84% PBSC: 16% | 50 | qPCRp >50 copies/mL | 48(24/50) | Day 18 (0–48) | N/A | Ganciclovir treatment: CMV reactivation or HHV-6 disease | UP = .08 (grades II-IV) |
| Tomonari 2005 [40] (retrospective cohort) | CB: 100% | 23 | qPCRs Any HHV-6 DNA detection | 87(20/23) | N/A | Day 32 (range 10–42) | Ganciclovir treatment: CMV reactivation | UP< .05 (grades II-IV) |
| Radonic 2005 [41],¶ (prospective cohort) | BM: 23% PBSC: 77% | 82 | qPCRp >200 copies/mL | 42.7 (35/82) | Day 41 (5–212) | N/A | N/A | UP = .047 (grades II-IV) mHR2.3 [1.1–4.7]; P =.023 (grades II-IV)1 |
| Ljungman 2000 [42], §(prospective cohort) | BM: 80% PBSC: 20% | 74 | Nested PCRPBL Any HHV-6 DNA detection | 78.4(58/74) | N/A | N/A | Foscarnet or ganciclovir treatment: CMV reactivation | UP =NS (Grades II-IV) |
| Imbert-Marcille 2000 [43] (prospective cohort) | BM: 68% PBSC: 32% | 28 | Qualitative pcrpbmc+p Any HHV-6 DNA detection | 42 (12/28) | Day 17 (6–117) | N/A | Ganciclovir treatment: CMV reactivation | UP =.04 (grades III-IV) |
| Wang 1999 [44] (prospective cohort) | BM: 33% PBSC: 67% | 24 | Nested PCRPBL any HHV-6 DNA detection in >3 consecutive samples | 83 (20/24) | N/A | N/A | N/A | UP =.009 (grades II-IV) |
| Maeda 1999 [45],¶ (prospective cohort) | BM: 58% PBSC: 42% | 38 | Nested PCRPBL Any HHV-6 DNA detection | 56 (9/16; peak week 3) | N/A | N/A | N/A | UP = .051 (grades II-IV)¶ |
| Wang 1996 [46],‡ (prospective cohort) | BM: 100% | 37 | Nested PCRPBL Any HHV-6 DNA detection | 70(26/37) | N/A | N/A | Foscarnet or ganciclovir treatment: CMV reactivation | P =NS (grades II-IV) |
| Appleton 1995 [47]∥,¶(prospective case control) | BM: 100% | 31 | Nested pcrpbl+sb Any HHV-6 DNA detection in PBL or skin biopsy | 71 (22/31) | N/A | N/A | N/A | PBL: P =.85(allgrades) Biopsy: UOdds ratio 22.00 [2.3213]; P=.008† (severe GVHD)¶ |
*
HHV-6 infection (20.5%) was defined as HHV-6 DNAemia ≥ 3 log 10 copies/mL whole blood, whereas active infection (13.9%) was ≥ 2 consecutive HHV-6 DNAemia > 3 log10 copies/mL whole blood.
†
Univariate analysis of onset of aGVHD vs. HHV-6 reactivation(P = .016). Univariate analysis of stage of aGVHD vs. HHV-6 reactivation (P = .005).
‡
Univariate analyses: [incidence of aGVHD] in no viremia vs. HHV-6 viremia (P = .12), [incidence of aGVHD] in low level viremia (<25,000 copies/mL WB) vs. High level viremia (≥25,000 copies/mL WB)(P = .55).
§
All patients from Wang et al. 1996 were included in Ljungman et al. 2000, so only Ljungman et al. 2000 was used for the meta-analysis.
∥
Odds ratio was determined using HHV-6 DNA detection in after BM transplant biopsy as a risk factor for severe aGVHD.
¶
No odds ratio or 2 × 2 table provided (ie, study was excluded from meta-analysis).