Clinical and prognostic significance of initial fever in children with Langerhans cell histiocytosis

Introduction

Langerhans cell histiocytosis (LCH) is a clonal myeloproliferative disorder characterized by the accumulation of CD1a⁺ CD207⁺ Langerhans cells in damaged tissues. Continuous activation of mitogen-activated protein kinase (MAPK) pathway-related genes leads to the clonal proliferation, infiltration, and accumulation of Langerhans cells, which, in turn, give rise to the tissue or organ lesions observed in patients with LCH. LCH has been typically classified into cases with single-system involvement and those with multisystem involvement or into cases with risk-organ involvement (RO⁺) and those without risk-organ involvement (RO⁻) (1-3).

As LCH is an inflammatory myeloid neoplasm, individuals with LCH may exhibit fever at initial diagnosis. In 2002, Favara et al. reported that patients with LCH, fever, and accompanying hemophagocytic syndrome tend to have a poor prognosis (4-6). In 2019, Chellapandian et al. examined 384 patients with multisystem involvement of LCH (MS-LCH): 31 of these patients had fever, and the majority had accompanying hemophagocytic syndrome (7). In the 2018 study by Kobayashi et al., it was found that initial fever and skin involvement were highly correlated with the development of intractable and high-risk LCH (8).

We conducted this study to examine pediatric patients with LCH and found that only about 40% of the enrolled children with fever had accompanying hemophagocytic syndrome. Therefore, we speculated that children with fever in LCH could constitute a distinct cohort and subsequently sought to identify the differences in clinical characteristics, laboratory indicators, prognoses, and therapeutic efficacy of regimens between children with fever (52 cases) and those without fever (396 cases).

In addition, we attempted to identify more suitable treatment regimens through analyzing the 3-year progression-free survival (PFS) rates of children with fever and children without fever in our study. If patients with LCH and fever receive accurate and efficient treatment at first visit, the recurrence and refractory rate may be reduced. Our findings may better inform the clinical diagnosis and treatment of pediatric patients with LCH and initial fever. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0016/rc).

Methods

Study design

A portion of pediatric patients with LCH have recurrent or persistent disease-related fever at their first diagnosis. We retrospectively compared the clinical characteristics, laboratory indicators, and efficacy of regimens between pediatric LCH patients with fever at their first diagnosis (n=52) and those without fever (396 cases).

Study setting

A total of 448 pediatric patients first diagnosed with LCH at the Hematology Center of Beijing Children’s Hospital, China, from January 2016 to December 2019 were retrospectively enrolled. Depending on if patients had fever at their first clinical visit (“initial fever”), they were divided into two groups: children with fever and children without fever.

Follow-up

The median follow-up time of patients with LCH in this study was 151 weeks. Prognostic statistics were based on the latest clinical assessment of each patient. The follow-up time points (assessments of therapeutic efficacy) included six, 12, 25 and 52 weeks after first-line treatment; every four courses after the second-line treatment; after one, three, six, nine and 12 months of targeted therapy; every three months during maintenance treatment; and three months, six months, one year, two years, three years and five years after drug withdrawal. For patients on observation, the follow-up time included three months, six months, one year, two years, three years and five years after diagnosis.

Data collection

Data on clinical characteristics, laboratory indicators, and follow-up were retrieved from the electronic medical record system in our hospital. The follow-up information of some of the children was obtained via telephone.

Participants

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of Beijing Children’s Hospital, Capital Medical University (approval Nos. 2016-K-31, 2019-38, and 2020-k-16). Informed consent was obtained from the patients’ parents. The study protocols are registered in the Chinese Clinical Trial Registry (ChiCTR1900025783, ChiCTR2000030457, and ChiCTR2000032844).

Participant inclusion criteria

The inclusion criteria for patients were as follows: a diagnosis of LCH as confirmed by pathological results of lesion biopsy and CD1a-positive and/or CD207 (Langerin)-positive immunohistochemical staining, age ≤18 years, and signed informed consent.

Participant exclusion criteria

The exclusion criteria for patients were as follows: previous chemotherapy, allergy to any of the drugs examined in the study, concurrent participation in other clinical researches, and inability to follow the prescribed treatment schedule due to personal reasons or the missing of two follow-up appointments.

Diagnostic criteria

LCH was diagnosed according to patients’ clinical characteristics and laboratory examinations and via the definite identification of CD1a⁺ CD207⁺ cells in lesions through histochemical staining.

Therapeutic regimens

A total of 386 patients were treated with first-line regimens, including the Beijing Children’s Hospital (BCH)-LCH-2014 regimen (ChiCTR2000030457; patients enrolled from 2016 to 2018) (9) and the Chinese Children’s Histiocytic Group (CCHG)-LCH-2019 regimen (ChiCTR1900025783; patients enrolled in 2019) (Table S1). A further six patients with fever and 16 patients without fever received second-line treatment directly, either via the BCH-LCH-2014 regimen (ChiCTR2000030457) or the CCHG-LCH-2019 regimen (ChiCTR1900025783). In addition, 10 patients with fever and two patients without fever received targeted therapy directly (ChiCTR2000032844). The details of the CCHG-LCH-2019 treatment regimen are provided in Table S1. The treatment outcomes were evaluated according to the relative regimens.

Targeted therapy

The BRAF inhibitor dabrafenib was administered to those patients who harbored the BRAF^V600E mutation. A portion of the patients with LCH accompanying hemophagocytic syndrome received targeted therapy as first-line treatment, while the remaining patients received targeted therapy as second-line treatment. Dabrafenib was administered orally (2 mg/kg, once every 12 hours) over a period of 12 months and then adjusted according to the therapeutic response. The dosage was decreased (1 or 0.5 mg/kg, once every 12 hours) during maintenance treatment (9). The following patients were also switched to targeted therapy: those with bone marrow involvement and/or accompanying hemophagocytic syndrome; those with RO⁺ and a poorer prognosis after first-line or second-line treatment [evaluated as active disease-worse (AD-W) or AD-intermediate (AD-I) or no improvement in the risk organs]; those with central nervous system (CNS) involvement (including pituitary involvement) and no improvement after first-line treatment or second-line treatment; those evaluated as AD-W or AD-I after four courses and eight courses of second-line treatment, respectively; those who were plasma cell-free (cf) BRAF^V600E mutation-positive after eight courses of therapy in second-line treatment; and those with reactivation of LCH after second-line treatment.

Variables

Pediatric patients with LCH and initial fever

In our hospital, children who had persistent or intermittent fever with a daily peak axillary body temperature over 38 °C (basal body temperature ≥37.3 °C) at their first visit were diagnosed as children with initial fever, which is in line with the evaluation criteria of a 2018 study (8). The initial fever consistently occurs for more than seven days at the early onset of LCH. The median duration time of initial fever in our study was 28.5 days [interquartile range (IQR): 14–31 days]. In our hospital, systematic examinations were carried out for the children with LCH.

After the disease history of children was inquired, children were subjected to assessments of all five senses and underwent physical examinations of the chest, lung, heart, abdomen, spine, limbs, skin, mucosa, lymph, head, etc. This was followed by ultrasound examinations. If they had organ lesions or other abnormal phenomena, further imageological examinations were performed. Systematic laboratory examinations were also conducted, including blood culture, chest X-ray, respiratory pathogen tests, sputum culture, routine blood tests, biochemical blood tests, routine urine, routine stool tests, bacterial culture, anti-streptococcal hemolysin O test (ASO), tuberculosis (anti-nuclear antibody), Epstein-Barr virus test, coagulation tests, and peripheral T-cell subset tests, among others. Among children with initial fever, other causes of fever were excluded after systematic examinations and, importantly, after antibiotic therapies proved ineffective.

Organ involvement

Patients with organ involvement in LCH were diagnosed according to the Histiocyte Society evaluation and treatment guidelines (10). Lesions with craniofacial, auditory, and oral involvement were classified as having CNS risk involvements (11). Pituitary involvement was determined according to the presence of accompanying diabetes insipidus, occupying lesions, thickening of the pituitary stalk, and decreasing or disappearing signals in the posterior pituitary on magnetic resonance imaging (MRI) scanning (12,13). Patients with CNS-risk lesions also underwent nervous system examinations and cranial MRI scanning. Patients with CNS involvements were followed up by our neurologist for more than five years after their first diagnosis.

Diagnostic criteria of hemophagocytic syndrome

Accompanying hemophagocytic syndrome was diagnosed according to the relevant guidelines (14). The clinical indicators of the 23 patients with accompanying hemophagocytic syndromes are listed in Table S2.

Detection of the BRAFV600E mutation

The methods for detecting cfBRAF^V600E mutations were conducted according to the protocol described in our previous study (15). Detection of cfBRAF^V600E mutations in tissue started in January 2018, and detections of cfBRAF^V600E mutation in plasma were started in June 2018. Not all patients underwent the cfBRAF^V600E mutation detections for tissue and plasma due to insufficient tissue samples or failed sequencing of poor quality samples.

Detections of cytokines

Plasma samples from patients with LCH were collected via centrifugation at 3000 rpm for 10 minutes. The levels of cytokines were detected via the FACSCalibur system (BD, Franklin Lakes, NJ, USA) with a human Th1/Th2 cytokine kit (Cellgene Biotech Co., Ltd., Hangzhou, China), including interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-10 (IL-10), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α).

Definitions of disease state, events, reactivation, and progression

The evaluation criteria for the therapeutic efficacy (PFS rates and disease assessments) of patients with LCH were based on the previous work (9,16). Disease status assessments were also according to our previous work, including non-AD (NAD), AD-better (AD-B), AD-stable (AD-S), AD-I, and AD-W (9,15,16).

Reactivation was considered to be the reappearance of signs and symptoms of the AD after either complete disease resolution or a period of disease control that persisted for more than 3 months on maintenance therapy (15).

Events were considered to be the occurrence of disease progression, reactivation, or death during treatment or a change in treatment (9). The final PFS rates were evaluated from the date of diagnosis until the date of AD-I, AD-W, reactivation, or death due to any reason, whichever came first, or the last contact with the patients. The PFS rate of first-line treatment, second-line treatment, or targeted therapy was limited to the respective treatment and was evaluated until the date of events due to any reason, whichever came first, or the last contact with the patients.

The overall survival (OS) of patients with LCH was defined as the time from the date of diagnosis to the date of death due to any reasons, or the last contact with the patients.

Data sources and measurement

The laboratory indicators of pediatric patients with LCH were detected at their first visit through enzyme-linked immunosorbent assays or flow cytometry. The data of laboratory indicators were recorded from the electronic medical record system of our hospital. The pediatric patients were analyzed after grouping into patients with fever and patients without fever groups.

Bias

For all the pediatric patients with LCH, the initial fever caused by other potential infections was excluded by systematic examinations at their first visit.

Study size

The number of cases newly diagnosed in our hospital during the study period determined the sample size.

Quantitative variables

Quantitative variables including laboratory indicators [including the levels of IFN-γ, IL-4, soluble CD25 (sCD25), ferritin, and procalcitonin] were retrieved from the electronic medical record system of our hospital. Grouping was performed according to the respective normal and abnormal ranges of indicators. We analyzed the relationships between these laboratory indicators and initial fever.

Statistical analysis

All statistical analyses were performed with SPSS 16.0 software (IBM Corp., Armonk, NY, USA). Data distributions were analyzed through the Kolmogorov-Smirnov test and Q-Q plots. The Independent-samples t-test or Mann-Whitney U test was applied to analyze the differences in relative clinical indicator levels between the children with and without fever (for data with a normal or skewed distribution, respectively). The Fisher’s exact test was used to identify the relationships between clinical indicators and fever. Kaplan-Meier analysis and the log-rank test were used to compare the differences in PFS rates between children with and without fever.

Univariate analyses were used to analyze the critical factors correlated with the outcomes of first-line, second-line, and targeted regimens. We analyzed all the clinical characteristics and laboratory indicators correlated with the prognosis of first-line treatment in children with LCH. Multivariate Cox regression analysis was used to identify the factors associated with the outcomes of first-line treatment based on their clinical significance and the events-per-variable (EPV) principle. A P value less than 0.05 indicated statistical significance. Cases that were lost to follow-up were excluded. When laboratory indicator data were missing, analyses were conducted with the observed values without imputation.

Results

Participants

From January 2016 to December 2019, 448 pediatric patients diagnosed with LCH were enrolled in our study. They were divided into two groups: children with fever (52 cases) and children without fever (396 cases). All patients had participated in standardized therapy and were followed up regularly (Figure 1).

Figure 1 Cohort diagram of the treatment decision pathways of enrolled pediatric patients with LCH. LCH, Langerhans cell histiocytosis.

In LCH, pediatric patients with fever had distinct clinical characteristics and laboratory indicators

For the children with fever, the median age at disease onset was 1.17 years (range, 0.17–9.00 years). For the children without fever, the median age at disease onset was 3.17 years (range, 0.04–17.00 years).

First, we analyzed the clinical characteristics of pediatric patients with LCH at disease onset. Results showed that the following clinical characteristics were correlated with the fever: age younger than 2 years old, accompanying hemophagocytic syndrome, lung involvement, skin involvement, lymph node involvement, RO⁺, involvement of multiple bones, and multisystem involvement, pituitary involvement, and cfBRAF^V600E mutation in plasma (Table 1).

Second, we summarized the laboratory indicators of pediatric patients with LCH at disease onset and found that the levels of some laboratory indicators were correlated with fever (Table 2), including IFN-γ, IL-10, sCD25, D-dimer, ferritin, procalcitonin, C-reactive protein (CRP), and hemoglobin, among others. Further statistical analysis also revealed that the levels of BRAF^V600E mutation in plasma and total B-cell count, along with levels of sCD25, CRP, D-dimer, procalcitonin, ferritin, IL-10, total bilirubin, direct bilirubin, indirect bilirubin, total serum bile acid, triglyceride, lactate dehydrogenase, and IFN-γ, were significantly increased in the peripheral blood of pediatric patients with fever. However, absolute lymphocyte value, total T-cell count, red blood cell count, platelet count, immunoglobulin A (IgA), percentage of eosinophils, hemoglobin, total unsaturated iron-binding force (UIBF), and total iron-binding capacity, along with the levels of albumin, creatine kinase, high-density lipoprotein, cholinesterase, prealbumin, and transferrin, were decreased. The results of the Independent-samples t-test and Mann-Whitney U tests for the differences between groups are provided in Figure 2 and Table S3. In addition, we analyzed the correlations between clinical characteristics and laboratory indicators including inflammatory makers and the duration time of initial fever. It was found that gender was correlated with the duration time of initial fever (Fisher’s exact P=0.03; data not shown).

Figure 2 Comparison of laboratory indicators between pediatric LCH patients with and without fever. CRP, C-reactive protein; IgA, immunoglobulin A; IL-10, interleukin-10; LCH, Langerhans cell histiocytosis; sCD25, soluble CD25.

Therapeutic efficacy of clinical treatment regimens among pediatric LCH patients with or without fever

In the enrolled pediatric patients with LCH, the 3-year PFS rate of children with fever was significantly lower than that of children without fever after the entire treatment course (P<0.001; Figure 3A).

Figure 3 The 3-year PFS rates of first-line treatment in pediatric LCH patients with and without fever. (A) The 3-year PFS rates of pediatric LCH patients after the full course of therapy. (B) The 3-year PFS rates of pediatric LCH patients with and without fever after first-line treatment. (C-F) The therapeutic responses of pediatric LCH patients with and without fever at different courses after first-line treatment (6, 12, 25, and 52 weeks). LCH, Langerhans cell histiocytosis; PFS, progression-free survival.

A total of 35 children with fever and 351 children without fever received first-line treatment. Significant poorer response to the first-line treatment was observed in children with fever at post-treatment week six (responses of worse or reactivation: 11 vs. 24 cases; Fisher’s exact P<0.001) and post-treatment week 12 (responses of worse or reactivation: 4 vs. 9 cases, Fisher’s exact P=0.005) (Table 1). Among the included patients, 29 children (82.86%) with fever and 114 children (32.48%) without fever had their treatment regimens upgraded. The children in the fever group had a significantly higher percentage of regimen upgrade after the first-line treatment as compared to patients without fever (Fisher’s exact test P<0.001; Figure 1). The 3-year PFS rates of children with or without fever after first-line treatment were approximately 5.22% and 64.23%, respectively (progression events: 25 vs. 123 cases; log-rank and Kaplan-Meier P<0.001; Figure 3B and Table S4). We also analyzed the 3-year PFS rates of the first-line treatment of children with LCH at different stages (six, 12, 25, and 52 weeks; Figure 3C-3F). Furthermore, the 1- and 2-year OS rates of children with fever were significantly lower than those of children without fever (P=0.01 and P=0.04, respectively, for the Fisher’s exact test; Table 1).

Moreover, six children with fever and 16 children without fever received second-line treatment directly. The 3-year PFS rates among children with fever after receiving second-line treatment were similar to that of children without fever, with progression events occurring in 3 (50.00%) cases and 6 cases (37.50%), respectively (log-rank and Kaplan-Meier P=0.71; Figure S1A-S1C).

Additionally, 10 children with fever and two children without fever received targeted therapy directly after diagnosis. Among them, 11 children had pituitary involvement, and one had poorer peripheral vascular condition. The 3-year PFS rates were not significantly different between these two groups, with progression events occurring in 4 (40.00%) cases and 1 (50.00%) case, respectively (log-rank and Kaplan-Meier P=0.62; Figure S1D). In addition, in the children with fever, there were no significant differences in the therapeutic efficacy between children receiving second-line treatment (n=6) and those directly receiving targeted therapy (n=10) (P=0.61).

The therapeutic efficacy in children with fever treated with the second-line regimen and target regimen (n=7) (five patients with multisystem involvement, accompanying hemophagocytic syndrome, and RO⁺; one patient with RO⁺ and pituitary involvement, one patient with skin and paranasal sinuses involvements) was similar to that in children receiving targeted treatment alone (n=6) (progression events: 4 vs. 2 cases; Fisher’s exact test, P=0.59) and that in children receiving the second-line treatment directly (n=3) (progression events: 4 vs. 0 cases; Fisher exact test, P=0.20).

Moreover, among patients with single-system involvement and RO⁻ (240 cases) and those with multisystem involvement and RO⁻ (121 cases), there were no differences in response to first-line treatment or outcomes of regimens between the fever and no-fever groups. Meanwhile, among patients with multisystem involvement and RO⁺ (83 cases), there were 62 children who received first-line treatment. Children with fever (24 cases), as compared to those without fever (38 cases), had a significantly poorer treatment response at week six (Fisher’s exact test, P=0.02) and a poorer prognosis from first-line treatment (Fisher’s exact test, P=0.03). Thus, the identification of additional risk factors may be important for patients with multisystem involvement and RO⁺.

Prognostic significance of fever in children with LCH receiving first-line treatment

Based on the above analyses, we performed a univariate analysis to identify the factors associated with the prognosis of children with LCH following first-line treatment, including age, fever, occurrence of hemophagocytic syndrome, sCD25, risk-organ involvement, lung involvement, skin involvement, direct bilirubin levels, D-dimer levels, procalcitonin levels, ferritin levels, and plasma cfBRAF^V600E mutation, among others (Table S4).

According to univariate analysis and principle of EPV, the clinical characteristics associated with the prognosis of children with LCH following first-line treatment were age, fever, plasma cfBRAF^V600E, risk-organ involvement, pituitary involvement, skin involvement, and total T-cell count, along with the levels of hemoglobin, platelet, albumin, D-dimer, procalcitonin, and IFN-γ. These factors were incorporated into the Multivariate Cox regression analysis.

It was found that in the children with LCH who had received the first-line regimen, fever (P=0.004), RO⁺ (P=0.001), skin involvement (P=0.001), ferritin level (P<0.001), and dynamic erythrocyte sedimentation rate (P<0.001) were independent prognostic factors for the prognosis of first-line treatment (Table 3). Furthermore, we analyzed the influence of fever on the prognosis of children with RO⁺, single-system involvement, multiple bone involvement, and multisystem involvement. Among patients with RO⁺, multiple-system involvement, and multiple-bone involvement, those with fever had poorer prognoses at week six and over the whole course of first-line treatment as compared to children without fever. However, in the patients with single-system involvement, there were no significant differences in the prognoses from first-line treatment between children with and without fever (Table S5).

Discussion

Neoplasms, certain drugs, and venous thromboembolism are critical triggers for fever in patients with hematological and solid tumor malignancies (17).

In our study, we examined the clinical characteristics of 52 pediatric patients with fever at the first diagnosis. This study is the first of its kind to identify the clinical characteristics and laboratory indicators that were significantly correlated with children with LCH and initial fever, which were younger than 2 years old (82.69%), RO⁺ (69.23%), multisystem involvement, hemophagocytic syndrome (44.23%, 22 cases participated the detection of plasma cfBRAF^V600E mutation), cfBRAF^V600E mutation in plasma, IFN-γ, IL-10, and CRP, among others.

Plasma cfBRAF^V600E mutation level was correlated with the fever of children with LCH. Our previous study showed that plasma cfBRAF^V600E mutation levels of children with fever are significantly higher than those of children without fever (18). However, the BRAF^V600E mutation frequencies in biopsied tissues of these two groups showed no differences, which may due to failed sequencing of insufficient or poor-quality samples. The higher plasma cfBRAF^V600E level may reflect disease activity and higher levels of inflammatory cytokines, which may be the cause of fever (19,20).

In our study, 63.46% of the children with multiple bone involvement had initial fever, which may be attributable to inflammatory responses and cytokines in bone lesions (21). The levels of IFN-γ, IL-10, and IL-6 were significantly increased in the peripheral blood of children with fever, and these may be secreted by T cells and constitute a key cause of inflammation and fever (22). However, the percentages of peripheral blood T cells and total B cells in our study were closely associated with fever, and this relationship should be further examined (Table S3). Inflammatory cytokines can be secreted by the peripheral blood T cells, whereas B cells may produce anti-proinflammatory cytokines to regulate the immune microenvironment (23).

Elevated levels of CRP, D-dimer, or procalcitonin results in inflammation (24-26). Meanwhile, low red blood cell count, total iron-binding capacity, and UIBF, along with decreased levels of hemoglobin and transferrin, may suggest that children with LCH have abnormal iron metabolism. However, the correlation between the decreased creatine kinase level and fever remains unknown. Higher levels of ferritin and sCD25 have been reported to be diagnostic indicators of hemophagocytic lymphohistiocytosis (27). It should be noted that the missing data for IL-10 (missing in 16 cases, 3.57%), sCD25 (missing in 136 cases; 30.35%), D-dimer (missing in 69 cases; 15.40%), and the BRAF^V600E mutation frequency in plasma and biopsied tissues in our study could have affected the accuracy of the results.

Heightened levels in total bilirubin, direct bilirubin, indirect bilirubin, serum total bile acid, triglycerides, and lactate dehydrogenase are common in individuals with liver damage. Meanwhile, decreased levels of high-density lipoprotein, cholinesterase, and prealbumin have been found in children with liver damage (28). However, the reasons for the decrease in IgA levels and eosinophil percentage in the pediatric LCH patients with fever remain unclear.

We believe that the causes of fever in patients with LCH are similar to those in patients with multiple bone disease, hepatosplenomegaly, or hemophagocytic lymphohistiocytosis. Multiple bone disease is consistently accompanied by fever, which is due to neoplastic fever and the inflammatory responses (21). Fever accompanied with hepatosplenomegaly is usually caused by the disease itself. Up to 98% of children with hemophagocytic lymphohistiocytosis have fever, which is mainly due to cytokine storm and autoinflammatory disorder (29).

Our study also showed that children with LCH and initial fever had worse response to first-line treatment (at six and 12 weeks) and had a lower 3-year PFS rate after first-line treatment than did children without fever. In addition, a higher proportion of children with fever had upgraded treatment regimens as compared with the children without fever. Multivariate Cox regression analysis indicated that fever was an independent prognostic factor affecting the prognosis of patients with LCH after first-line treatment. Therefore, first-line treatment might not be an effective regimen for children with fever. It is also worth noting that the 3-year PFS rates among children administered second-line treatment directly did not differ between the children with fever (n=6) and children without fever (n=16) groups (P=0.71). Therefore, second-line treatment may be more effective for children with fever than the first-line treatment, but this should be confirmed in a larger-sample, prospective study.

Our previous work revealed that targeted therapy provides better short-term efficacy and safety in children with hemophagocytic syndrome (18). In the present study, targeted therapy also demonstrated better therapeutic efficacy in children with LCH and fever, although it was always used in children with the BRAF^V600E mutation. Thus, targeted therapy, including regimens targeting key regulators of the MAPK pathway and inflammatory cytokines, may be safer and more effective regimens for LCH children with fever and gene mutations in the MAPK pathway (30).

A limitation of this study is its single-center, retrospective design, and thus residual confounding could have occurred. A larger-scale, multicenter, prospective study is necessary to strengthen the credibility and generalizability of our findings.

Conclusions

Our study retrospectively clarified the clinical characteristics and laboratory indicators of pediatric LCH patients with initial fever. First, we identified the characteristics and laboratory indicators that were significantly correlated with initial fever in pediatric LCH patients, which included risk organ involvement, hemophagocytic syndrome, plasma cfBRAF^V600E mutation, and IFN-γ level, among others. Second, it was discovered that pediatric LCH patients with initial fever had significantly worse responses to first-line treatment than did those without fever. The second-line treatment or combination treatment with targeted therapy, including drugs targeting key regulators of the MAPK pathway and inflammatory cytokines, may constitute safer and more effective regimens for children with LCH and fever.

Acknowledgments

We would like to express our heartfelt gratitude to all the coauthors for their support and contributions in this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0016/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0016/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0016/prf

Funding: This work was supported by the Capital Health Research and Development of Special Grant (Nos. 2020-2-2093 and 2020-2-1141), the National Natural Science Foundation of China (Nos. 82070202 and 82141119), The Special Fund of The Pediatric Medical Coordinated Development Center of Beijing Hospitals Authority grant (No. XTZD20180201), and the Reform and Development of Beijing Municipal Health Commission (No. EYGF-XY-06).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0016/coif). The cfBRAF^V600E mutation testing in patients with LCH was conducted by MyGenostics Inc. (Beijing, China), which did not constitute a conflict of interest. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of Beijing Children’s Hospital, Capital Medical University (approval Nos. 2016-K-31, 2019-38, and 2020-k-16). Informed consent was obtained from the patients’ parents.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Lin H, Batajoo A, Peckham-Gregory E, et al. BRAF V600E-positive mononuclear cells in blood at diagnosis portend treatment failure and neurodegeneration in pediatric LCH. Blood 2025;146:206-18. [Crossref] [PubMed]
2. Héritier S, Emile JF, Barkaoui MA, et al. BRAF Mutation Correlates With High-Risk Langerhans Cell Histiocytosis and Increased Resistance to First-Line Therapy. J Clin Oncol 2016;34:3023-30. [Crossref] [PubMed]
3. Rodriguez-Galindo C, Allen CE. Langerhans cell histiocytosis. Blood 2020;135:1319-31. [Crossref] [PubMed]
4. Hesseling PB, Wessels G, Egeler RM, et al. Simultaneous occurrence of viral-associated hemophagocytic syndrome and Langerhans cell histiocytosis: a case report. Pediatr Hematol Oncol 1995;12:135-41. [Crossref] [PubMed]
5. Klein A, Corazza F, Demulder A, et al. Recurrent viral associated hemophagocytic syndrome in a child with Langerhans cell histiocytosis. J Pediatr Hematol Oncol 1999;21:554-6.
6. Favara BE, Jaffe R, Egeler RM. Macrophage activation and hemophagocytic syndrome in langerhans cell histiocytosis: report of 30 cases. Pediatr Dev Pathol 2002;5:130-40. [Crossref] [PubMed]
7. Chellapandian D, Hines MR, Zhang R, et al. A multicenter study of patients with multisystem Langerhans cell histiocytosis who develop secondary hemophagocytic lymphohistiocytosis. Cancer 2019;125:963-71. [Crossref] [PubMed]
8. Kobayashi T, Koga Y, Ishimura M, et al. Fever and Skin Involvement at Diagnosis Predicting the Intractable Langerhans Cell Histiocytosis: 40 Case-Series in a Single Center. J Pediatr Hematol Oncol 2018;40:e148-53. [Crossref] [PubMed]
9. Cui L, Wang CJ, Lian HY, et al. Clinical outcomes and prognostic risk factors of Langerhans cell histiocytosis in children: Results from the BCH-LCH 2014 protocol study. Am J Hematol 2023;98:598-607. [Crossref] [PubMed]
10. Minkov M, Grois N, McClain K, et al. Histiocyte Society Evaluation and Treatment Guidelines. 2009. Available online: https://docslib.org/doc/935699/histiocyte-society-lch-treatment-guidelines
11. Lee JW, Shin HY, Kang HJ, et al. Clinical characteristics and treatment outcome of Langerhans cell histiocytosis: 22 years’ experience of 154 patients at a single center. Pediatr Hematol Oncol 2014;31:293-302. [Crossref] [PubMed]
12. Prayer D, Grois N, Prosch H, et al. MR imaging presentation of intracranial disease associated with Langerhans cell histiocytosis. AJNR Am J Neuroradiol 2004;25:880-91.
13. Yeh EA, Greenberg J, Abla O, et al. Evaluation and treatment of Langerhans cell histiocytosis patients with central nervous system abnormalities: Current views and new vistas. Pediatr Blood Cancer 2018;
14. Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48:124-31. [Crossref] [PubMed]
15. Cui L, Zhang L, Ma HH, et al. Circulating cell-free BRAF V600E during chemotherapy is associated with prognosis of children with Langerhans cell histiocytosis. Haematologica 2020;105:e444-e447. [Crossref] [PubMed]
16. Gadner H, Minkov M, Grois N, et al. Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood 2013;121:5006-14. [Crossref] [PubMed]
17. Cunha BA, Lortholary O, Cunha CB. Fever of unknown origin: a clinical approach. Am J Med 2015;128:1138.
18. Wang D, Chen XH, Wei A, et al. Clinical features and treatment outcomes of pediatric Langerhans cell histiocytosis with macrophage activation syndrome-hemophagocytic lymphohistiocytosis. Orphanet J Rare Dis 2022;17:151. [Crossref] [PubMed]
19. Gulati N, Allen CE. Langerhans cell histiocytosis: Version 2021. Hematol Oncol 2021;39.
20. Canna SW, Marsh RA. Pediatric hemophagocytic lymphohistiocytosis. Blood 2020;135:1332-43. [Crossref] [PubMed]
21. Murakami H, Takada S, Hatsumi N, et al. Multiple myeloma presenting high fever and high serum levels of lactic dehydrogenase, CRP, and interleukin-6. Am J Hematol 2000;64:76-7. [Crossref] [PubMed]
22. Blomqvist A, Engblom D. Neural Mechanisms of Inflammation-Induced Fever. Neuroscientist 2018;24:381-99. [Crossref] [PubMed]
23. Rosser EC, Mauri C. Regulatory B cells: origin, phenotype, and function. Immunity 2015;42:607-12. [Crossref] [PubMed]
24. Robson SC, Shephard EG, Kirsch RE. Fibrin degradation product D-dimer induces the synthesis and release of biologically active IL-1 beta, IL-6 and plasminogen activator inhibitors from monocytes in vitro. Br J Haematol 1994;86:322-6. [Crossref] [PubMed]
25. Becker KL, Snider R, Nylen ES. Procalcitonin assay in systemic inflammation, infection, and sepsis: clinical utility and limitations. Crit Care Med 2008;36:941-52. [Crossref] [PubMed]
26. Sproston NR, Ashworth JJ. Role of C-Reactive Protein at Sites of Inflammation and Infection. Front Immunol 2018;9:754. [Crossref] [PubMed]
27. Naymagon L, Tremblay D, Mascarenhas J. Reevaluating the role of ferritin in the diagnosis of adult secondary hemophagocytic lymphohistiocytosis. Eur J Haematol 2020;104:344-51. [Crossref] [PubMed]
28. Favari E, Thomas MJ, Sorci-Thomas MG. High-Density Lipoprotein Functionality as a New Pharmacological Target on Cardiovascular Disease: Unifying Mechanism That Explains High-Density Lipoprotein Protection Toward the Progression of Atherosclerosis. J Cardiovasc Pharmacol 2018;71:325-31. [Crossref] [PubMed]
29. Griffin G, Shenoi S, Hughes GC. Hemophagocytic lymphohistiocytosis: An update on pathogenesis, diagnosis, and therapy. Best Pract Res Clin Rheumatol 2020;34:101515. [Crossref] [PubMed]
30. Yang Y, Wang D, Li N, et al. Improvement in Pituitary Imaging After Targeted Therapy in Three Children with BRAF-Mutated Langerhans Cell Histiocytosis with Pituitary Involvement. Onco Targets Ther 2020;13:12357-63. [Crossref] [PubMed]

(English Language Editor: J. Gray)