«This case report describes a 46-year-old male with no prior comorbidities who developed progressive neurological symptoms—ataxia and diplopia—shortly after the second Comirnaty (Pfizer-BioNTech) COVID-19 vaccine dose. The aim is to highlight the diagnostic challenges of central nervous system-dominant hemophagocytic lymphohistiocytosis (HLH) and its overlap with neuroinflammatory disorders».
Research doctors from prestigious Italian universities, Flaminia Bellisario 1, Assunta Bianco 2, Francesco D’Alo’ 1, Chiara Passarelli 3, Rosellina Russo 4, Massimiliano Mirabella 2-5, Simona Sica 6 and Stephan Hoaus 1, write in the abstract of the study.
- Extramedullary Lymphoproliferative Diseases Unit, Department of Laboratory and Hematological Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
- Multiple Sclerosis Center, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
- Translational Cytogenomics Research Unit, Laboratory of Medical Genetics, Bambino Gesù Children’s Hospital IRCCS, 00165 Rome, Italy
- Diagnostic Neuroradiology Unit, Department of Diagnostic Imaging and Oncology Radiation Therapy, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
- Anna Paola Batocchi Multiple Sclerosis Research Center, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Department of Laboratory and Hematological Sciences, Hematology and Cell Transplantation Unit Hematopoietic Stem Cells, A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy
The Fondazione Policlinico Universitario Agostino Gemelli IRCCS Università Cattolica del Sacred Heart is a private university hospital in Rome, located on the slopes of Monte Mario, in the Trionfale neighborhood, on land donated in 1934 by Pope Pius XI to the Giuseppe Toniolo Institute for Higher Studies, the founding body and guarantor of the Catholic University.
Designed by Giuseppe Cigni and Gaetano Minnucci, it is home to the Faculty of Medicine and Surgery of the Catholic University of the Sacred Heart and is the institution designated to treat the pathologies of the Pontiffs of the Catholic Church.
«Initial MRI showed demyelinating lesions in the brain and spinal cord, suggesting acute disseminated encephalomyelitis (ADEM). The patient had only transient improvement with corticosteroids and then multiple relapses with expanding CNS lesions despite cyclophosphamide, plasmapheresis, and rituximab. After 27 months, systemic features appeared, including fever, cytopenias, elevated inflammatory markers, and splenomegaly. Bone marrow analysis revealed hemophagocytosis, fulfilling HLH-2004 criteria, with an H-score of 200 supporting secondary HLH. Given consanguinity and persistent immune activation, next-generation sequencing identified two homozygous PRF1 variants—one pathogenic (p.Arg232His) and one of uncertain significance (p.Ala91Val)—consistent with autosomal recessive familial type 2 HLH».
The medical doctors added in the Abstract.
«The patient underwent matched unrelated donor hematopoietic stem cell transplantation (HSCT) 11 months after HLH diagnosis, achieving initial stabilization, but ultimately died from infectious complications in March 2025 without evidence of HLH relapse».
This is the bitter conclusion of the researchers.
«This case illustrates an atypical adult-onset presentation of familial HLH manifesting primarily with recurrent neuroinflammatory symptoms that initially mimicked ADEM. The diagnostic delay reflects the challenge of recognizing CNS-dominant HLH, especially in adults and in the absence of early systemic features. The identification of biallelic PRF1 variants confirmed an underlying genetic predisposition. This is the first reported case of adult-onset familial HLH presenting predominantly with neurological symptoms following COVID-19 vaccination. The case emphasizes the need to consider genetic forms of HLH in relapsing neuroinflammatory disorders and raises the hypothesis that vaccination may unmask subclinical immune dysregulation in genetically susceptible individuals».
Carlo Domenico Cristofori
Discussion – Full Excerpt from the Study
Excerpt by the MDPI peer reviewed study
The links to previous Gospa News articles have been added in the aftermath by virtue of the ties with covered topics
The case report describes an adult-onset form of familial hemophagocytic lymphohistiocytosis (HLH) presenting initially with neurological symptoms following the second dose of the Comirnaty vaccine. The initial diagnosis was ADEM. Notably, a similar case has been reported of a 20-year-old patient, initially diagnosed with ADEM, later confirmed to have HLH due to a homozygous PRF1 gene mutation [10]. This patient presented with bilateral vision loss with MRI findings of demyelinating lesions in the cerebral white matter, particularly in the occipital lobes, corpus callosum, cerebellar hemispheres, and dorsal pons, with nodular and linear contrast enhancement. Despite initial treatment with methylprednisolone and plasmapheresis, the patient’s condition deteriorated, leading to the identification of HLH through genetic testing. Meeting the HLH-2004 criteria, the patient was subsequently referred for allogeneic transplant [9].
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In the literature, seven additional cases of adult-onset familial HLH with neurological presentations have been reported. A retrospective study on adult-onset HLH, encompassing both primary and secondary forms, found CNS involvement in 10% (29 out of 289 patients) [11]. In pediatric HLH, CNS involvement rates range from 37% to 73% [12], with hemorrhagic lesions also reported. However, CNS-HLH incidence varies significantly, primarily due to reliance on retrospective data.
PRF1 dysfunction leads to excessive cytokine release and inability to switch off the immune response, resulting in damage to the blood–brain barrier. This increases permeability, permitting leukocytes, macrophages, and histiocytes to infiltrate the CNS and directly trigger inflammatory cascades affecting the myelin. Typically, the cerebrospinal fluid (CSF) is sterile with variable pleocytosis (10–47%) and protein elevation (11–41%) [13,14,15]. PRF1 mutations account for 20–40% of childhood primary HLH cases; their incidence in adults remains less well-characterized [16].
Genetic studies on adult-onset familial HLH reveal considerable variability. According to a review by Southam et al. [11], most cases involved mutations in the PRF1 gene (4 out of 8), typically in compound heterozygosity or double heterozygosity. PRF1 mutations manifest in various forms, including missense mutations, frameshift mutations, nonsense mutations, and in-frame insertions/deletions, with the first three being the most prevalent. Over 70 different mutations have been identified across the two coding exons of PRF1, with p.W374X being the most common. Geographic and racial variations in PRF1 mutations have also been documented [16,17,18].
In the study by Cetica et al., based on a large Italian registry investigating genetic predisposition to HH, the genes associated with familial forms of the disease were retrospectively analyzed in a cohort of 500 individuals, including 44 adult patients [19]. Consistent with previous literature, PRF1 was the most frequently affected gene, followed by UNC13D. The registry revealed a high prevalence of biallelic mutations (34%) but also underscored that genetic predisposition alone is insufficient for HLH development. Even in primary forms, an external trigger is required to initiate the hyperinflammatory response.
A study by Wang et al. [20] found that among 252 adult patients with HLH without a known family history of HLH, 7.1% (18 cases) exhibited genetic alterations linked to primary HLH. PRF1 mutations were present in 50% of these cases in both monoallelic and biallelic forms. These patients demonstrated reduced NK cell activity, yet prognosis did not differ based on mutation type or number. In patients with mutations associated with primary HLH, an allogeneic transplant was pursued.
Similarly, another study found that UNC13D mutations are more frequently implicated in the onset of HLH compared to PRF1 mutations [21]. Liu et al. proposed that the age of onset of familial HLH type 2 (FHL2) correlates with the degree of PRF1-dependent cytotoxicity impairment caused by specific PRF1 mutations [22]. While nonsense mutations predominate in pediatric HLH, missense mutations are more common in adult HLH, potentially contributing to delayed disease onset [21].
A parallel discussion concerns HLH cases following COVID-19 vaccination.
A parallel discussion concerns HLH cases following COVID-19 vaccination. By February 2023, 25 cases of HLH associated with COVID-19 vaccination were reported, with only one patient previously diagnosed with familial HLH type 3 [23].
The review revealed that both mRNA and viral vector vaccines were implicated, with 14 cases associated with Comirnaty (including 4 after the second dose), 5 with Vaxzevria (only after the first dose), and 3 with Moderna (COVID-19 mRNA-1273 vaccine). The median time to symptom onset was 16.5 days, and most cases received steroid therapy. Among these cases, three fatalities were reported, including one due to encephalopathy and shock.
Kim et al. described a case similar to ours, involving a 58-year-old patient who developed HLH following the first dose of the AstraZeneca (ChAdOx1) vaccine. The patient initially presented with neurological symptoms and cognitive deterioration, suspected to be ADEM, and was treated with methylprednisolone and intravenous immunoglobulins [24]. However, fever and pancytopenia emerged, leading to an HLH diagnosis. The patient ultimately died due to multiple organ failure (MOF), with no genetic testing conducted to confirm a hereditary form.
Another case reported by Yifan He [25] described a patient diagnosed with familial HLH following the first dose of Comirnaty. The patient developed annular erythema after the initial dose, which recurred post-boost, followed by fever and cytopenia. Further investigations confirmed familial HLH type 3 due to UNC13D gene mutation. The patient subsequently underwent an allogeneic transplant and remains in follow-up.
These cases highlight the potential role of COVID-19 vaccination in unmasking previously undiagnosed hereditary HLH. Although HLH remains a rare complication, its potential severity necessitates awareness.
Nevertheless, cases of neurological complications related to COVID-19 vaccination have been reported in the literature without the development of HLH, including cases of demyelinating disorders, acute disseminated encephalomyelitis (ADEM), other immune-mediated neurological syndromes, and even Susac syndrome [26,27].
Conclusions
The case report highlights an atypical presentation of a rare disease, representing the first known instance of primary HLH following COVID-19 vaccination with an initial neurological onset characterized by progressive gait ataxia, balance impairment, and cranial nerve involvement.
MRI findings demonstrated a highly pleomorphic pattern, with involvement of both white and gray matter, including hemorrhagic lesions, encephalic tumefactive lesions, and extensive longitudinal lesions of the spinal cord, with ring or nodular enhancement. No pathognomonic imaging features for adult CNS-HLH exist, and understanding of adult-onset primary HLH and the role of missense mutations remains limited. Some hypotheses suggest a “double hit” mechanism may trigger disease onset, as possibly observed in our patient.
Given the rarity of adult HLH, treatment follows pediatric protocols, and our patient achieved clinical and radiological disease control after undergoing an allogeneic transplant from an unrelated donor, despite the limited duration of the response.
This case emphasizes the importance of early recognition and aggressive management of HLH in adults presenting with neurological symptoms and contributes to the understanding of rare immune-mediated events potentially associated with vaccination. Nevertheless, we acknowledge that a single case cannot establish a causal relationship between HLH and SARS-CoV-2 vaccination.
Excerpt by the MDPI peer-reviewed study
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