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Absence of infectious triggers in Hemophagocytic lymphohistiocytosis (HLH)

Maximilian Heeg

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory condition that can arise from genetic mutations affecting the cytotoxic pathway, particularly in genes like PRF1, which are crucial for the function and regulation of cytotoxic T lymphocytes and NK cells. While HLH has traditionally been understood to be triggered by infections, most notably Epstein-Barr virus (EBV), our research across two distinct cohorts has revealed that HLH can manifest without an infectious trigger. The first cohort focused on CNS-isolated HLH cases, demonstrating that the disease can present in a localized manner rather than systemically. The second cohort examined newborns and cases of intrauterine HLH, where the disease developed before or immediately after birth, in the absence of infection exposure, providing compelling evidence that the genetic defect alone can be sufficient to initiate the inflammatory cascade characteristic of HLH.

Neuroinflammatory Disease as an Isolated Manifestation of Hemophagocytic Lymphohistiocytosis

In this study, we investigated isolated neuroinflammatory disease as the initial presentation of familial hemophagocytic lymphohistiocytosis (HLH), a rare immune dysregulation disorder. Through an international survey and literature review, 38 cases of isolated cerebral HLH were analyzed. We highlight that HLH can be an overlooked diagnosis in patients with neurological symptoms like ataxia and seizures, and that delayed diagnosis often led to disease progression and systemic HLH. Hematopoietic stem cell transplantation (HSCT) improved outcomes, with better survival and neurological recovery compared to non-transplanted patients. The study underscores the need for earlier recognition and targeted treatment of this rare condition. Interestingly, in many patients, the infectious trigger was absent, highlighting that HLH might occur spontaneously in patients with an underlying genetic defect.

Lessons from in utero and neonatal HLH disease

In our study, we challenge the prevailing assumption that an infectious trigger is necessary for the onset of hemophagocytic lymphohistiocytosis (HLH) in individuals with primary genetic defects in cytotoxic lymphocyte function. By analyzing two cohorts, including neonates and in utero cases, we found that a substantial number of HLH cases occurred without identifiable infections, even with comprehensive viral and microbiological investigations.

We highlight that HLH can emerge in sterile environments, suggesting non-infectious triggers such as developmental processes or localized tissue damage may suffice to initiate immune dysregulation. Our findings emphasize the central role of lymphocyte cytotoxicity in maintaining immune homeostasis beyond viral defense. These observations pave the way for a deeper understanding of HLH pathogenesis and call for broadening diagnostic and therapeutic approaches to this life-threatening condition.

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