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. 2024 Feb 13:15:1282804.
doi: 10.3389/fimmu.2024.1282804. eCollection 2024.

HLH as an additional warning sign of inborn errors of immunity beyond familial-HLH in children: a systematic review

Silvia Ricci #  1   2 , Walter Maria Sarli #  1   2 , Lorenzo Lodi  1   2 , Clementina Canessa  2 , Francesca Lippi  2 , Donata Dini  3 , Marta Ferrari  3 , Laura Pisano  3 , Elena Sieni  4 , Giuseppe Indolfi  3   5 , Massimo Resti  3 , Chiara Azzari  1   2
Affiliations

HLH as an additional warning sign of inborn errors of immunity beyond familial-HLH in children: a systematic review

Silvia Ricci et al. Front Immunol. .

Erratum in

Abstract

Background: Hemophagocytic Lymphohistiocytosis (HLH) is a rare and life-threatening condition characterized by a severe impairment of the immune homeostasis. While Familial-HLH (FHL) is a known cause, the involvement of other Inborn Errors of Immunity (IEI) in pediatric-HLH remains understudied.

Objective: This systematic review aimed to assess the clinical features, triggers, laboratory data, treatment, and outcomes of pediatric HLH patients with IEI other than FHL (IEInotFHL), emphasizing the importance of accurate identification and management.

Methods: A systematic search for studies meeting inclusion criteria was conducted in PubMed, EMBASE, MEDLINE, and Cochrane Central. Quality assessment was performed through JBI criteria.

Results: A comprehensive search yielded 108 records meeting inclusion criteria, involving 178 patients. We identified 46 different IEI according to IUIS 2022 Classification. Combined immunodeficiencies, immune dysregulation disorders, and phagocyte defects were the IEI most frequently associated with HLH. In 75% of cases, HLH preceded the IEI diagnosis, often with an unrecognized history of severe infections. Triggers reflected the specific infection susceptibilities within IEI groups. Liver and central nervous system involvement were less common than in FHL cases. Treatment approaches and outcomes varied, with limited long-term follow-up data, limiting the assessment of therapeutic efficacy across IEI groups.

Conclusion: A comprehensive evaluation encompassing immunological, infectious, and genetic aspects is essential in pediatric-HLH. Relying solely on FHL or EBV susceptibility disorders tests is insufficient, as diverse other IEI can contribute to HLH. Early recognition of HLH as a potential warning sign can guide timely diagnostic investigations and facilitate tailored therapeutic interventions for improved outcomes.

Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=371425, PROSPERO, CRD42022371425.

Keywords: familial hemophagocytic lymphohistiocytosis; hemophagocytic lymphohistiocytosis; hemophagocytic syndrome; immune deficiency; inborn errors of immunity; macrophage activation syndrome.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Selected reports flow-chart according to PRISMA Guidelines.
Figure 2
Figure 2
Distribution of HLH in Groups (A) of IEInotFHL and Subgroups (B) of IEInotFHL according with IUIS 2022 Classification of IEI and distribution of subgroup according to age (C).
Figure 3
Figure 3
Triggers of HLH in patients with underlying IEInotFHL.
See this image and copyright information in PMC

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