Underrecognised Functional Hyposplenism Associated With Chronic Graft-Versus-Host Disease: A Case Report

Abstract

Haematopoietic stem cell transplantation (HSCT) is a curative treatment for haematologic malignancies; however, complications such as graft-versus-host disease (GVHD) and infections remain major causes of morbidity and mortality [1-4]. Functional hyposplenism, often linked to chronic GVHD, is an underrecognised complication of HSCT that increases the risk of severe infections caused by encapsulated organisms [5]. This report describes a case of a patient with chronic GVHD who developed progressive splenic atrophy and persistent Howell–Jolly bodies (HJBs) in peripheral blood smears, indicative of functional hyposplenism [6-9]. The case highlights the importance of blood smear examinations and imaging studies for early diagnosis and management of this overlooked complication.

A 44-year-old man with acute myeloid leukaemia (AML) harbouring NPM1 and DNMT3 mutations underwent allogeneic HSCT from an HLA-identical sibling donor after induction therapy, which caused persistent pancytopenia despite achieving complete remission. Myeloablative conditioning with cyclophosphamide and busulphan was administered, and GVHD prophylaxis included cyclosporine (CSA) and short-term methotrexate. Engraftment was achieved with full donor chimerism, and no acute GVHD or initial complications occurred, allowing CSA tapering.

On day 185 post-HSCT, cryptogenic organising pneumonia (COP) developed, requiring prednisolone (PSL; 0.5 mg/kg/day). PSL tapering followed symptom improvement. However, oral lichenoid lesions and elevated liver enzyme levels on day 380 led to a diagnosis of chronic GVHD. PSL was increased to 10 mg/day, but tapering PSL and CSA proved challenging due to worsening GVHD symptoms.

At 2.5 years post-HSCT, HJBs were detected in peripheral blood smears (Figure 1), and computed tomography (CT) scans revealed significant splenic atrophy. The spleen volume, normal at HSCT (136 mL, Figure 2A), progressively declined—34 mL at 2.5 years (Figure 2B), 22 mL at 3.5 years (Figure 2C), 12 mL at 4.5 years (Figure 2D), and 8 mL at 5.5 years (Figure 2E).

This case highlights the need to recognise functional hyposplenism as a complication of chronic GVHD post-HSCT. The patient's progressive splenic atrophy, identified via routine CT imaging, and persistent HJBs in peripheral blood smears indicated functional hyposplenism. Despite its clinical significance, functional hyposplenism is often underdiagnosed due to overlooked splenic atrophy in radiology reports and the limited use of blood smear examinations.

The spleen plays a key role in immune defence and erythrocyte filtration, and its dysfunction increases susceptibility to infections by encapsulated microorganisms [7, 10]. This patient received PCV13 and PPV23 vaccinations and prophylactic antibiotics, including trimethoprim-sulphamethoxazole and levofloxacin, which effectively prevented pneumococcal infections. Such preventive measures are consistent with guidelines for managing functional hyposplenism [6].

While advanced diagnostic methods like radioisotope imaging and pitted erythrocyte detection are available, HJB detection is a simple, cost-effective alternative. Combining blood smear examinations with imaging, such as CT or ultrasonography, improves diagnostic accuracy when splenic atrophy is present [6, 9, 11].

In this case, chronic GVHD is the likely cause of splenic atrophy, as total body irradiation was not used, and prolonged immunosuppressive therapy was required. Chronic GVHD is believed to involve persistent alloimmune reactions by donor T cells, pro-inflammatory cytokines, and eventual tissue remodelling or fibrosis in affected organs, including the spleen [12]. Although the precise mechanisms remain unclear, it is speculated that ongoing immune-mediated damage and disrupted tissue repair pathways may induce atrophy in the splenic microarchitecture. Such processes have been proposed in comprehensive reviews by the National Institutes of Health Consensus Development Project on Chronic GVHD, though direct evidence of splenic fibrosis remains sparse and largely inferential [13]. Hence, our explanation that chronic GVHD contributed to this patient's progressive splenic atrophy should be viewed cautiously, as definitive proof is lacking and warrants further study.

Comprehensive management, including vaccinations and prophylactic antibiotics, appears beneficial in reducing infection risks associated with functional hyposplenism. Regular HJB screening and splenic size assessments post-HSCT, regardless of GVHD status, may aid in the early detection and management of this complication. This case suggests the potential importance of routine evaluation for functional hyposplenism in post-HSCT patients to improve clinical outcomes.

Kaori Uchino wrote the manuscript. Yuya Nakagami, Megumi Enomoto, Nozomi Shimizu, Kenichi Kondo, and Takahiro Yamamoto contributed to data collection. Yukie Sugita, Hideshige Seki, Sakura Saigusa, Yusuke Iida, Saki Shinohara, Soichi Takasugi, Tomohiro Horio, Satsuki Murakami, Shohei Mizuno, Kazuhiro Ikegame, and Ichiro Hanamura reviewed and edited the manuscript. Akiyoshi Takami revised the manuscript. All authors approved the final manuscript.

We obtained ethical approval from the Institutional Review Board of Aichi Medical University School of Medicine.

Informed consent was obtained from the patient in this case report. Permission has been granted to include all relevant clinical details in the manuscript.

A.T. received research funding from AIR WATER; lecture fees from NOVARTIS Pharmaceuticals; and donation funds from Chugai Pharmaceutical Co., Ltd, Kyowa Kirin, and Zenyaku Kogyo. I.H. received research funding from the Japanese Myeloma Patient Society and lecture fees from Janssen Pharmaceuticals, Bristol Pharmaceuticals, and Sanofi. S.M. received research funding from Hayashikane Sangyo.