Case Report: When an unknown fever unmasks Erdheim-Chester disease: a case showing the use of multimodality imaging and the successful interferon alpha therapy.

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Multiple organs can be affected mimicking other systemic diseases both clinically and radiologically. This makes timely diagnosis more challenging. Case Presentation We report the case of a 39-year-old male presented with a 15-day history of fever and retrosternal chest pain. Ha has a long history of diabetes insipidus, hypogonadism of unknown aetiology. On exploration, computed tomography revealed retroperitoneal fibrosis and “hairy” kidney appearance. Subsequent multimodality imaging studies showed the extensive multisystemic involvement including the skeletal system, retroperitoneum, pituitary, retroperitoneum, kidneys, heart, central nervous system, myocardium, pleura, lymph nodes and GI tract. Histopathology confirmed CD68+/CD1a- histiocytosis. Molecular analysis for BRAF mutation is currently pending. Pegylated interferon α and corticosteroids induced rapid clinical and biochemical improvement. Therapeutic response using a follow-up 18F-FDG PET scan revealed subsequent improved systemic lesions. Conclusion A prolonged history of unexplained endocrine abnormalities in the context of fever of unknown origin should evoke the diagnosis of ECD. Multimodal imaging is essential for diagnosis and for monitoring treatment response. This case highlights the importance of the multidisciplinary approach that integrates clinical evaluation, histological analysis, and imaging studies for the optimal the management of this disease. Early initiation of immunomodulatory therapy can lead to better outcomes, even prior to confirmation of molecular findings. 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F1000Research 2025, 14 :838 ( https://doi.org/10.12688/f1000research.169202.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Case Report Case Report: When an unknown fever unmasks Erdheim-Chester disease: a case showing the use of multimodality imaging and the successful interferon alpha therapy. [version 1; peer review: 1 approved, 1 approved with reservations] Hajer Boudriga https://orcid.org/0000-0003-3230-5426 1 , Imen Ben Hassine https://orcid.org/0000-0001-5459-3460 2 , Omar Ben Elkilani https://orcid.org/0009-0008-6830-4103 1 , [...] Raja Sfar 1 , Abir Ezzine 1 , Jihed Anoun 2 , Anis Mzabi 2 , Fatma Ben Fredj 2 , Kaouthar Chatti 1 Hajer Boudriga https://orcid.org/0000-0003-3230-5426 1 , Imen Ben Hassine https://orcid.org/0000-0001-5459-3460 2 , [...] Omar Ben Elkilani https://orcid.org/0009-0008-6830-4103 1 , Raja Sfar 1 , Abir Ezzine 1 , Jihed Anoun 2 , Anis Mzabi 2 , Fatma Ben Fredj 2 , Kaouthar Chatti 1 PUBLISHED 29 Aug 2025 Author details Author details 1 Department of internal medicine-Sahloul University Hospital, University of Sousse, Sousse, Tunisia 2 Department of Nuclear Medicine-Sahloul Universty Hospital, University of Sousse, Sousse, Tunisia Hajer Boudriga Roles: Conceptualization, Data Curation, Methodology, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Imen Ben Hassine Roles: Conceptualization, Methodology, Resources, Writing – Original Draft Preparation Omar Ben Elkilani Roles: Conceptualization, Methodology, Resources, Writing – Original Draft Preparation Raja Sfar Roles: Writing – Review & Editing Abir Ezzine Roles: Writing – Review & Editing Jihed Anoun Roles: Conceptualization, Data Curation, Resources Anis Mzabi Roles: Conceptualization, Data Curation, Resources Fatma Ben Fredj Roles: Supervision Kaouthar Chatti Roles: Supervision OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Rare diseases collection. Abstract Background Erdheim-Chester disease (ECD) is an extremely rare histiocytic neoplasm with a highly variable and often unpredictable clinical course and prognosis. Multiple organs can be affected mimicking other systemic diseases both clinically and radiologically. This makes timely diagnosis more challenging. Case Presentation We report the case of a 39-year-old male presented with a 15-day history of fever and retrosternal chest pain. Ha has a long history of diabetes insipidus, hypogonadism of unknown aetiology. On exploration, computed tomography revealed retroperitoneal fibrosis and “hairy” kidney appearance. Subsequent multimodality imaging studies showed the extensive multisystemic involvement including the skeletal system, retroperitoneum, pituitary, retroperitoneum, kidneys, heart, central nervous system, myocardium, pleura, lymph nodes and GI tract. Histopathology confirmed CD68+/CD1a- histiocytosis. Molecular analysis for BRAF mutation is currently pending. Pegylated interferon α and corticosteroids induced rapid clinical and biochemical improvement. Therapeutic response using a follow-up 18F-FDG PET scan revealed subsequent improved systemic lesions. Conclusion A prolonged history of unexplained endocrine abnormalities in the context of fever of unknown origin should evoke the diagnosis of ECD. Multimodal imaging is essential for diagnosis and for monitoring treatment response. This case highlights the importance of the multidisciplinary approach that integrates clinical evaluation, histological analysis, and imaging studies for the optimal the management of this disease. Early initiation of immunomodulatory therapy can lead to better outcomes, even prior to confirmation of molecular findings. READ ALL READ LESS Keywords Erdheim-Chester disease; histiocytosis, non-langerhans-cell; diabetes insipidus, neurogenic; Positron-Emission Tomography; diagnostic imaging; interferon-alpha Corresponding Author(s) Hajer Boudriga ( [email protected] ) Close Corresponding author: Hajer Boudriga Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2025 Boudriga H et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Boudriga H, Ben Hassine I, Ben Elkilani O et al. Case Report: When an unknown fever unmasks Erdheim-Chester disease: a case showing the use of multimodality imaging and the successful interferon alpha therapy. [version 1; peer review: 1 approved, 1 approved with reservations] . F1000Research 2025, 14 :838 ( https://doi.org/10.12688/f1000research.169202.1 ) First published: 29 Aug 2025, 14 :838 ( https://doi.org/10.12688/f1000research.169202.1 ) Latest published: 17 Oct 2025, 14 :838 ( https://doi.org/10.12688/f1000research.169202.2 )  There is a newer version of this article available. Suppress this message for one day. Introduction Erdheim-Chester Disease (ECD) is an extremely rare haematological malignancy, characterized by the abnormal proliferation and deposition of histiocytes thus classified among the non-Langerhans-cell histiocytosis. The onset of ailment is typically in the middle age. Biopsy is the key element for the diagnosis through the integration of xanthogranuloma histology with compatible clinical and radiographic findings with the support of molecular analysis. 1 The disease can produce a variety of symptoms depending on the sites affected by the tumoral cell proliferation with the possibility of having multiple organs involved. 2 , 3 Long bones involvement is nearly universal and is a key element of positive diagnosis. Extraskeletal involvement is seen in nearly half of the cases 4 and includes potentially life-threatening or disabling manifestations such as central nervous system infiltration, recurrent pericardial or pleural effusion, hypopituitarism, retroperitoneal fibrosis, hypopituitarism and exophthalmos. 2 , 5 The diagnostic process of ECD is often complex and based on biopsy, and increasingly molecular testing. Imaging, nevertheless, has a central role in guiding the diagnostic process, both in lesion detection and biopsy planning. Functional imaging, such as Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography 18F-FDG PET/CT is especially useful in identifying multisystem involvement and monitoring therapeutic response. 1 , 4 , 6 We discuss in this case report of a patient with ECD, the impact of multimodality imaging on the diagnostic workup and therapeutic management of this rare malignancy. Case report A 39-year-old man presented with a 15-day history of persistent fever peaking at 39-39.5 °C, associated with retrosternal chest pain radiating to the shoulders. He reported dull, bilateral ankle pain which had preceded the fever by several weeks with no associated swelling or erythema or joint stiffness. His medical history consisted of central diabetes insipidus diagnosed a year before the current admission and was managed with desmopressin, and secondary hypogonadism under endocrinologic follow-up. There was no significant family or psychological history. On physical examination, the patient was febrile but haemodynamically stable. There were no overt signs of arthritis or joint inflammation. Neurological examination was normal, and a right sided exophthalmos was noted. No cutaneous abnormalities were identified. Laboratory evaluation revealed elevated inflammatory markers, including a CRP level of 229 mg/L, and a mild thrombocytosis, raising initial concern for an underlying infectious, inflammatory, or myeloproliferative process. Infectious causes were ruled out during primary investigations with negative viral serologies, unremarkable blood cultures and sterile urine testing. In the context of acute chest pain and fever, differential diagnoses included aortic dissection, infective endocarditis, pericarditis, and vasculitis. Urgent thoracic computed tomography (CT) angiography excluded vascular emergencies and instead revealed a perivascular fibrosis of the descending aorta, a moderate pericardial effusion, anterior mediastinal fat infiltration along with symmetric retroperitoneal infiltration that surrounded the kidneys and extending to proximal ureters. This “hairy kidney” appearance raised suspicion of Erdheim-Chester disease ( Figure 1 ). Figure 1. Contrast-enhanced CT images showing characteristic abdominal and thoracic involvement in ECD. (A1–A2) Axial (A1) and coronal (A2) contrast-enhanced CT views showing circumferential, bilateral perirenal soft tissue thickening (yellow arrows) consistent with the “hairy kidney” sign. (B1–B2) Axial (B1) and sagittal (B2) CT views showing retrosternal anterior mediastinal soft tissue thickening (*, red arrows) extending to the pericardium, in keeping with pericardial and mediastinal involvement described on the report. Abbreviations : CT = computed tomography; ECD = Erdheim–Chester disease. Given the forementioned pathognomonic sign, and to further investigate skeletal involvement, a whole body 99mTc-HDP bone scintigraphy with single photon computed tomography/computed tomography (SPECT/CT) was performed. It demonstrated a markedly increased and symmetric radiotracer uptake in the lower femoral extremities, tibial bones, feet, and forearms, consistent with long bone osteosclerosis ( Figure 2 ). Additionally, tracer uptake was noted in the sphenoid, maxillary, and frontal sinuses with cortical thickening of the mandible, along with bilateral retro-orbital tracer accumulation on CT ( Figure 2 ). These findings, in conjunction with the absence of lytic lesions, were inconsistent with Langerhans cell histiocytosis and supported a diagnosis of ECD. Apart from the pathological bone aspect, there have been signs of accumulated radiotracer in both renal cavities. A subsequent renal ultrasound confirmed bilateral dilatated pyelocaliceal cavities likely due to the periureteral fibrotic compression. A JJ ureteral stent, was placed to relieve obstruction, resulting in stabilisation of renal function. Figure 2. Multimodal nuclear bone imaging demonstrating typical skeletal and craniofacial involvement in ECD. (A1) Whole-body planar bone scintigraphy (anterior and posterior views) shows diffuse symmetric and bilateral metaphyseal-diaphyseal increased radiotracer uptake in the distal femora, tibiae, feet, and maxillofacial skeleton (black arrows), consistent with systemic osseous involvement. (B1) Coronal fused SPECT/CT and (B2) corresponding CT of the lower limbs show bilateral metaphyseal-diaphyseal uptake in the femurs and tibiae (white arrows), with associated cortical thickening and sclerosis (white arrowheads). (A2) Static planar view of the hands and forearms highlights pronounced tracer uptake in the metacarpals and distal radius/ulna (black arrows), supporting upper extremity involvement, which is less commonly reported in Erdheim-Chester disease. (B3) Coronal MIP SPECT image confirms symmetrical uptake in the long bones of the lower extremities (black arrows). (C1) Coronal fused SPECT/CT and (C2) CT of the maxillofacial bones highlight tracer accumulation in the maxillae, zygomatic arches, and mandibles (white arrows) and corresponding sclerotic changes (white arrowheads). (C3) MIP SPECT image of the skull reveals diffuse symmetric craniofacial tracer uptake, notably involving the orbitomaxillary complex and mandible (black arrows). Abbreviations : SPECT = single photon emission computed tomography; CT = computed tomography; MIP = maximum intensity projection; ECD = Erdheim–Chester disease. To assess systemic disease burden and metabolic activity, a whole body 18F-FDG PET/CT was performed. The scan showed hypermetabolic retro-orbital masses, pachymeningeal thickening, and an active suprasellar lesion, correlating with the patient’s known central diabetes insipidus and confirming hypothalamic-pituitary axis involvement ( Figure 3 ). Additionally, there was cardiac manifestations through intense uptake in retrosternal thickened tissue, pericardiac nodular thickening, perivascular fibrosis of the descending aorta and a focal hypermetabolism in the atrio-ventricular sulcus. There was also diffuse hypermetabolic pleural activity associated with mild bilateral effusion, periaortic bilateral axillary lymphadenopathy, peri-renal and retroperitoneum fibrosis, epiploic fat nodules, bilateral testicular hypermetabolism and subcutaneous nodular lesions in the right gluteal region ( Figure 4.A ). The extent of the skeletal involvement was also confirmed through the hypermetabolic symmetric osteosclerotic lesions of particularly the long and feet bones and craniofacial bones ( Figure 4.A ). Figure 3. MRI and FDG PET/CT demonstrating orbital, craniofacial and central nervous system involvement in Erdheim–Chester disease before treatment. Axial post-contrast T1-weighted MRI (A1) and corresponding axial FDG PET/CT fusion image (A2) demonstrate intense enhancement and hypermetabolism of the maxillary sinuses (arrows). Axial post-contrast T1-weighted MRI (B1) and PET/CT (B2) show bilateral hypermetabolic frontal sinus involvement (arrows). Sagittal T1-weighted MRI (C1) and PET/CT (C2) reveal a suprasellar mass thickening the infundibulum (red arrows) and pachymeningeal enhancement of the tentorium cerebelli and adjacent meninges (arrowheads). Axial T1-weighted MRI (D3) and PET/CT (D4) show bilateral retroorbital masses (white arrows) encasing the optic nerves, along with hypermetabolism in the suprasellar mass (red arrows) and tentorium cerebelli (arrowheads). Abbreviations: MRI = magnetic resonance imaging; FDG PET/C T= fluorodeoxyglucose positron emission tomography/computed tomography. Figure 4. Pre-treatment FDG PET/CT (A) and post-treatment (B) MIP and axial fused PET/CT images illustrating multisystemic response in ECD. Lesions that resolved completely include pleural thickening (black arrows, A1–A3), axillary lymph nodes (blue arrows, A1), and testicular uptake (purple arrows, A1 and B1). Partial metabolic response was seen in periaortic vascular fibrosis (white arrows, A6 and B6), atrioventricular sulcus lesion (green arrows, A4 and B4), peritoneal and subcutaneous lesions (red arrows, A5–A6 and B5–B6), and perirenal/retroperitoneal “hairy kidney” involvement (yellow arrows, A7 and B7), with persistent uptake in the mediastinal retrosternal nodule (white arrowheads, B1 and B6). Bone uptake (A1, B1) remained visible but reduced . Abbreviations : FDG PET/CT = fluorodeoxyglucose positron emission tomography/computed tomography; MIP = maximum intensity projection; ECD = Erdheim–Chester disease. MRI of the brain and orbits complemented PET/CT by showing retrobulbar soft tissue thickening encasing the optic nerves, hypothalamic mass with infundibular thickening, and pansinusitis. These findings further supported CNS involvement ( Figure 3 ). A transthoracic echocardiography showed concentric left ventricular hypertrophy with preserved ejection fraction (55-60%). Initial bone biopsies of the left tibia and maxillary bones were inconclusive. Consequently, a CT guided biopsy of the retroperitoneal tissue was performed and showed the fibrous infiltration with CD68-positive, CD1-negative foamy histiocytes ( Figure 5 ), confirming a non-Langerhans histiocytosis compatible with ECD and further ruling out Langerhans cell histiocytosis. The patient also tested negative for the JAK2 mutation, effectively ruling out an associated myeloproliferative neoplasm, which can occasionally co-occur with ECD. Molecular testing for the BRAFV600E mutation and other MAPK pathway alterations was ordered but was not conducted due to financial restrictions, and thus the BRAF mutation status remained pending to date. Figure 5. Histopathological features of ECD on hematoxylin and eosin staining. (A) Intermediate-power view (H&E, original magnification ×100) showing sheets of foamy histiocytes with abundant pale, vacuolated cytoplasm within a fibrotic background. (B) High-power view (H&E, ×200) highlighting the large lipid-laden histiocytes with small, eccentric nuclei . Abbreviations : H&E = hematoxylin and eosin; ECD = Erdheim–Chester disease First line therapy included the administration of corticosteroids and methotrexate with a dose of 10 mg on day 1 and 25 mg on Day 2 weekly. Given the multisystem disease, including cardiovascular, CNS and the unknown BRAF status, the patient was initiated on weekly subcutaneous pegylated interferon alpha at a dose of 180 micrograms. Clinical improvement was evident within weeks, with resolution of fever, improved general status, and normalisation of inflammatory markers (CRP declined from 229 to 14 mg/L). The ophthalmologic assessment revealed stable right exophthalmos without visual impairment. The patient tolerated the treatment well with no documented side effects. A follow-up 18F-FDG PET/CT scan after 7 months of therapy showed a partial metabolic response, with reduction in standardised uptake (SUV) values and size of the suprasellar lesion and pericardial thickening, complete regression of bilateral testicular and pleural hypermetabolism, and improvement of the axillary lymphadenopathy ( Figure 4.B ). Persistent, though attenuated, uptake was still noted in the long bones and paranasal sinuses, consistent with residual disease ( Figure 4.B ). These findings validated the early efficacy of interferon-α, and highlighted PET/CT as an essential modality for treatment monitoring in ECD ( Table 1 ). Table 1. Chronological summary of clinical presentation, diagnostic investigations, and management in the reported case. Date/Interval Event 1 year prior to admission Diagnosis of central diabetes insipidus, with desmopressin therapy 6 weeks prior to admission Bilateral ankle pain without swelling or erythema 15 days prior to admission Onset of persistent fever and retrosternal chest pain Day 0-Day 3 Hospital admission, infectious causes excluded; urgent CT angiography shows mediastineal fat infiltration and small percardial effusion, with a “hairy kidneys” appearance Day 4-Day 10 Whole body 99mTc-HDP bone scintigraphy and SPECT/CT performed; typical findings of skeletal uptake in ECD Day 10-Day 14 FDG PET/CT confirms multisystem involvement, including CNS, cardiac, retroperitoneal and skeletal lesions Day 14 CT guided retroperitoneal biopsy confirms ECD Week 3 Initiation of corticosteroids and pegylted interferon-alpha therapy Week 4 onwrads Cinical improvement, fever resolved, inflammation biochemical response Month 7 of treatment Follow- FDG PET/CT shows patial morphologic and metabolic response nd regression of several lesions Discussion ECD is a rare histiocytic disorder, with fewer than 2000 cases reported to date since its discovery in 1930 4 . The disease mostly affects male adults with a mean age at diagnosis at 55 and sex ration of 3:1. Childhood onset is exceptionnally rare with only 20 recorded cases in history. 4 Within the xanthogranuloma family, it has a spectrum of histopathological features and is characterized by the infiltration of tissues by foamy CD68, factor XIIIa, and negative for CD1a and CD207 (langerin) histoiocytes. 7 Rosai-Dorfman disease (RDD), Along with juvenile xanthogranuloma (JXG), ALK-positive histiocytosis (APH), and histiocytic sarcoma (HS), it belongs to the histiocytic neoplasms in the The 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours. 8 The typical cause of the disease is constitutive MAPK signaling pathway mutations which are one of the first targets for molecular therapeutics for histiocytes. 4 , 7 The disease is clinically heterogenous, varying according to the location and extent of organ involvement. Its natural course is characterized by the progressive accumulation of lesions in multiple systems with spontaneous regression being only rarely observed and are fatal if left untreated. 7 Diagnosis is often delayed due to variable clinical presentations. Endocrine dysfunction, particularly diabetes insipidus is observed in 25-30% of patients and may precede diagnosis by years and is a frequent early manifestation. 9 , 10 While bone osteosclerosis occurs in more than 90% of cases, bone pain only appears in only half of patients usually localized in knees and ankles 3 , 4 which was the case of our patient. Extraskeletal involvement includes retroperitoneal fibrosis, pericardial and mediastinal infiltration as well as CNS lesions. 11 Our patient’s clinical course manifested the typical multisystemic pattern of ECD but also presented several distinctive features. Fever of unknown origine (FUO), and elevated inflammatory markers were dominant early features marking the atypical inflammatory presentation. Constitutional symptoms such as fatigue, night sweats, and weight loss are reported but not among the most frequent features, 4 , 11 implying its relative rarity in ECD cases. This systemic feature is in line with the Th-1 mediated systemic immune activation described in ECD. Arnaud et al. 12 reported elevated IL-12, IFN-α, and CP-1, with increased IL-6 in untreated patients. These cytokines are implicated in both systemic inflammatory responses and bone remodeling. This disease specific profile likely underlies the atypical inflammatory onset in our case. Accurate diagnosis and optimal treatment planning in CED relay heavily on multimodality imaging, including MRI, CT, and nuclear medicine hybrid imaging. Symmetric retroperitoneal fibrosis and perirenal sheathing (“hairy kidneys”), which are hallmarks of ECD, were discovered by CT and are present in a third of patients. 13 Retroperitoneal fibrosis can also arise as an IgG4-related disorder or related to other causes, but in ECD it most often circumferentially encases the abdominal aorta and involves the perirenal space. This contrasts with IgG4-related disease, which typically affects the anterolateral aortic wall and displaces rather than obstructs the distal ureters. 14 Our patient had ureteral obstruction which required JJ stent placement. This intervention alleviated renal hydronephrosis, reflecting a known complication of ECD-related fibrosis. 13 Other CT findings included loss of the fat interface with the myocardium and dense, infiltrative thickening of the anterior mediastinal fat and pericardium as well as the infiltration of the atrio-ventricular sulcus and the peri-aortic infiltration. These changes are commonly observed in ECD cardiac involvement which are usually asymptomatic. 5 , 15 Our patient, however, presented with chest pain, and one possible explanation could be coronary stenosis which is reported in 23% of cases. 5 A dedicated coronary angiography could be helpful in more accurately assessing the extent and severity of coronary involvement. MRI of the brain explained the long-standing DI as it identified a suprasellar mass and pituitary stalk thickening, present in 24% of ECD patients as the first clinical manifestation, and usually several years before ECD diagnosis. 4 The importance of histologic confirmation is emphasized by the possibility that these results could be mistakenly attributed to Langerhans cell histiocytosis or other adenomatous, granulomatous or inflammatory processes of this region. 11 Notably, CNS involvement occurs in about half of ECD patients and is associated with increased mortality. 16 Clinical manifestations vary and may include DI, exophthalmos, cerebellar ataxia, cranial nerve palsies, and cognitive impairment, 16 paralleling the site and extent of radiologic lesions. Like in our patients, reports show that ECD lesions are often extra-axial, contiguous with facial or orbital bone, and may be associated with osteosclerosis of the clavarial and facial bones. 17 Dural and meningeal involvement, seen in up to 23% of cases, 18 can present as diffuse thickening or mass-like lesions. 17 The coexistence of facial bone osteosclerosis with orbital or meningeal disease, as in our patient, is a recognized association that may help direct clinicians toward the diagnosis of ECD. 18 SPECT/CT of the bone scintigraphy provided anatomical-functional correlation, showing strikingly tracer uptake corresponding to metaphyseal osteosclerosis of long bones and facial bones. Associated epiphyseal sparing ruled out other conditions responsible for radiotracer symmetric uptake like progressive diaphyseal dysplasia, Gaucher disease and multifocal osteonecrosis. 13 Notably, unlike Langerhans cell histiocytosis, the mandible and axial skeleton are typically spared. This modality proved particularly helpful for bone mapping and diagnosis confirmation with the typical uptake distribution. FDG PET/CT was crucial in depicting the full extent of the disease, revealing both typical and atypical sites of extraosseous involvement. 19 It showed mirrored skeletal lesions to those in bone scintigraphy. It also confirmed hypermetabolic lesions in the CNS, right atrium, pericardium, pleura, retro-orbital regions, retroperitoneum, and bilateral axillary lymph nodes, while also identifying bilateral testicular involvement, a particularly rare manifestation of ECD. 15 Importantly, the scan also revealed hypermetabolic involvement of the omentum, peritoneum, and subcutaneous soft tissues in the form of hypermetabolic nodules. When reviewing patterns in ECD, Young et al. 3 proposed that higher SUV values may correlate with BRAF mutation status. PET/CT’s superior sensitivity compared to CT or bone scan was also illustrated by Kim et al., 20 where ECD lesions were occult on structural imaging but evident on FDG uptake. Follow-up PET/CT showed partial response to treatment, with phenomenal metabolic regression in most of the pathological sites. In our patient, follow-up PET/CT demonstrated only residual moderate perirenal hypermetabolism and less extensive bone manifestations along with the persistence of moderate to high FDG uptake in the nodular lesions of the retrosternal space and the pericardium. The patient’s persistent thrombocytosis raised suspicion for an associated myeloproliferative neoplasm, as hematologic malignancies could be an overlap in up to 10% of ECD patients. 1 However, JAK2 mutation testing was negative. While almost half of the patients (50-60%) harbor a BRAFV600E mutation. 15 The BRAF status of our patient is still unknow since the molecular analysis is still pending. This limited therapeutic options to immunomodulators, primarily interferon-α (IFN-α) which remain the cornerstone of treatment and the currently conventional therapy with largest evidence-base in ECD. 7 Its preferable pegylated formulation is recommended and increasing doses may be needed in cases of CNS and cardiovascular manifestations 18 as was the case in our patient. The rapid fever resolution and CRP normalization with IFN- α and Methotrexate align with prior reports of IFN- α efficacy in systemic inflammation. 21 This regimen achieved fever resolution within 72 hours of corticosteroid initiation, stabilization of cardiac and CNS lesions at 7-month follow-up. IFN- α is known the high prevalence of side effects that our patient didn’t present. They include fatigue, depression and cytopenia. 7 This treatment proved to be a crucial therapeutic option for the patient in a setting where targeted therapies are unavailable and the BRAF mutation status remained unknow to date. In contrast to cases where response to IFN-α was poorest in the CNS, lungs, and heart, 21 our patient demonstrated a favorable partial response as shown on the 7-month follow-up PET/CT scan. This case further illustrates the utility of PET/CT in monitoring treatment response and guiding follow-up. 11 That was particularly in osseous and soft tissue lesions that are nor evaluable by conventional anatomic criteria. This reflects growing evidence that PET-based metrics, such as modified PERSIST, may be better suited than RECIST for assessing response in ECD. 19 Although expert consensus supports FDG PET/CT for response assessment in ECD and other histiocytic disorders, the correlation between metabolic changes and clinical benefit still requires further validation in prospective studies. 7 , 19 A sustained partial metabolic response in the setting of clinical improvement represents a favorable outcome, 7 that’s why, the patient was put under surveillance with the current treatment along with a planned additional PET/CT scan. Conclusion This case illustrates the diagnostic and therapeutic challenges of Erdheim-Chester disease and highlights the critical role of multimodal imaging in guiding clinical decision-making. Our patient presented with fever of unknown origin preceding central diabetes insipidus and ultimately diagnosed of extensive multiorgan manifestations of ECD including rare ones. The unknown BRAF mutation status along with cardiac and CNS involvement in the setting of limited resources led to the pegylated IFN- α treatment. The obstructive hydronephrosis urged the need for urologic intervention. This case further reinforces current recommendations supporting FDG PET/CT as a valuable tool for monitoring disease response. Multidisciplinary collaboration remains essential in optimizing care for patients with rare, multisystem histiocytosis such as ECD. Strengths and limitations The strengths of this report include the documentation of a rare inflammatory presentation with FUO as a dominant early sign, the use of comprehensive multimodal imaging to map both typical and atypical disease sites, and longitudinal PET/CT follow-up demonstrating partial metabolic response despite CNS and cardiac involvement. Limitations include the single-case nature, pending molecular results, which restricted mutation-directed therapy selection and the short-term follow-up relative to the chronic disease course. Learning points • ECD as an FUO Mimic: Persistent fever with endocrine abnormalities (e.g., DI) warrants ECD evaluation, even in younger patients. • Imaging Triad: (FDG PET/CT and SPECT/CT (metabolic mapping), MRI (CNS/orbital detail), and CT (“hairy kidney”) are synergistic in ECD diagnosis. • Multidisciplinary Care: Urologic intervention (stenting) is critical for obstructive complications. • Extensive multisystem disease with CNS and cardiac involvement with an unknow BRAF-status: Pegylated IFN-α + methotrexate offers accessible, effective and a viable regimen for first-line therapy. Patient perspective The patient reported having dealt with unexplained fever and pain for weeks without any clear explanation for the diabetes insipidus for almost a year. Following the initiation of treatment, most symptoms were resolved, and he expressed relief at finally receiving a definitive diagnosis. Ethical approval Ethical approval was not required. Consent Written informed consent for publication of their clinical details was obtained from the patient. Contributor information Hajer Boudriga: [email protected] Imen Ben Hassine: [email protected] Omar Ben Elkilani: [email protected] Raja Sfar: [email protected] Abir Ezzine: [email protected] Jihed Anoun: [email protected] Anis Mzabi: [email protected] Fatma Ben Fredj: [email protected] Kaouthar Chatti: [email protected] Disclosure of AI use The authors used ChatGPT (OpenAI, GPT-4, 2025 version) to assist in correcting minor language errors and improving the sentence formulation in the manuscript. All authors reviewed and approved the final manuscript to ensure its accuracy and integrity. Data availability Underlying data No data are associated with this article. Extended data All relevant supporting materials, including the completed CARE checklist, are openly available in Zenodo. 22 This project contains the following extended data: “CARE Checklist for case report on “When an unknown fever unmasks Erdheim-Chester disease: a case showing the use of multimodality imaging and the successful interferon alpha therapy”. DOI: https://doi.org/10.5281/zenodo.16794958 . 22 Data is available under the terms of the Creative Commons Zero v1.0 Universal license. References 1. Kemps PG, Kester L, Scheijde-Vermeulen MA, et al. : Demographics and additional haematologic cancers of patients with histiocytic/dendritic cell neoplasms. Histopathology. 2024; 84 : 837–846. PubMed Abstract | Publisher Full Text 2. Bartoli L, Angeli F, Stefanizzi A, et al. : Genetics and clinical phenotype of Erdheim–Chester disease: A case report of constrictive pericarditis and a systematic review of the literature. Front Cardiovasc. Med. 2022; 9 : 876294. PubMed Abstract | Publisher Full Text | Free Full Text 3. Young JR, Johnson GB, Murphy RC, et al. : 18F-FDG PET/CT in Erdheim-Chester disease: Imaging findings and potential BRAF mutation biomarker. J. Nucl. Med. 2018; 59 : 774–779. PubMed Abstract | Publisher Full Text 4. Haroche J, Cohen-Aubart F, Amoura Z: Erdheim-Chester disease. Blood. 2020; 135 : 1311–1318. Publisher Full Text 5. Cohen-Aubart F, Emile JF, Carrat F, et al. : Phenotypes and survival in Erdheim-Chester disease: Results from a 165-patient cohort. Am. J. Hematol. 2018; 93 : E114–E117. PubMed Abstract | Publisher Full Text 6. Arnaud L, Malek Z, Archambaud F, et al. : 18F-fluorodeoxyglucose-positron emission tomography scanning is more useful in followup than in the initial assessment of patients with Erdheim-Chester disease. Arthritis Rheum. 2009; 60 : 3128–3138. PubMed Abstract | Publisher Full Text 7. Goyal G, Heaney ML, Collin M, et al. : Erdheim-Chester disease: consensus recommendations for evaluation, diagnosis, and treatment in the molecular era. Blood. 2020; 135 : 1929–1945. PubMed Abstract | Publisher Full Text 8. The WHO Classification of Tumours Editorial Board: WHO Classification of Tumours of Haematolymphoid Tumours. Lyon, France: IARC; 5th ed. 2020. 9. Courtillot C, Laugier Robiolle S, Cohen Aubart F, et al. : Endocrine Manifestations in a Monocentric Cohort of 64 Patients With Erdheim-Chester Disease. J. Clin. Endocrinol. Metab. 2016; 101 : 305–313. PubMed Abstract | Publisher Full Text 10. Manaka K, Makita N, Iiri T: Erdheim-Chester disease and pituitary involvement: A unique case and the literature. Endocr. J. 2014; 61 : 185–194. PubMed Abstract | Publisher Full Text 11. Mazor RD, Manevich-Mazor M, Shoenfeld Y: Erdheim-Chester Disease: A comprehensive review of the literature. Orphanet J. Rare Dis. 2013; 8 : 1–13. 12. Arnaud L, Gorochov G, Charlotte F, et al. : Systemic perturbation of cytokine and chemokine networks in Erdheim-Chester disease: a single-center series of 37 patients. Blood. 2011; 117 : 2783–2790. PubMed Abstract | Publisher Full Text 13. Bountas D, Bountas M, Exadactylou P, et al. : Erdheim-Chester disease and nuclear medicine imaging. A case report and brief review. Skeletal Radiol. 2024; 54 : 359–365. Publisher Full Text 14. Gagliardo CM, Giammanco A, Vaglio A, et al. : Erdheim-Chester disease as complex clinical presentation and diagnosis: A case report and concise review of literature. Med (United States). 2024; 103 : E37870. Publisher Full Text 15. Ozkaya N, Rosenblum MK, Durham BH, et al. : The histopathology of Erdheim-Chester disease: A comprehensive review of a molecularly characterized cohort. Mod. Pathol. 2018; 31 : 581–597. PubMed Abstract | Publisher Full Text | Free Full Text 16. Papo M, Emile JF, Maciel TT, et al. : Erdheim-Chester Disease: a Concise Review. Curr. Rheumatol. Rep. 2019; 21 : 1–9. 17. Kumar P, Singh A, Gamanagatti S, et al. : Imaging findings in Erdheim-Chester disease: what every radiologist needs to know. Pol. J. Radiol. 2018; 83 : 54–62. Publisher Full Text 18. Papo M, Emile JF, Maciel TT, et al. : Wrong Erdheim-Chester Disease: a Concise Review. Curr. Rheumatol. Rep. 2019; 21 : 86. 19. Kirchner J, Hatzoglou V, Buthorn JB, et al. : 18F-FDG PET/CT versus anatomic imaging for evaluating disease extent and clinical trial eligibility in Erdheim-Chester disease: results from 50 patients in a registry study. Eur. J. Nucl. Med. Mol. Imaging. 2021; 48 : 1154–1165. 20. Kim M, Rowe SP, Mehta TI: Erdheim-Chester Disease Occult on Radiographs and CT but Visible on MRI and PET. Am. J. Case Rep. 2024; 25 : e941169. Publisher Full Text 21. Iaremenko O, Petelytska L, Dyadyk O, et al. : Clinical presentation, imaging and response to interferon-alpha therapy in Erdheim–Chester disease: case-based review. Rheumatol. Int. 2020; 40 : 1529–1536. PubMed Abstract | Publisher Full Text 22. Boudriga H, Ben Hassine I, Ben Elkilani O, et al. : CARE Checklist for case report on ‘When an unknown fever unmasks Erdheim-Chester disease: a case showing the use of multimodality imaging and the successful interferon alpha therapy’. Zenodo. 2025. Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 29 Aug 2025 ADD YOUR COMMENT Comment Author details Author details 1 Department of internal medicine-Sahloul University Hospital, University of Sousse, Sousse, Tunisia 2 Department of Nuclear Medicine-Sahloul Universty Hospital, University of Sousse, Sousse, Tunisia Hajer Boudriga Roles: Conceptualization, Data Curation, Methodology, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Imen Ben Hassine Roles: Conceptualization, Methodology, Resources, Writing – Original Draft Preparation Omar Ben Elkilani Roles: Conceptualization, Methodology, Resources, Writing – Original Draft Preparation Raja Sfar Roles: Writing – Review & Editing Abir Ezzine Roles: Writing – Review & Editing Jihed Anoun Roles: Conceptualization, Data Curation, Resources Anis Mzabi Roles: Conceptualization, Data Curation, Resources Fatma Ben Fredj Roles: Supervision Kaouthar Chatti Roles: Supervision Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (2) version 2 Revised Published: 17 Oct 2025, 14:838 https://doi.org/10.12688/f1000research.169202.2 version 1 Published: 29 Aug 2025, 14:838 https://doi.org/10.12688/f1000research.169202.1 Copyright © 2025 Boudriga H et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Boudriga H, Ben Hassine I, Ben Elkilani O et al. Case Report: When an unknown fever unmasks Erdheim-Chester disease: a case showing the use of multimodality imaging and the successful interferon alpha therapy. [version 1; peer review: 1 approved, 1 approved with reservations] . F1000Research 2025, 14 :838 ( https://doi.org/10.12688/f1000research.169202.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 29 Aug 2025 Views 0 Cite How to cite this report: Nasr H. Reviewer Report For: Case Report: When an unknown fever unmasks Erdheim-Chester disease: a case showing the use of multimodality imaging and the successful interferon alpha therapy. [version 1; peer review: 1 approved, 1 approved with reservations] . F1000Research 2025, 14 :838 ( https://doi.org/10.5256/f1000research.186495.r417076 ) The direct URL for this report is: https://f1000research.com/articles/14-838/v1#referee-response-417076 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 14 Oct 2025 Hatem Nasr , Cairo University, Giza, Egypt; Nuclear Medicine, Cairo University Kasr Alainy Faculty of Medicine, Cairo, Cairo Governorate, Egypt Approved VIEWS 0 https://doi.org/10.5256/f1000research.186495.r417076 Overall Evaluation This case report provides a valuable contribution to the literature on Erdheim–Chester Disease (ECD) , a rare histiocytic neoplasm. It demonstrates a well-illustrated multimodal diagnostic pathway and documents clinical improvement with pegylated interferon-α. The report offers an ... Continue reading READ ALL Overall Evaluation This case report provides a valuable contribution to the literature on Erdheim–Chester Disease (ECD) , a rare histiocytic neoplasm. It demonstrates a well-illustrated multimodal diagnostic pathway and documents clinical improvement with pegylated interferon-α. The report offers an educational value to clinicians managing rare multisystemic diseases. 1. Title and Abstract The title is informative, concise, and effectively summarizes the case’s novelty (fever as a presenting symptom, multimodality imaging, interferon therapy). The abstract is well-structured, outlining the clinical background, case details, and main outcomes. 2. Introduction Strengths: Provides a succinct and accurate overview of ECD, with up-to-date references. Highlights the diagnostic complexity and role of imaging. Limitations: In the 2 nd paragraph the word “hypopituitarism” is mistakenly repeated. 3. Case Presentation Strengths: Exceptionally detailed chronology, thorough clinical, imaging, and histologic data. Use of multiple imaging modalities (CT, SPECT/CT, MRI, PET/CT) enhances diagnostic rigor. Inclusion of clear, well-annotated figures. Limitations: No quantitative PET/CT metrics (SUV values). The BRAF mutation testing being unavailable weakens the precision of molecular diagnosis. Lack of follow-up beyond 7 months limits understanding of long-term treatment efficacy. 4. Discussion Strengths: Balanced incorporation of clinical, radiologic, and therapeutic aspects supported by contemporary literature. Explains atypical presentation (fever of unknown origin) with plausible immunologic mechanisms. Discusses differential diagnoses and imaging correlations comprehensively. Limitations: Some repetition across imaging discussions could be condensed for clarity. 5. Conclusion Clear and concise; emphasizes multimodal imaging and multidisciplinary care. 6. References Strengths: Recent and high-quality sources. Properly formatted with DOIs and PubMed links. Limitations: Duplication (entries 16 and 18 both cite Papo et al., 2019). One reference (“Wrong Erdheim-Chester Disease”) appears mis-titled. Final Opinion: The case report is scientifically sound and contributes meaningful insights into a rare disease diagnostics and management. This is a well-prepared and clinically valuable case report that merits indexing following minor revisions. Final Recommendation Decision: Accept with minor revisions Is the background of the case’s history and progression described in sufficient detail? Yes Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes Is the case presented with sufficient detail to be useful for other practitioners? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Nuclear Medicine, nuclear oncology, nuclear cardiology, PET/CT imaging, SPECT/CT imaging, theranostics, infection imaging, radionuclide imaging, transarterial radionuclide embolization (TARE), Ga-68 DOTATATE imaging, F-18-FES imaging, PSMA imaging, F-18 DOPA imaging I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Nasr H. Reviewer Report For: Case Report: When an unknown fever unmasks Erdheim-Chester disease: a case showing the use of multimodality imaging and the successful interferon alpha therapy. [version 1; peer review: 1 approved, 1 approved with reservations] . F1000Research 2025, 14 :838 ( https://doi.org/10.5256/f1000research.186495.r417076 ) The direct URL for this report is: https://f1000research.com/articles/14-838/v1#referee-response-417076 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 17 Oct 2025 Hajer Boudriga , Department of internal medicine-Sahloul University Hospital, University of Sousse, Sousse, Tunisia 17 Oct 2025 Author Response We sincerely thank the reviewer for their thorough and constructive evaluation of our manuscript entitled We appreciate the positive comments regarding the educational value, clarity of presentation, and comprehensive multimodal ... Continue reading We sincerely thank the reviewer for their thorough and constructive evaluation of our manuscript entitled We appreciate the positive comments regarding the educational value, clarity of presentation, and comprehensive multimodal diagnostic approach. Below, we address each point raised. Title and Abstract: We thank the reviewer for this positive assessment. No further changes were required in this section. Introduction: We appreciate the reviewer’s attention to detail. The redundant occurrence of the word “hypopituitarism” in the second paragraph has been corrected in the revised version. Case Presentation: We have now included quantitative PET/CT data (SUVmax values) in the Case Presentation and highlighted that the CNS lesions demonstrated disproportionately higher SUV values compared to other organ sites. The issue of unavailable BRAF mutation testing has been addressed and expanded in the Discussion . We added a paragraph explaining the diagnostic and therapeutic importance of BRAF testing , the risk of false negatives due to mosaic mutation distribution , and the recommendation for multi-tissue sampling and high-sensitivity methods Regarding follow-up , we have acknowledged this as a study limitation in the Strengths and Limitations section, clarifying that follow-up remains ongoing. Conclusion: We thank the reviewer for this positive feedback. References: Both issues have been corrected. Duplicate references were removed, and the incorrect title has been replaced with the accurate citation. All references were rechecked for formatting consistency. Finally, we are grateful for the reviewer’s insightful remarks, which have strengthened the clarity, accuracy, and scientific rigor of our case report. We sincerely thank the reviewer for their thorough and constructive evaluation of our manuscript entitled We appreciate the positive comments regarding the educational value, clarity of presentation, and comprehensive multimodal diagnostic approach. Below, we address each point raised. Title and Abstract: We thank the reviewer for this positive assessment. No further changes were required in this section. Introduction: We appreciate the reviewer’s attention to detail. The redundant occurrence of the word “hypopituitarism” in the second paragraph has been corrected in the revised version. Case Presentation: We have now included quantitative PET/CT data (SUVmax values) in the Case Presentation and highlighted that the CNS lesions demonstrated disproportionately higher SUV values compared to other organ sites. The issue of unavailable BRAF mutation testing has been addressed and expanded in the Discussion . We added a paragraph explaining the diagnostic and therapeutic importance of BRAF testing , the risk of false negatives due to mosaic mutation distribution , and the recommendation for multi-tissue sampling and high-sensitivity methods Regarding follow-up , we have acknowledged this as a study limitation in the Strengths and Limitations section, clarifying that follow-up remains ongoing. Conclusion: We thank the reviewer for this positive feedback. References: Both issues have been corrected. Duplicate references were removed, and the incorrect title has been replaced with the accurate citation. All references were rechecked for formatting consistency. Finally, we are grateful for the reviewer’s insightful remarks, which have strengthened the clarity, accuracy, and scientific rigor of our case report. Competing Interests: The authors declare that they have no competing interests related to this article. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 17 Oct 2025 Hajer Boudriga , Department of internal medicine-Sahloul University Hospital, University of Sousse, Sousse, Tunisia 17 Oct 2025 Author Response We sincerely thank the reviewer for their thorough and constructive evaluation of our manuscript entitled We appreciate the positive comments regarding the educational value, clarity of presentation, and comprehensive multimodal ... Continue reading We sincerely thank the reviewer for their thorough and constructive evaluation of our manuscript entitled We appreciate the positive comments regarding the educational value, clarity of presentation, and comprehensive multimodal diagnostic approach. Below, we address each point raised. Title and Abstract: We thank the reviewer for this positive assessment. No further changes were required in this section. Introduction: We appreciate the reviewer’s attention to detail. The redundant occurrence of the word “hypopituitarism” in the second paragraph has been corrected in the revised version. Case Presentation: We have now included quantitative PET/CT data (SUVmax values) in the Case Presentation and highlighted that the CNS lesions demonstrated disproportionately higher SUV values compared to other organ sites. The issue of unavailable BRAF mutation testing has been addressed and expanded in the Discussion . We added a paragraph explaining the diagnostic and therapeutic importance of BRAF testing , the risk of false negatives due to mosaic mutation distribution , and the recommendation for multi-tissue sampling and high-sensitivity methods Regarding follow-up , we have acknowledged this as a study limitation in the Strengths and Limitations section, clarifying that follow-up remains ongoing. Conclusion: We thank the reviewer for this positive feedback. References: Both issues have been corrected. Duplicate references were removed, and the incorrect title has been replaced with the accurate citation. All references were rechecked for formatting consistency. Finally, we are grateful for the reviewer’s insightful remarks, which have strengthened the clarity, accuracy, and scientific rigor of our case report. We sincerely thank the reviewer for their thorough and constructive evaluation of our manuscript entitled We appreciate the positive comments regarding the educational value, clarity of presentation, and comprehensive multimodal diagnostic approach. Below, we address each point raised. Title and Abstract: We thank the reviewer for this positive assessment. No further changes were required in this section. Introduction: We appreciate the reviewer’s attention to detail. The redundant occurrence of the word “hypopituitarism” in the second paragraph has been corrected in the revised version. Case Presentation: We have now included quantitative PET/CT data (SUVmax values) in the Case Presentation and highlighted that the CNS lesions demonstrated disproportionately higher SUV values compared to other organ sites. The issue of unavailable BRAF mutation testing has been addressed and expanded in the Discussion . We added a paragraph explaining the diagnostic and therapeutic importance of BRAF testing , the risk of false negatives due to mosaic mutation distribution , and the recommendation for multi-tissue sampling and high-sensitivity methods Regarding follow-up , we have acknowledged this as a study limitation in the Strengths and Limitations section, clarifying that follow-up remains ongoing. Conclusion: We thank the reviewer for this positive feedback. References: Both issues have been corrected. Duplicate references were removed, and the incorrect title has been replaced with the accurate citation. All references were rechecked for formatting consistency. Finally, we are grateful for the reviewer’s insightful remarks, which have strengthened the clarity, accuracy, and scientific rigor of our case report. Competing Interests: The authors declare that they have no competing interests related to this article. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Todisco A. Reviewer Report For: Case Report: When an unknown fever unmasks Erdheim-Chester disease: a case showing the use of multimodality imaging and the successful interferon alpha therapy. [version 1; peer review: 1 approved, 1 approved with reservations] . F1000Research 2025, 14 :838 ( https://doi.org/10.5256/f1000research.186495.r410847 ) The direct URL for this report is: https://f1000research.com/articles/14-838/v1#referee-response-410847 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 09 Oct 2025 Antonio Todisco , Neurology, Università Campus Bio-Medico di Roma, Rome, Italy Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.186495.r410847 Boudriga and colleagues presented an interesting case report, namely: "When an unknown fever unmasks Erdheim-Chester disease: a case showing the use of multimodality imaging and the successful interferon alpha therapy". They comprehensively describe the clinical history and therapeutic management, in ... Continue reading READ ALL Boudriga and colleagues presented an interesting case report, namely: "When an unknown fever unmasks Erdheim-Chester disease: a case showing the use of multimodality imaging and the successful interferon alpha therapy". They comprehensively describe the clinical history and therapeutic management, in particular in a low-resource setting in absence of BRAF characterization. The discussion is adequate and the diagnostic approach is clear. However, since the BRAF mutation was not characterized, that part of the diagnostic/therapeutic approach is not complete. In case of ECD, the role of BRAF analysis is crucial to start a specific molecular targeted therapy and, sometimes, multiple testing is necessary, due to false negatives. I suggest to integrate few words about it, as described in Todisco et al [Reference 1]. The English is good and fluent. Is the background of the case’s history and progression described in sufficient detail? Yes Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes Is the case presented with sufficient detail to be useful for other practitioners? Partly References 1. Todisco A, Cavaliere C, Vaglio A, Marano M, et al.: Erdheim-Chester disease: A challenging diagnosis for an effective therapy. Clinical Neurology and Neurosurgery . 2020; 194 . Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: Neuroimmunology, neurodegenerative disease, rare neurological disease, neuromuscular disease, EMG I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Todisco A. Reviewer Report For: Case Report: When an unknown fever unmasks Erdheim-Chester disease: a case showing the use of multimodality imaging and the successful interferon alpha therapy. [version 1; peer review: 1 approved, 1 approved with reservations] . F1000Research 2025, 14 :838 ( https://doi.org/10.5256/f1000research.186495.r410847 ) The direct URL for this report is: https://f1000research.com/articles/14-838/v1#referee-response-410847 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 17 Oct 2025 Hajer Boudriga , Department of internal medicine-Sahloul University Hospital, University of Sousse, Sousse, Tunisia 17 Oct 2025 Author Response We thank the reviewer for this valuable comment emphasizing the importance of BRAF mutation analysis in the diagnostic and therapeutic management of ECD. We have now expanded the Discussion section ... Continue reading We thank the reviewer for this valuable comment emphasizing the importance of BRAF mutation analysis in the diagnostic and therapeutic management of ECD. We have now expanded the Discussion section to address this point. Specifically, we added a paragraph highlighting that: Molecular testing for BRAFV600E is a key diagnostic and therapeutic step in ECD. False-negative results may occur due to mosaic distribution or low variant allele frequency, as described by Todisco et al. Performing molecular analysis on multiple tissue specimens using high-sensitivity techniques is recommended to confirm mutation status and guide targeted treatment. In our case, the absence of local molecular testing constrained the therapeutic strategy to interferon-α–based therapy, which remains an effective alternative in resource-limited settings. We thank the reviewer for this valuable comment emphasizing the importance of BRAF mutation analysis in the diagnostic and therapeutic management of ECD. We have now expanded the Discussion section to address this point. Specifically, we added a paragraph highlighting that: Molecular testing for BRAFV600E is a key diagnostic and therapeutic step in ECD. False-negative results may occur due to mosaic distribution or low variant allele frequency, as described by Todisco et al. Performing molecular analysis on multiple tissue specimens using high-sensitivity techniques is recommended to confirm mutation status and guide targeted treatment. In our case, the absence of local molecular testing constrained the therapeutic strategy to interferon-α–based therapy, which remains an effective alternative in resource-limited settings. Competing Interests: The authors declare that they have no competing interests related to this article. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 17 Oct 2025 Hajer Boudriga , Department of internal medicine-Sahloul University Hospital, University of Sousse, Sousse, Tunisia 17 Oct 2025 Author Response We thank the reviewer for this valuable comment emphasizing the importance of BRAF mutation analysis in the diagnostic and therapeutic management of ECD. We have now expanded the Discussion section ... Continue reading We thank the reviewer for this valuable comment emphasizing the importance of BRAF mutation analysis in the diagnostic and therapeutic management of ECD. We have now expanded the Discussion section to address this point. Specifically, we added a paragraph highlighting that: Molecular testing for BRAFV600E is a key diagnostic and therapeutic step in ECD. False-negative results may occur due to mosaic distribution or low variant allele frequency, as described by Todisco et al. Performing molecular analysis on multiple tissue specimens using high-sensitivity techniques is recommended to confirm mutation status and guide targeted treatment. In our case, the absence of local molecular testing constrained the therapeutic strategy to interferon-α–based therapy, which remains an effective alternative in resource-limited settings. We thank the reviewer for this valuable comment emphasizing the importance of BRAF mutation analysis in the diagnostic and therapeutic management of ECD. We have now expanded the Discussion section to address this point. Specifically, we added a paragraph highlighting that: Molecular testing for BRAFV600E is a key diagnostic and therapeutic step in ECD. False-negative results may occur due to mosaic distribution or low variant allele frequency, as described by Todisco et al. Performing molecular analysis on multiple tissue specimens using high-sensitivity techniques is recommended to confirm mutation status and guide targeted treatment. In our case, the absence of local molecular testing constrained the therapeutic strategy to interferon-α–based therapy, which remains an effective alternative in resource-limited settings. Competing Interests: The authors declare that they have no competing interests related to this article. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 29 Aug 2025 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 Version 2 (revision) 17 Oct 25 read read Version 1 29 Aug 25 read read Antonio Todisco , Università Campus Bio-Medico di Roma, Rome, Italy Hatem Nasr , Cairo University, Giza, Egypt; Cairo University Kasr Alainy Faculty of Medicine, Cairo, Egypt Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Todisco A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 06 Nov 2025 | for Version 2 Antonio Todisco , Neurology, Università Campus Bio-Medico di Roma, Rome, Italy 0 Views copyright © 2025 Todisco A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Corrections have been made. Competing Interests No competing interests were disclosed. Reviewer Expertise Neuroimmunology, neurodegenerative disease, rare neurological disease, neuromuscular disease, EMG I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Todisco A. Peer Review Report For: Case Report: When an unknown fever unmasks Erdheim-Chester disease: a case showing the use of multimodality imaging and the successful interferon alpha therapy. [version 1; peer review: 1 approved, 1 approved with reservations] . F1000Research 2025, 14 :838 ( https://doi.org/10.5256/f1000research.189785.r425046) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-838/v2#referee-response-425046 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Nasr H. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 28 Oct 2025 | for Version 2 Hatem Nasr , Cairo University, Giza, Egypt; Nuclear Medicine, Cairo University Kasr Alainy Faculty of Medicine, Cairo, Cairo Governorate, Egypt 0 Views copyright © 2025 Nasr H. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions I would like to thank the authors for the their efforts and amendments performed for this clinically valuable case report. Competing Interests No competing interests were disclosed. Reviewer Expertise Nuclear Medicine, nuclear oncology, nuclear cardiology, radionuclide brain imaging, PET/CT imaging, SPECT/CT imaging, theranostics, infection imaging, radionuclide imaging, transarterial radionuclide embolization (TARE), Ga-68 DOTATATE imaging, F-18-FES imaging, PSMA imaging, F-18 DOPA imaging I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Nasr H. Peer Review Report For: Case Report: When an unknown fever unmasks Erdheim-Chester disease: a case showing the use of multimodality imaging and the successful interferon alpha therapy. [version 1; peer review: 1 approved, 1 approved with reservations] . F1000Research 2025, 14 :838 ( https://doi.org/10.5256/f1000research.189785.r425045) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-838/v2#referee-response-425045 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Nasr H. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 14 Oct 2025 | for Version 1 Hatem Nasr , Cairo University, Giza, Egypt; Nuclear Medicine, Cairo University Kasr Alainy Faculty of Medicine, Cairo, Cairo Governorate, Egypt 0 Views copyright © 2025 Nasr H. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Overall Evaluation This case report provides a valuable contribution to the literature on Erdheim–Chester Disease (ECD) , a rare histiocytic neoplasm. It demonstrates a well-illustrated multimodal diagnostic pathway and documents clinical improvement with pegylated interferon-α. The report offers an educational value to clinicians managing rare multisystemic diseases. 1. Title and Abstract The title is informative, concise, and effectively summarizes the case’s novelty (fever as a presenting symptom, multimodality imaging, interferon therapy). The abstract is well-structured, outlining the clinical background, case details, and main outcomes. 2. Introduction Strengths: Provides a succinct and accurate overview of ECD, with up-to-date references. Highlights the diagnostic complexity and role of imaging. Limitations: In the 2 nd paragraph the word “hypopituitarism” is mistakenly repeated. 3. Case Presentation Strengths: Exceptionally detailed chronology, thorough clinical, imaging, and histologic data. Use of multiple imaging modalities (CT, SPECT/CT, MRI, PET/CT) enhances diagnostic rigor. Inclusion of clear, well-annotated figures. Limitations: No quantitative PET/CT metrics (SUV values). The BRAF mutation testing being unavailable weakens the precision of molecular diagnosis. Lack of follow-up beyond 7 months limits understanding of long-term treatment efficacy. 4. Discussion Strengths: Balanced incorporation of clinical, radiologic, and therapeutic aspects supported by contemporary literature. Explains atypical presentation (fever of unknown origin) with plausible immunologic mechanisms. Discusses differential diagnoses and imaging correlations comprehensively. Limitations: Some repetition across imaging discussions could be condensed for clarity. 5. Conclusion Clear and concise; emphasizes multimodal imaging and multidisciplinary care. 6. References Strengths: Recent and high-quality sources. Properly formatted with DOIs and PubMed links. Limitations: Duplication (entries 16 and 18 both cite Papo et al., 2019). One reference (“Wrong Erdheim-Chester Disease”) appears mis-titled. Final Opinion: The case report is scientifically sound and contributes meaningful insights into a rare disease diagnostics and management. This is a well-prepared and clinically valuable case report that merits indexing following minor revisions. Final Recommendation Decision: Accept with minor revisions Is the background of the case’s history and progression described in sufficient detail? Yes Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes Is the case presented with sufficient detail to be useful for other practitioners? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Nuclear Medicine, nuclear oncology, nuclear cardiology, PET/CT imaging, SPECT/CT imaging, theranostics, infection imaging, radionuclide imaging, transarterial radionuclide embolization (TARE), Ga-68 DOTATATE imaging, F-18-FES imaging, PSMA imaging, F-18 DOPA imaging I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (1) Author Response 17 Oct 2025 Hajer Boudriga, Department of internal medicine-Sahloul University Hospital, University of Sousse, Sousse, Tunisia We sincerely thank the reviewer for their thorough and constructive evaluation of our manuscript entitled We appreciate the positive comments regarding the educational value, clarity of presentation, and comprehensive multimodal diagnostic approach. Below, we address each point raised. Title and Abstract: We thank the reviewer for this positive assessment. No further changes were required in this section. Introduction: We appreciate the reviewer’s attention to detail. The redundant occurrence of the word “hypopituitarism” in the second paragraph has been corrected in the revised version. Case Presentation: We have now included quantitative PET/CT data (SUVmax values) in the Case Presentation and highlighted that the CNS lesions demonstrated disproportionately higher SUV values compared to other organ sites. The issue of unavailable BRAF mutation testing has been addressed and expanded in the Discussion . We added a paragraph explaining the diagnostic and therapeutic importance of BRAF testing , the risk of false negatives due to mosaic mutation distribution , and the recommendation for multi-tissue sampling and high-sensitivity methods Regarding follow-up , we have acknowledged this as a study limitation in the Strengths and Limitations section, clarifying that follow-up remains ongoing. Conclusion: We thank the reviewer for this positive feedback. References: Both issues have been corrected. Duplicate references were removed, and the incorrect title has been replaced with the accurate citation. All references were rechecked for formatting consistency. Finally, we are grateful for the reviewer’s insightful remarks, which have strengthened the clarity, accuracy, and scientific rigor of our case report. View more View less Competing Interests The authors declare that they have no competing interests related to this article. reply Respond Report a concern Nasr H. Peer Review Report For: Case Report: When an unknown fever unmasks Erdheim-Chester disease: a case showing the use of multimodality imaging and the successful interferon alpha therapy. [version 1; peer review: 1 approved, 1 approved with reservations] . F1000Research 2025, 14 :838 ( https://doi.org/10.5256/f1000research.186495.r417076) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-838/v1#referee-response-417076 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Todisco A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 09 Oct 2025 | for Version 1 Antonio Todisco , Neurology, Università Campus Bio-Medico di Roma, Rome, Italy 0 Views copyright © 2025 Todisco A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Boudriga and colleagues presented an interesting case report, namely: "When an unknown fever unmasks Erdheim-Chester disease: a case showing the use of multimodality imaging and the successful interferon alpha therapy". They comprehensively describe the clinical history and therapeutic management, in particular in a low-resource setting in absence of BRAF characterization. The discussion is adequate and the diagnostic approach is clear. However, since the BRAF mutation was not characterized, that part of the diagnostic/therapeutic approach is not complete. In case of ECD, the role of BRAF analysis is crucial to start a specific molecular targeted therapy and, sometimes, multiple testing is necessary, due to false negatives. I suggest to integrate few words about it, as described in Todisco et al [Reference 1]. The English is good and fluent. Is the background of the case’s history and progression described in sufficient detail? Yes Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes Is the case presented with sufficient detail to be useful for other practitioners? Partly References 1. Todisco A, Cavaliere C, Vaglio A, Marano M, et al.: Erdheim-Chester disease: A challenging diagnosis for an effective therapy. Clinical Neurology and Neurosurgery . 2020; 194 . Publisher Full Text Competing Interests No competing interests were disclosed. Reviewer Expertise Neuroimmunology, neurodegenerative disease, rare neurological disease, neuromuscular disease, EMG I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 17 Oct 2025 Hajer Boudriga, Department of internal medicine-Sahloul University Hospital, University of Sousse, Sousse, Tunisia We thank the reviewer for this valuable comment emphasizing the importance of BRAF mutation analysis in the diagnostic and therapeutic management of ECD. We have now expanded the Discussion section to address this point. Specifically, we added a paragraph highlighting that: Molecular testing for BRAFV600E is a key diagnostic and therapeutic step in ECD. False-negative results may occur due to mosaic distribution or low variant allele frequency, as described by Todisco et al. Performing molecular analysis on multiple tissue specimens using high-sensitivity techniques is recommended to confirm mutation status and guide targeted treatment. In our case, the absence of local molecular testing constrained the therapeutic strategy to interferon-α–based therapy, which remains an effective alternative in resource-limited settings. View more View less Competing Interests The authors declare that they have no competing interests related to this article. reply Respond Report a concern Todisco A. Peer Review Report For: Case Report: When an unknown fever unmasks Erdheim-Chester disease: a case showing the use of multimodality imaging and the successful interferon alpha therapy. [version 1; peer review: 1 approved, 1 approved with reservations] . F1000Research 2025, 14 :838 ( https://doi.org/10.5256/f1000research.186495.r410847) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-838/v1#referee-response-410847 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list: Examples of 'Non-Financial Competing Interests' Within the past 4 years, you have held joint grants, published or collaborated with any of the authors of the selected paper. You have a close personal relationship (e.g. parent, spouse, sibling, or domestic partner) with any of the authors. You are a close professional associate of any of the authors (e.g. scientific mentor, recent student). You work at the same institute as any of the authors. 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