An infant with severe combined immunodeficiency, osteopetrosis, chromosomally integrated herpesvirus‐6 infection, and hemophagocytic syndrome: What are the links?

Singh, Pragya; Pappas, Kara; Savaşan, Süreyya

doi:10.1002/pbc.28564

Cited by 5 publications

(4 citation statements)

References 16 publications

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“…Studies were excluded if they did not discuss nHLH ( n = 280); aggregated nHLH patient data with all ages ( n = 83); provided insufficient detail and/or data describing a case of nHLH ( n = 28); and for other reasons ( n = 8). Two‐hundred‐five cases of nHLH from 142 articles were included in our analysis 12–152 …”

Section: Resultsmentioning

confidence: 99%

Neonatal hemophagocytic lymphohistiocytosis: A meta‐analysis of 205 cases

Kranz,

Hahn,

Thompson

et al. 2024

Pediatric Blood & Cancer

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BackgroundNeonatal hemophagocytic lymphohistiocytosis (nHLH), defined as HLH that presents in the first month of life, is clinically devastating. There have been few large descriptive studies of nHLH.ObjectivesThe objective of this study was to perform a meta‐analysis of published cases of nHLH.MethodsA comprehensive literature database search was performed. Cases of HLH were eligible for inclusion if clinical analysis was performed at age ≤30 days. Up to 70 variables were extracted from each case.ResultsA total of 544 studies were assessed for eligibility, and 205 cases of nHLH from 142 articles were included. The median age of symptom onset was day of life 3 (interquartile range [IQR]: 0–11, n = 141). Median age at diagnosis was day of life 15 (IQR: 6–27, n = 87). Causes of HLH included familial HLH (48%, n = 99/205), infection (26%, n = 53/205), unknown (17%, n = 35/205), macrophage activation syndrome/rheumatologic (2.9%, n = 4/205), primary immune deficiency (2.0%, n = 5/205), inborn errors of metabolism (2.4%, n = 5/205), and malignancy (2.0%, n = 4/205). Fever was absent in 19% (n = 28/147) of all neonates and 39% (n = 15/38) of preterm neonates. Bicytopenia was absent in 26% (n = 47/183) of patients. Central nervous system (CNS) manifestations were reported in 63% of cases (n = 64/102). Liver injury (68%, n = 91/134) and/or liver failure (24%, n = 32/134) were common. Flow cytometry was performed in 22% (n = 45/205) of cases. Many patients (63%, n = 121/193) died within the period of reporting. Discernable values for HLH diagnostic criteria were reported between 30% and 83% of the time.ConclusionsEvaluation of nHLH requires rapid testing for a wide range of differential diagnoses. HLH diagnostic criteria such as fever and bicytopenia may not occur as frequently in the neonatal population as in older pediatric populations. Neurologic and hepatic manifestations frequently occur in the neonatal population. Current reports of nHLH suggest a high mortality rate. Future publications containing data on nHLH should improve reporting quality by reporting all clinically relevant data.

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Section: Resultsmentioning

confidence: 99%

Neonatal hemophagocytic lymphohistiocytosis: A meta‐analysis of 205 cases

Kranz,

Hahn,

Thompson

et al. 2024

Pediatric Blood & Cancer

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“…16 HHV-6-induced HLH (one with co-infection with adenoviruses) were noted in two patients aged 11 and 21 months. HLH and HHV6 have been described in the context of primary immune deficiency, with pathogenic variants in IL-2R, 17 XIAP deficiency 18 and isolated CNS HLH. 19 Both our HHV6 patients are long-term survivors with no suggested immune deficiency or CNS involvement.…”

Section: Discussionmentioning

confidence: 99%

HLH Syndrome in a Community Hospital: The Challenge of an Early Diagnosis

Wagner,

Adam,

Pomeranz Engelberg

et al. 2024

PHMT

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Introduction Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory cytokine storm. It can be secondary to infections, malignancies, autoimmune diseases, or the manifestation of genetic disorders, including primary immune deficiency. HLH requires a high index of suspicion and is challenging for community hospitals. Methods Medical records of children with HLH admitted to the Meir Medical Center in Israel between 2014 and 2017 were reviewed. Results Nine children met ≥5/8 HLH‐2004 criteria. The median age was 1.1 year, and 78% of the patients were aged <2 years. All patients had prolonged fever, cytopenia, and elevated soluble interleukin‐2 receptor, and 89% had elevated ferritin levels. Of three children who underwent gene panel evaluation, one had heterozygote genetic variants of UNC13D and STXBP2 of unclear significance, whereas the other two had no variants. Infection was identified in 8 of 9 patients: adenovirus, HHV6, EBV, and Streptococcus Group A. Only 2 patients received HLH-2004 therapy (dexamethasone, etoposide, cyclosporin-A) and the others received dexamethasone and/or intravenous gamma globulins (IVIG), with rapid resolution of fever (median 2 days). One patient (11%) died of Pseudomonas septicemia and multiorgan failure. At a median follow-up of 7 years (range 2.6–8.1 years), all others (8/9) are long-term survivors with no recurrent HLH, but 2 patients developed adenovirus-related bronchiolitis obliterans. Conclusion Children presenting with prolonged fever and abnormal blood counts should be evaluated with ferritin, triglycerides, and fibrinogen levels which indicate possible HLH. Early intervention with corticosteroids and/or IVIG may prevent deterioration, spare them from chemotherapy and provide time for more elaborate testing to identify true HLH. Unfortunately, mortality remains a significant risk for these children.

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“…We previously speculated that in utero HHV-6 viremia on a fetal severe combined immune deficiency background might have suppressed OCL development from hematopoietic cells leading to OP phenotype in the first patient. 3 As emphasized above, HHV-6 viremia inevitably continues following successful allogeneic HSCT, though at a much lower level, and is controlled by immune surveillance. Thus, HHV-6 cannot affect neither donor nor recipient hematopoietic stem cells anymore.…”

Section: Osteoclast Culture Characterization and Short Tandem Repeat ...mentioning

confidence: 99%

“…We previously reported an infant with severe combined immunodeficiency (SCID) due to interleukin-2 receptor g chain gene mutation, congenital chromosomally-integrated herpesvirus-6 (HHV-6) infection, hemophagocytic syndrome and OP. 3 The patient tested negative for known OP mutations by whole-exome and genome sequencing. Bone biopsy report emphasized the lack of osteoclastic activity.…”

mentioning

confidence: 99%