Incidence and clinical presentation of primary hemophagocytic lymphohistiocytosis in Sweden

Meeths, Marie; Horne, AnnaCarin; Sabel, Magnus; Bryceson, Yenan T.; Henter, Jan‐Inge

doi:10.1002/pbc.25308

Cited by 70 publications

(61 citation statements)

References 32 publications

(48 reference statements)

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“…Such studies have identified 0.12–0.15 HLH cases per 100,000 children per year in Sweden [44], 1 HLH case per 100,000 children per year in Texas [2], and 1 HLH case per 800,000 individuals per year in Japan [45]. Therefore, the incidence of familial HLH identified in this investigation (0.04 per 100,000 children per year) is several fold lower than that observed in previous studies.…”

Section: Discussionmentioning

confidence: 99%

Incidence and Risk Factors for Developing Dengue-Associated Hemophagocytic Lymphohistiocytosis in Puerto Rico, 2008 - 2013

Ellis¹,

Sharp²,

Pérez-Padilla³

et al. 2016

PLoS Negl Trop Dis

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BackgroundHemophagocytic lymphohistiocytosis (HLH) is a rare, potentially fatal disorder characterized by fever, pancytopenia, hepatosplenomegaly, and increased serum ferritin. HLH is being increasingly reported as a complication of dengue, a common tropical acute febrile illness.Methodology/Principal FindingsAfter a cluster of pediatric dengue-associated HLH patients was identified during the 2012–2013 dengue epidemic in Puerto Rico, active surveillance and a case-control investigation was conducted at four referral hospitals to determine the incidence of HLH in children and identify risk factors for HLH following dengue. Patients with dengue-associated HLH (cases) were matched by month of illness onset and admission hospital to dengue patients that did not develop HLH (controls). During 2008–2013, a total of 33 HLH patients were identified, of which 22 (67%) were associated with dengue and 1 died (dengue-associated HLH case-fatality rate: 4.5%). Two patients with dengue-associated HLH had illness onset in 2009, none had illness onset during the 2010 dengue epidemic, and 20 had illness onset during the 2012–2013 epidemic. Frequency of infection with either dengue virus (DENV)-1 or DENV-4 did not differ between cases and controls. Cases were younger than controls (median age: 1 vs. 13 years, p < 0.01), were hospitalized longer (18 vs. 5 days, p < 0.01), and were admitted more frequently to pediatric intensive care units (100% vs. 16%, p < 0.01). Cases had co-infection (18.2% vs. 4.5%, p = 0.04), recent influenza-like illness (54.5% vs. 25.0%, p = 0.01), and longer duration of fever (7 vs. 5 days; p < 0.01). Cases were more likely to have lymphadenopathy, hepatomegaly, splenomegaly, anemia, and elevated liver transaminases (p ≤ 0.02).Conclusions/SignificanceDuring this cluster of dengue-associated HLH cases that was temporally associated with the 2012–2013 epidemic, most patients with dengue-associated HLH were infants and had higher morbidity than dengue inpatients. Physicians throughout the tropics should be aware of HLH as a potential complication of dengue, particularly in patients with anemia and severe liver injury.

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Section: Discussionmentioning

confidence: 99%

Incidence and Risk Factors for Developing Dengue-Associated Hemophagocytic Lymphohistiocytosis in Puerto Rico, 2008 - 2013

Ellis¹,

Sharp²,

Pérez-Padilla³

et al. 2016

PLoS Negl Trop Dis

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“…These genes are essential to apoptosis and play an important role in downregulating the immune response (Horne et al, 2017). Dysfunction in this pathway leads to histiocyte proliferation and hypercytokinemia (Meeths et al, 2015), which cause end-organ damage. The inflammatory cells can also cause CNS involvement by crossing the blood-brain barrier (Gratton et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Neurological symptoms of familial hemophagocytic lymphohistiocytosis type 2

Wang

Tuo

Lin

et al. 2020

Journal of Integrative Neuroscience

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Hemophagocytic lymphohistiocytosis with central nervous system involvement is caused by inflammatory factor storms. The inflammatory factors invade the blood-brain barrier and further infiltrate brain tissue resulting in associated neurological and/or psychiatric symptoms in hemophagocytic lymphohistiocytosis with central nervous system involvement patients. This case report is based on a 14-year-old male patient who experienced intermittent dizziness and blurred vision about five years before admission as well as lower limb weakness and unstable walking approximately three years before admission. His brain MRI showed abnormal signals in the bilateral cerebellar hemisphere and vermis, right occipital lobe, and bilateral basal ganglia. The cerebrospinal fluid examination revealed an increase in nucleated cells, mainly monocytes, and elevated protein. He had no typical manifestation of hemophagocytic lymphohistiocytosis in the early stage, such as fever, cytopenia, or hepatosplenomegaly. He was misdiagnosed with meningoencephalitis or tuberculous meningitis. Perforin gene detection revealed a mutation in the PRF1 gene. The final diagnosis of type 2 familial hemophagocytic lymphohistiocytosis was made based on the neurological symptoms and genetic test. The possibility of hemophagocytic lymphohistiocytosis needs to be considered in patients with unexplained central nervous system symptoms, even if the patient does not have typical hemophagocytic lymphohistiocytosis symptoms, such as fever, cytopenia, or hepatosplenomegaly. We present the neurological symptoms of familial hemophagocytic lymphohistiocytosis type 2.

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“…This aberration represents the predominant cause of autosomal recessive, early‐onset HLH in northern Sweden . With an allele frequency of the UNC13D inversion higher than that originally predicted using national incidence figures, the relatively isolated population in northern Sweden provided a unique opportunity to evaluate the impact of haploinsufficiency in a gene required for lymphocyte cytotoxicity and immune surveillance of cancer.…”

Section: Discussionmentioning

confidence: 99%

“…This aberration represents the predominant cause of autosomal recessive, early-onset HLH in northern Sweden. 22 With an allele frequency of the UNC13D inversion higher than that originally predicted using national incidence figures, 25 the relatively isolated population in northern Sweden provided a unique opportunity to evaluate the impact of haploinsufficiency in a gene required for lymphocyte cytotoxicity and immune surveillance of cancer. Establishing a higher carrier frequency of the UNC13D inversion in individuals with lymphoma (OR, 3.0; P = .002), the results of the current study greatly strengthen the theory that haploinsufficiency of autosomal genes required for lymphocyte cytotoxicity predispose an individual to cancer.…”

Section: Discussionmentioning

confidence: 99%

Haploinsufficiency of UNC13D increases the risk of lymphoma

Löfstedt

Ahlm

Tesi

et al. 2019

Cancer

Self Cite

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Background Experimental models have demonstrated that immune surveillance by cytotoxic lymphocytes can protect from spontaneous neoplasms and cancer. In humans, defective lymphocyte cytotoxicity is associated with the development of hemophagocytic lymphohistiocytosis, a hyperinflammatory syndrome. However, to the best of the authors’ knowledge, the degree to which human lymphocyte cytotoxicity protects from cancer remains unclear. In the current study, the authors examined the risk of lymphoma attributable to haploinsufficiency in a gene required for lymphocyte cytotoxicity. Methods The authors exploited a founder effect of an UNC13D inversion, which abolishes Munc13‐4 expression and causes hemophagocytic lymphohistiocytosis in an autosomal recessive manner. Within 2 epidemiological screening programs in northern Sweden, an area demonstrating a founder effect of this specific UNC13D mutation, all individuals with a diagnosis of lymphoma (487 patients) and matched controls (1844 controls) were assessed using polymerase chain reaction for carrier status . Results Among 487 individuals with lymphoma, 15 (3.1%) were heterozygous carriers of the UNC13D inversion, compared with 18 controls (1.0%) (odds ratio, 3.0; P = .002). It is interesting to note that a higher risk of lymphoma was attributed to female carriers (odds ratio, 3.7; P = .004). Conclusions Establishing a high regional prevalence of the UNC13D inversion, the authors have reported an overrepresentation of this mutation in individuals with lymphoma. Therefore, the results of the current study indicate that haploinsufficiency of a gene required for lymphocyte cytotoxicity can predispose patients to lymphoma, suggesting the importance of cytotoxic lymphocyte‐mediated surveillance of cancer. Furthermore, the results of the current study suggest that female carriers are more susceptible to lymphoma.

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Incidence and clinical presentation of primary hemophagocytic lymphohistiocytosis in Sweden

Abstract: The annual incidence of primary HLH in Sweden is 0.12-0.15 per 100,000 children per year. Pediatr Blood Cancer 2015;62:346-352. © 2014 Wiley Periodicals, Inc.

Cited by 70 publications

References 32 publications

Incidence and Risk Factors for Developing Dengue-Associated Hemophagocytic Lymphohistiocytosis in Puerto Rico, 2008 - 2013

Incidence and Risk Factors for Developing Dengue-Associated Hemophagocytic Lymphohistiocytosis in Puerto Rico, 2008 - 2013

Neurological symptoms of familial hemophagocytic lymphohistiocytosis type 2

Haploinsufficiency of UNC13D increases the risk of lymphoma

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