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

Abstract

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.

Plain Language Summary

In the emergency department, children with common infections may have a severe complication called Hemophagocytic Lymphohistiocytosis or HLH. HLH can be life threatening if not rapidly recognized. HLH is rare and challenging for doctors in community hospitals. We describe nine patients who presented to a community hospital who were later diagnosed with HLH, posing a dilemma for physicians. Most (78%) were less than 2 years, all had prolonged fever, abnormal blood counts, elevated marker of HLH called soluble interleukin‐2 receptor and 8 of 9 had elevated ferritin, which can be a marker of HLH. HLH could be genetic therefore three children had genetic studies, with one having minor abnormalities, but the contribution to HLH is unclear. Infection as cause for HLH was identified in 8 of 9 patients. Chemotherapy that is used for severe HLH was required for 2 patients and the others received steroids and/or intravenous gamma globulin with rapid improvement. One patient who received chemotherapy and had suppressed immunity died of a severe bacterial infection. Others (8 of 9) are long-term survivors with no evidence of recurrent HLH. Two patients developed a pulmonary complication from adenovirus known as bronchiolitis obliterans. We conclude that children presenting with prolonged fever and abnormal blood counts should be evaluated with ferritin and other markers of possible HLH. Early intervention may prevent deterioration, may spare them from chemotherapy, and allow further assessment of true HLH. However, the death of one (11%), demonstrates the significant risks to these children.

Video abstract

Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use:

https://youtu.be/vfoBIA6kt9M

© 2024 Wagner et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

Keywords:

• hemophagocytic lymphohistiocytosis
• children
• community hospital
• infections
• early diagnosis

Abbreviations

CNS, Central nervous system; CSF, Cerebrospinal fluid; CT, Computerized Tomography; CSA; Cyclosporine A; CTL, Cytotoxic T-cell; ESR, Erythrocyte sedimentation rate; FHL3, Familial hemophagocytic lymphohistiocytosis type 3; HLH, Hemophagocytic lymphohistiocytosis; HSCT, Hematopoietic stem-cell transplantation; IVIG, Intravenous gamma globulins; KD, Kawasaki disease; MAS, Macrophage activation syndrome; MRI, Magnetic Resonance Imaging; NACHO, North American Consortium for Histiocytosis; sIL-2R, Soluble interleukin-2 receptor; SJIA, Systemic Juvenile Idiopathic Arthritis.

Data Sharing Statement

All data generated or analyzed during this study are included in this published article (Table 1).

Ethics Approval

The study was approved by the Helsinki Committee at the Meir Medical Center, Kfar Saba, Israel (number 0002-17-MMC). We confirm that it complies with the Declaration of Helsinki.

Consent for Publication

Owing to the retrospective nature of this study, anonymized data are presented in Table 1. The Helsinki Committee of the Meir Medical Center waived the requirement for consent for this study.

Acknowledgments

The authors acknowledge the dedicated work of the staff at the pediatric intensive care unit of the Meir Medical Center, Kfar-Saba, for their dedicated care of these patients and their families.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare no competing interests in this work.

Additional information

Funding

This work did not receive any funding from any funding agency.