Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by the uncontrolled activation of cytotoxic T lymphocytes and macrophages, resulting in a cytokine storm and immune-mediated organ damage (1). HLH is historically classified into primary (familial) HLH, caused by genetic mutations impairing cytotoxic function, and secondary (acquired) HLH, which occurs in the absence of a known genetic defect (2).

Secondary HLH is triggered by strong immunological stimuli. The most common triggers are infections, particularly viral (Epstein-Barr virus, EBV; Cytomegalovirus, CMV; Human Immunodeficiency Virus, HIV), followed by bacterial (e.g., Mycobacterium tuberculosis), parasitic, and tick-borne infections (3, 4). Other major categories include malignancy-associated HLH (predominantly lymphomas) and autoimmune-associated HLH (macrophage activation syndrome) (4). Although less common, drug-induced HLH is a recognized entity, with agents such as anticonvulsants, sulfonamides, and immunotherapies implicated (5).

Interferon-alfa (IFN-α) is a cornerstone therapy for Chronic Hepatitis B (CHB), aimed at achieving functional cure via immune modulation (6). While its common side effects (cytopenias, flu-like symptoms) are well-known, its potential to trigger severe dysregulated immunity like HLH is exceptionally rare. To our knowledge, no case has been reported where IFN-α therapy directly triggered HLH in a CHB patient without an intervening autoimmune disorder like SLE (7). Here, we report a case of HLH directly induced by Peginterferon alfa-2b (PegIFN-α-2b) in a CHB patient, further complicated by sequential opportunistic infections (Parvovirus B19 and HSV-1 encephalitis), highlighting a particularly challenging scenario in managing the balance between immunosuppression and infection risk.

This report presents a rare and instructive case of PegIFN-α-2b directly triggering HLH in a patient with CHB, which was further complicated by life-threatening opportunistic infections during immunosuppressive therapy. The case underscores the delicate balance between controlling a hyperinflammatory state and preserving host immunity, while highlighting the critical role of advanced diagnostic technologies. The successful outcome underscores the importance of vigilant monitoring, advanced diagnostic techniques, and a multidisciplinary approach in managing such critically ill patients.

Establishing the trigger is vital. We identified PegIFN-α-2b as the culprit based on temporal association and exclusion of alternatives. The onset occurred 3 weeks after PegIFN cessation. This aligns with the long half-life of PegIFN, which can exert immunomodulatory effects for weeks (8), creating a “cytokine storm” environment even after drug withdrawal (9). Other potential triggers were systematically excluded. HBV-associated HLH usually occurs during high viral replication (10). Our patient had undetectable HBV DNA due to effective TAF suppression. Furthermore, the liver biopsy showed confluent necrosis and lymphocytic infiltration typical of HLH/DILI, distinct from the piecemeal necrosis and ground-glass hepatocytes seen in active CHB (11, 12). The hepatic injury observed in the biopsy (March 20) significantly predated the onset of Parvovirus B19 viremia (April 17), arguing against Parvovirus as the cause of the liver pathology. TAF itself lacks significant immunomodulatory activity and was continued throughout the HLH crisis and recovery (13). Had TAF been the trigger, the disease would likely have persisted. Additionally, TAF is not a known trigger for HLH in current literature. Thorough investigation ruled out other common secondary causes like malignancy or active infection with typical HLH-associated pathogens (e.g., EBV, CMV) at presentation (2, 3). To our knowledge, this is the first reported case of HLH directly induced by IFN-α therapy in a CHB patient without an intervening autoimmune disorder.

This case highlights the challenge of managing HLH: the need to control a life-threatening cytokine storm with immunosuppressive therapy, which weakens the body’s defenses against infections (14). Our patient’s experience exemplified this dilemma, resulting in two consecutive viral complications. The development of localized perioral herpes during initial chemotherapy was a critical warning sign. In immunocompromised hosts, mucocutaneous herpes simplex virus (HSV) infection should not be viewed as a benign complication but as an indicator of systemic reactivation risk (15). The subsequent diagnosis of HSV-1 encephalitis, likely due to neuronal spread from reactivated latent virus in the setting of T-cell immunosuppression, underscores this point. This suggests that the appearance of such lesions in similar patients warrants not only local therapy but strong consideration of systemic antiviral prophylaxis to prevent catastrophic central nervous system dissemination (16). The subsequent parvovirus B19 infection, causing pure red cell aplasia, is a well-documented complication in immunocompromised adults due to the virus’s tropism for erythroid progenitor cells (17).

For secondary HLH with an identified and removable trigger, such as a drug, therapy aims to control hyperinflammation while facilitating trigger removal (18). The HLH-2004 protocol (etoposide/dexamethasone) remains standard for its proven efficacy in rapidly abating the hyperinflammatory state (19). The emergence of targeted biologics (e.g., anakinra, emapalumab) offers promise for more precise immunomodulation with potentially fewer infectious complications (20). The prognosis of HLH varies significantly by trigger. Infection-associated HLH, particularly with viruses like EBV, carries high mortality if untreated (21). Bacterial and tick-borne triggers also confer substantial risk (22, 23). In contrast, drug-induced HLH often has a more favorable outcome if the offending agent is withdrawn and immunosuppression is initiated promptly (24). This underscores the prognostic importance of meticulous trigger identification.

This case serves as a powerful testament to the value of mNGS in managing complex, immunocompromised patients (25). Conventional, targeted microbiological tests repeatedly returned negative results, leaving the team without a diagnosis at critical junctures. The unbiased nature of plasma mNGS allowed for the rapid and unexpected identification of parvovirus B19, directly guiding successful treatment with IVIG. More critically, mNGS of the cerebrospinal fluid provided a life-saving diagnosis of HSV-1 encephalitis at a stage when clinical symptoms were non-specific and CSF abnormalities were mild. This enabled the immediate initiation of high-dose acyclovir, an intervention where delays are directly linked to poor neurological outcomes (26, 27). This case strongly supports the early deployment of mNGS in immunocompromised hosts with unexplained febrile syndromes or neurological decline, as it can circumvent diagnostic biases and reveal unexpected pathogens (28).

In summary, PegIFN-α-2b is a rare but potent trigger for HLH. Clinicians must distinguish this from viral flares or sepsis. Furthermore, the necessary treatment for HLH imposes a severe risk of opportunistic infections, necessitating vigilant monitoring and a low threshold for advanced diagnostics like mNGS.