Macrophage Activation Syndrome Following Vaccination After HSCT

Dear Editor, Macrophage activation syndrome (MAS) is a hyperinflammatory condition most commonly associated with autoimmunity. It carries a high risk of morbidity and mortality, necessitating prompt diagnosis and treatment. MAS following allogeneic hematopoietic stem cell transplantation (HSCT) is rare but can have a severe course [1]. Current literature suggests that post-HSCT MAS cases are most often triggered by infections or graft-versus-host disease (GVHD) [2]. Here, we report a case of MAS developing after administration of the conjugate pneumococcal vaccine (PCV13) in a patient who underwent allogeneic HSCT. A 27-year-old male patient with no known comorbidities was diagnosed with myelodysplastic syndrome. Next-generation sequencing revealed a heterozygous variant in the GATA2 gene (c.1118G>T, p.Cys373Phe). On April 17, 2025, he underwent allogeneic HSCT from an unrelated donor. On Day 36 posttransplant, the patient developed CMV infection, which was treated with foscarnet. On Day 51, he developed Grade 2–3 gastrointestinal GVHD. At that time, his immunosuppressive regimen consisted of cyclosporine and mycophenolate mofetil. Methylprednisolone (1 mg/kg) was initiated, and when an adequate response was not achieved, ruxolitinib was added. Gastrointestinal symptoms subsequently improved. On Day 67 posttransplant, quadruple antituberculosis therapy with isoniazid, rifampin, pyrazinamide, and ethambutol was started for urinary tuberculosis. On Day 120 posttransplant, the patient received the PCV13 vaccine as part of the vaccination program. Ten days after vaccination, he presented with high fever and diffuse myalgia, without additional symptoms. Physical examination and imaging studies revealed no findings, suggestive of infection or GVHD. Complete blood count showed a leukocyte count of 3.61 × 109/L, neutrophils 2.18 × 109/L, lymphocytes 0.97 × 109/L, platelets 145 × 109/L, and hemoglobin 11 g/dL. Biochemical tests revealed ferritin 998 ng/mL, triglyceride 285 mg/dL, LDH 359 U/L, erythrocyte sedimentation rate (ESR) 66 mm/h, C-reactive protein (CRP) 113 mg/L, and procalcitonin 0.03 ng/mL. Liver and renal function tests, coagulation parameters, haptoglobin, and urinalysis were all within normal limits. Viral and fungal panels as well as rheumatologic tests were negative. PET-CT and echocardiography showed no evidence of infection or inflammation. Chimerism analysis demonstrated 99% donor dominance. Despite broad-spectrum antibiotic therapy, no clinical improvement was observed. GVHD recurrence and drug reactions were excluded. These findings supported a non-infectious hyperinflammatory response. Due to suspicion of MAS, a bone marrow biopsy was performed on Day +130 after HSCT. The biopsy revealed an overall normocellular marrow with focally hypocellular, narrow parenchymal areas (Figure 1A; hematoxylin–eosin [H&E], 20× objective). Immunohistochemical analysis demonstrated an increased number of CD68-positive histiocytes with abundant cytoplasm, some of which showed features consistent with hemophagocytosis (Figure 1B; CD68 immunohistochemistry, 20× objective). Reticulin fibrosis was graded as Grade 1, and no morphological evidence of malignancy was identified. After exclusion of infectious etiologies and other secondary causes, the clinical picture was considered consistent with MAS. On August 28, 2025, dexamethasone was initiated at a dose of 10 mg/m2/day in accordance with the HLH-2004 protocol, followed by gradual dose tapering after 1 week. Following treatment, marked improvement in fever and other systemic symptoms was observed, accompanied by a decline in inflammatory markers. As shown in Figure 2, initiation of corticosteroid therapy was followed by a rapid decrease in CRP levels, while the ESR showed a progressive decline over time. Persistently low procalcitonin levels throughout the course supported a hyperinflammatory process rather than an infectious etiology. In light of the favorable clinical and biochemical response, the vaccination schedule was discontinued. Following HSCT, the immune system undergoes a process of reconstitution. During this period, vaccination or other immune-stimulating interventions may elicit atypical and sometimes exaggerated inflammatory responses. Although rare, cases in the literature have reported MAS triggered by vaccination after immune stimulation; for instance, MAS has been reported following mRNA vaccination in adult-onset Still's disease [3]. In addition, the incidence of MAS after HSCT has been reported to be approximately 1% [2]. Studies on early post-HSCT administration of immunostimulatory vaccines have generally shown them to be safe; however, caution is warranted regarding inflammatory responses and increased reactogenicity [4]. In particular, in the presence of immune-modulating factors such as GVHD or CMV, immune triggers like vaccination can lead to excessive cytokine release along the macrophage/monocyte axis and MAS-like syndromes [5]. The present case demonstrates MAS occurring after PCV13 vaccination administered in the third month posttransplant. This observation aligns with previously described mechanisms in the literature and highlights that, in the “reset” immune environment following HSCT, exaggerated inflammatory responses can rarely occur. Studies on post-HSCT mRNA vaccination have also reported heterogeneous immune responses and increased reactogenicity, which may predispose to severe complications such as MAS [6]. A case of MAS characterized by high fever, cytopenia, and hemophagocytosis in the bone marrow has been reported following influenza vaccination in a healthy adult [7]. MAS following HPV vaccination has been more frequently associated with vaccine-triggered autoinflammatory responses in adults and adult-onset Still's disease, with secondary MAS cases reported [8]. MAS following COVID-19 vaccination has been reported more frequently in both adult and pediatric patients. The clinical features of these cases typically include fever, cytopenia, hyperferritinemia, and hemophagocytosis in the bone marrow. Treatment usually involves corticosteroids and IVIG, with favorable responses [9]. The present case represents one of the rare clinical situations in which MAS occurs in the context of both posttransplant and vaccination-related triggers. The development of MAS following PCV13 vaccination in the early posttransplant period emphasizes the risk of hyperinflammatory responses after vaccination during this vulnerable phase. This underscores the need to consider GVHD status, CMV history, and immunosuppression when planning post-HSCT vaccination. Furthermore, unexplained fever, cytopenia, and hyperferritinemia following vaccination should prompt evaluation for MAS to enable early diagnosis. This case further highlights the importance of individualizing vaccination programs in the posttransplant period. The authors thank Prof. Şeniz Öngören and Prof. Mustafa Pehlivan for their valuable support in patient management and manuscript review. The authors have nothing to report. Written informed consent was obtained from the patient for publication of this clinical correspondence and any accompanying images. The authors declare no conflicts of interest.