New Insights in Current Practice in the Management of DNA Viruses in Children Following Allogeneic HSCT at EBMT Centers
Authors: Ince Elif , Sedlacek Petr , Feuchtinger Tobias , Le Goff Jérôme , Truong Tony H , Lion Thomas , Styczynski Jan , Abouqateb Mouad , Dalissier Arnaud , De La Camara Rafael , Averbuch Dina , Kalwak Krzysztof 
Published: December 2024

Persistent DNA viruses can cause severe diseases leading to high morbidity and mortality in immunocompromised patients following allogeneic (allo) HSCT. Evidence based guidelines have been published for the management of these viruses but the adherence to guidelines is uncertain. 155 EBMT pediatric transplant centers were approached to respond to a survey from September 2023 till May 2024. 68 centers (44 %) participated including 58 centers (85%) that performed at least 10 allo HSCTs in children in the past year, 25 being JACIE-accredited.

For HSV/VZV, prophylaxis is used for all patients in 54 (79%) centers and only for seropositive patients in 14 centers. Acyclovir/valacyclovir is the preferred prophylaxis in all centers. Prophylaxis is continued for up to 1 year in 29 (43%) centers and 25 (37%) centers extend prophylaxis for patients with ongoing GvHD. HSV resistance testing is available in 38/68 (56%) centers, the most common methods being PCR in 18 or NGS in 13 centers.

For CMV, a seronegative donor (D-) is preferred for a seronegative patient (R-) in MUD and haploidentical (haplo) HSCT in 54 (79%) and 51 centers (75%), respectively. For CMV seropositive patients (R+), a seropositive donor (D+) is preferred in 59 (87%) centers for MUD and 54 (79%) centers for haplo HSCT. CMV prophylaxis is used for MUD (10/10 or 9/10) in 38, haplo (T-cell depleted, TCD) in 36, haplo (PTCY) in 36 and MSD without serotherapy HSCT in 33 centers, respectively. The most common indication for prophylaxis is D-/R+ HSCTs in 38, followed by D+/R- in 29 and D+/R+ HSCTs in 28 centers, respectively. Letermovir is used for prophylaxis with different limitations in 35/68 centers (51%). CMV prophylaxis is continued until day +100 in 32 and extended prophylaxis is used in 23 centers. CMV PCR monitoring is performed in all centers (100%). Monitoring is weekly in 44 (66%) and twice weekly in 21 (31%) centers. The specimen is whole blood in 66% and plasma in 34% of centers. Most centers stop monitoring CMV on day +100, 72% centers extend monitoring mostly in case of cGvHD (86%). CMV specific T cell immunity is routinely monitored in only 6 centers. Ganciclovir is used for first line preemptive treatment in 53 centers (78%). Foscarnet is used as second line in 59 centers (87%). CMV viral resistance testing is available in 51 (75%) centers, using PCR in 27, NGS in 15 and/or Sanger sequencing in 11 centers.

Rituximab (RTX) is considered for use as EBV prophylaxis in 24/68 (35%) centers, mostly for haplo TCD HSCTs (17/24; 71%), followed by haplo PTCY (8/24; 33%). Only very few centers use RTX for EBV prophylaxis in MUD (9-10/10) (17%) or MSD HSCTs (13%). EBV PCR monitoring is performed in 97 % centers using whole blood in 41 (63%), and/or plasma in 25, and/or serum in 10 centers. Twenty five centers (37%) stop monitoring EBV on day +100 and 29 centers (43%) continue monitoring until the end of immunosuppressive therapy. Additionally, 40 centers (59%) centers reported extended monitoring mostly for acute or chronic GvHD (29/40; 72%).

Routine HAdV PCR monitoring after HSCT is performed in 53 centers (39 in all HSCTs); blood only in 26, stool and blood in 25, stool only in 2 centers. Weekly monitoring is performed in 39 centers. Routine qPCR monitoring is performed for HHV6 in 27 centers, for BKV in 23 centers (plasma in 15, urine in 19 centers), respectively.

Intravenous immunoglobulin (IVIG) substitution following allo HSCT was reported by 75% of centers, 11 centers use IVIG regardless of IgG levels, 38 centers use a specific IgG level. Discontinuation is determined by adequate IgG levels rather than a certain time after HSCT.

CTLs were used for treatment in 54% of centers.Access to HAdV, CMV and EBV Cytotoxic T-Lymphocytes were reported in 46%, 44% and 44% of centers. Access to BKV or HHV6 CTLs is low (1 and 6 centers).

Despite published recommendations (Styczynski J et al, 2009; Styczynski J et al, 2016; Ljungman P et al, 2019 ; Ward KN et al, 2019; Matthes-Martin S et al, 2011 ; Hiwarkar P et al, 2018 ; Cesaro S et al, 2018, Tomblyn M et al, 2009) centers reported IVIG use regardless of IgG levels, use of HSV/VZV acyclovir prophylaxis regardless of serology, regular monitoring for HAdV and HHV6. Prophylactic Letermovir is provided increasingly ahead of publications and approval. RTX is considered for use as EBV prophylaxis mostly in haplo HSCT settings. Addressing the causes of deviations from guidelines in routine practice may help improve the management of these viruses.

*On Behalf of the European Society for Blood and Marrow Transplan tation (EBMT) Infectious Diseases Working Party (IDWP) and Pediatric Diseases Working Party (PDWP).