{"doi":"10.1111/1346-8138.16785","title":"Identification of skin‐infiltrating donor lymphocytes in a case of pre‐engraftment syndrome","abstract":"Umbilical cord transplantation (UCBT) has emerged as an alternative to bone marrow transplantation (BMT) for the treatment of hematologic malignancies due to its permissive HLA mismatching and easier procurement logistics. Engraftment in UCBT is slower but with lower incidence of graft-versus-host disease (GVHD) than conventional BMT.1, 2 Interestingly, UCBT has led to the recognition of pre-engraftment syndrome (PES) as an entity distinct from acute GVHD (aGHVD) and engraftment syndrome (ES), with reported incidence rates of 20%–86.6%.1-3 aGVHD is a post-engraftment alloreactive response mediated by donor-derived T cells that typically develops 14–100 days post-transplant.4 ES occurs concomitantly with the emergence of peripheral neutrophils and is driven by cytokine production during early engraftment.5 Similar to ES, PES manifests as noninfectious fever associated with aGVHD-like rash and signs of fluid retention but occurs 5–11 days post-UCBT, prior to engraftment.1 Both ES and PES are attributed to cytokine storms.1 35% of PES display rash,3 the nature of which has not been well-characterized. Here, we report a case of PES in which we identified donor-derived leukocytes in the skin via in situ hybridization of the X and Y chromosomes (XY-FISH). A 51-year-old man with myelodysplastic syndrome that received UCBT (preconditioning: fludarabin, busulfan, melphalan) from a female donor developed fever, rash, and diarrhea 8 days post-UCBT. He presented diffuse, maculopapular erythema with 6.3% weight gain (Figure 1a,b) and no identifiable infectious etiologies. Complete blood count revealed a pre-engraftment status, showing lymphocytopenia (51/μL) and neutropenia (56/μL) (Figure 1b). Laboratory test was notable for increased serum C-reactive protein (9.9 mg/dL) level. Skin biopsy showed subtle vacuolar degeneration with scattered epidermal lymphocytic infiltrates (Figure 1c,d), primarily consisting of CD8+ T cells. CD4+ T cells and CD163+ macrophages localized to the dermis (Figure 1e-h). No dyskeratotic keratinocytes were observed, which argued against aGVHD. Taken together, the patient was diagnosed with PES. All symptoms resolved without corticosteroids, with no changes in medication or doses of tacrolimus (0.025 mg/kg) and mycophenolate mofetil (30 mg/kg), consistent with the PES diagnosis. Lymphocyte skin infiltrations render PES and aGVHD challenging to distinguish. To determine the origin of lymphocytes, we performed XY-FISH, taking advantage of the sex-mismatched transplant. This revealed donor-derived cells (XX) within the epidermis (Figure 1i,j), which likely represent CD8+ T cells based on immunohistochemical staining. Thus, while donor-derived T cells infiltrated PES skin, dyskeratotic keratinocytes that signifies alloreactivity and cytotoxicity, as observed in aGVHD, was absent. Given that PES emerges before engraftment, UCB might be contaminated with T cells that directly infiltrate recipient skin. It is attractive to postulate that, unlike conventional BMT, UCBT leads to donor lymphocyte-driven skin inflammation with less alloreactivity and cytotoxicity, perhaps activated in a bystander manner by the concomitant cytokine storm. Importantly, PES is either self-limiting or can be controlled via immunosuppression, as observed in this case. Such clinical response is distinct from hyperacute GVHD, which has higher rate of nonrelapse mortality.4 Performing XY-FISH on larger cohorts may provide more insights into mechanisms that drive tissue inflammation in PES. This work was supported by KAKENHI, Hamamatsu University School of Medicine Grant-in-Aid, and the Intramural Research Programs of NIAMS and NCI. The authors have no conflicts of interest to declare.","journal":"The Journal of Dermatology","year":2023,"id":403830,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.963,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1181791,"name":"Ibuki Takatsuka","orcid":null,"position":1,"is_corresponding":false},{"id":1181792,"name":"Tomonari Takemura","orcid":null,"position":2,"is_corresponding":false},{"id":1181419,"name":"Takaaki Ono","orcid":"0000-0003-3922-7432","position":3,"is_corresponding":false},{"id":1181793,"name":"Yuka Nagakura","orcid":null,"position":4,"is_corresponding":false},{"id":250439,"name":"Svetlana Pack","orcid":"0000-0003-3256-6626","position":5,"is_corresponding":false},{"id":246528,"name":"Keisuke Nagao","orcid":"0000-0002-7005-3138","position":6,"is_corresponding":false},{"id":1181420,"name":"Tetsuya Honda","orcid":"0000-0003-2355-4869","position":7,"is_corresponding":false},{"id":246523,"name":"Keiko Sakamoto","orcid":"0000-0001-8957-3232","position":0,"is_corresponding":true}],"reference_count":5,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:20:40.264741Z","pmid":"36938663","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}