HLH is a rare, life-threatening hyperinflammatory syndrome caused by uncontrolled activation of macrophages and cytotoxic T lymphocytes, leading to excessive cytokine release and multiorgan dysfunction. While primary HLH is associated with genetic defects and typically presents in childhood, secondary HLH is increasingly recognized in adults, usually triggered by infections, malignancies, autoimmune disorders or immunosuppression. Prompt treatment of HLH is critical for successful outcomes, but the greatest barrier to a successful outcome is often a delayed diagnosis due to its rarity, variable clinical presentation and lack of specificity of clinical and laboratory findings [1].

Adult HLH usually manifests with persistent fever, hepatosplenomegaly, cytopenias, transaminase elevation, coagulopathy and markedly elevated ferritin levels. Neurological symptoms may appear in up to one-third of cases, adding further diagnostic complexity. Imaging, although sometimes is nonspecific, it often reveals hepatosplenomegaly or lymphadenopathy. Because these findings are shared with several other acute conditions, HLH requires a combination of clinical suspicion and laboratory results rather than reliance on any single abnormality [3].

Diagnosis of non-familial HLH relies on the HLH-2024 criteria, with ≥5 fulfilled items required of the following: fever, splenomegaly, cytopenias in at least two lineages, hypofibrinogenemia or hypertriglyceridemia, hyperferritinemia, haemophagocytosis in bone marrow or other tissues and elevated sCD25 (Table 2). However, these criteria were originally designed for paediatric populations with more florid presentations and which may not fully capture the subtle or evolving forms of HLH seen in adults. In this context, the H-Score offers an alternative tool incorporating variables and threshold values more applicable to adult patients. Nevertheless, both systems have limitations and clinical judgement remains essential, particularly when HLH is suspected but the patient does not fulfil complete criteria [1,4].

Our patient exemplifies this scenario. She fulfilled three of HLH-2024 criteria (splenomegaly, hypertriglyceridemia and hyperferritinemia), along with cytopenias and elevated sCD25. Although she did not meet the five-criteria requirement, the constellation of findings, clinical trajectory and absence of alternative explanations strongly suggested an HLH-like hyperinflammatory syndrome. The unique features of our case highlights how strict adherence to classical criteria may delay diagnosis in adults and supports the need for flexible diagnostic strategies, especially in the context of identifiable triggers [4,7].

Triggers of HLH are crucial to identify because treating them may lessen the severity of HLH and, in some cases, enable avoidance of more cytotoxic HLH-specific therapy. The most important triggers include infections such as Epstein-Barr Virus (EBV) and hematologic malignancies like lymphomas. Autoimmune disorders and immunodeficiencies may also contribute to the underlying pathophysiology of the disease. The development of CMV-induced HLH in an immunocompetent adult, as in our case, is therefore unusual and clinically relevant. A full list of triggers can be found in the accompanying table (Table 3) [5].

Treatment of adult HLH must be individualized and depends primarily on severity, organ involvement and the identification of an underlying trigger. When the patient is clinically stable and a treatable trigger such as infection is identified, targeted therapy alone may be sufficient (antibiotic or antiviral therapy). In contrast, unstable patients or those with rapidly progressive disease may require immediate initiation of HLH-directed therapy, typically following the HLH-94 protocol based on dexamethasone and etoposide. Hematopoietic Cell Transplantation (HCT) is reserved for CNS involvement, refractory or genetic cases. Supportive care is critical and includes management of cytopenias, coagulopathy, blood pressure and prevention of secondary infections. Targeted therapies, such as emapalumab, an IFN-γ inhibitor, are increasingly considered for relapsed or refractory HLH [3].

Prognosis of HLH depends on early recognition, the underlying cause and response to treatment. Once our patient was under treatment of valganciclovir, CMV viremia effectively suppressed and led to partial recovery of infection without the need for corticosteroids or immunosuppressive therapy. This favourable response underscores the importance of identifying infectious triggers early and supports an approach where treatment is escalated only if clinical deterioration or failure to respond occurs. The benign evolution and absence of organ failure justified a conservative strategy and reflect the better prognosis generally associated with infection-mediated HLH as compared to malignancy-associated HLH, which carries a significantly worse outcome [6,7].

Long-term follow-up is essential to monitor for recurrence, late organ dysfunction or complications from therapy. Most relapses occur within the first year of the initial episode. Recommended follow-up includes serial assessment of hematologic parameters, inflammatory markers, liver and renal function and monitoring for potential neurologic sequelae. Improvements in survival are expected to come from increased disease recognition with earlier diagnosis, reductions in HCT-associated morbidity and disease-specific immunotherapies [6].

In conclusion, this course of events illustrates how early identification of a triggering factor can inform management decisions and improve outcomes and underscores the importance of maintaining a high index of suspicion for HLH even in patients without pre-existing immunodeficiency or malignancy. Finally, our case highlights the need for continued refinement of diagnostic approaches and exploration of emerging, less toxic therapeutic strategies for virus-associated HLH [8].