This case highlights the complex diagnostic and therapeutic challenges of hemophagocytic lymphohistiocytosis among kidney transplant recipients—a setting where clinical caution is crucial, yet the condition remains under-recognized.

Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome that can present with nonspecific symptoms such as fever, cytopenia, and organ dysfunction, features common to many post-transplant complications. In kidney transplant recipients, these signs initially raise suspicion of infection, rejection, or drug toxicity, delaying recognition of hemophagocytic lymphohistiocytosis. Thrombotic microangiopathy, post-transplant lymphoproliferative disorder, and occult infections such as cytomegalovirus can present similarly and must be ruled out early [5, 9]. Moreover, hemophagocytic lymphohistiocytosis itself may contribute to tissue injury that confounds interpretation, including renal dysfunction from acute tubular injury or glomerular microangiopathy [10].

In such scenarios, the HScore offers a helpful diagnostic framework. It integrates clinical and laboratory features—including fever, cytopenias, organomegaly, ferritin, triglycerides, and serum soluble CD25—to estimate the probability of reactive hemophagocytic lymphohistiocytosis in adults. An HScore > 250 carries a sensitivity exceeding 90% [7]. Although the Hemophagocytic lymphohistiocytosis-2004 criteria remain the standard for diagnosis, they were initially developed for pediatric populations and may not capture the full spectrum of hemophagocytic lymphohistiocytosis in adults, particularly in immunosuppressed patients [6]. In our case, the diagnosis became apparent only after seven criteria were met; however, earlier application of the HScore could have supported the diagnosis at an earlier stage. Importantly, bone marrow examination should not be delayed in patients with unexplained fever and cytopenias, particularly when ferritin is markedly elevated.

Hemophagocytic lymphohistiocytosis care in solid-organ transplant recipients is delicate: tapering immunosuppression aids immune recovery and infection control, yet stopping the cytokine storm demands higher doses. Escalation heightens infection risk, whereas delay invites irreversible organ damage [3, 11].

Standard protocols based on Hemophagocytic lymphohistiocytosis-94 and Hemophagocytic lymphohistiocytosis-2004 recommend the use of corticosteroids, etoposide, and cyclosporine A. However, these regimens are rarely adopted in transplant patients due to concerns about toxicity and further immunosuppression [6]. In our patient, high-dose dexamethasone provided transient improvement, but progression to multiorgan failure ensued. Mycophenolate was withheld; however, this intervention alone proved insufficient. There is currently no consensus on how aggressively to treat hemophagocytic lymphohistiocytosis in the transplant population. Case reports have described successful outcomes with steroids alone or in combination with intravenous immunoglobulin (IVIG) and plasma exchange, particularly when an apparent infectious trigger is addressed [3, 4]. More recently, targeted therapies—such as anti-interleukin-1 and Janus kinase inhibitors—have shown promise in refractory hemophagocytic lymphohistiocytosis but remain largely experimental in transplant recipients [11].

Our experience emphasizes that early, decisive therapy, tailored to address both the underlying trigger and the severity of inflammation, is essential. Equally essential is collaboration among transplant specialists, hematologists, and intensivists to weigh the risks and benefits of each therapeutic step.

Hemophagocytic lymphohistiocytosis in transplant recipients is paradoxical: even under chronic immunosuppression to prevent rejection, these individuals remain susceptible to uncontrolled immune activation. Hemophagocytic lymphohistiocytosis represents a breakdown in cytotoxic T-cell and NK-cell regulation, leading to persistent activation of macrophages and overwhelming cytokine release [11, 12]. Immunosuppressive agents, particularly calcineurin inhibitors, do not directly suppress this macrophage-driven process and may impair the clearance of viral or malignant triggers, allowing hemophagocytic lymphohistiocytosis to evolve unchecked [12].

Infections, especially from herpesviruses such as Epstein–Barr virus and CMV, are among the most frequent precipitating factors in transplant-associated hemophagocytic lymphohistiocytosis [13]. These pathogens not only evade immunosurveillance but also trigger dysregulated immune activation. Moreover, the immunocompromised state can mask typical signs of systemic inflammation, making hemophagocytic lymphohistiocytosis harder to detect until organ failure is imminent.

Timely recognition of hemophagocytic lymphohistiocytosis in transplant recipients is critical: unexplained fever, cytopenias, and elevated ferritin, even under immunosuppression, should trigger high suspicion, as early immunomodulatory therapy can prevent irreversible organ failure and death. This case shows that a non-diagnostic early marrow sample can give clinicians false reassurance; arranging a timely, well-prepared repeat biopsy can be decisive.