Pediatric Hemophagocytic Lymphohistiocytosis Presenting as a Refractory Febrile Illness: A CASE REPORT

Pediatric Hemophagocytic Lymphohistiocytosis Presenting as a Refractory Febrile Illness: A CASE REPORT | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Pediatric Hemophagocytic Lymphohistiocytosis Presenting as a Refractory Febrile Illness: A CASE REPORT Muhammad Taaha Siddiqui, Nawal Fatima, Khola Qazi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7235912/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Hemophagocytic Lymphohistiocytosis (HLH) is a life-threatening, exceedingly rare hyperinflammatory syndrome that typically presents with nonspecific symptoms such as fever and cytopenias. An early diagnosis of HLH is a significant clinical challenge, especially in children with presentations mimicking common infectious diseases. Case presentation A 9-year-old Pakistani girl came with a 2-week history of intractable high-grade fever, cough, and generalised weakness, unresponsive to broad-spectrum antibiotics. Physical examination showed hepatosplenomegaly and pallor. Laboratory tests showed pancytopenia, significantly elevated serum ferritin (1144 ng/ml), hypertriglyceridemia (349 mg/dL), and hypofibrinogenemia (107 mg/dL). Imaging showed hepatosplenomegaly and mild brain atrophic changes. Despite treatment with multiple antimicrobial therapies, the fever persisted, and thus, suspicion of HLH arose. She met five out of eight HLH-2004 diagnostic criteria, and on this basis, a presumptive diagnosis was established. Treatment consisted of supportive care, antipyretics, transfusions, and continued observation. Conclusion This case underscores the need to keep HLH in mind in children with chronic, treatment-resistant febrile illness, particularly in the setting of cytopenias and organomegaly. Early diagnosis and application of well-established diagnostic criteria are crucial to intervene early and enhance prognosis. Hemophagocytic lymphohistiocytosis cytopenia hyperferritinemia pediatric hyperinflammation fever of unknown origin Figures Figure 1 Figure 2 Figure 3 Introduction Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory, hyperferritinemic syndrome caused by uncontrolled cytotoxic T lymphocyte and macrophage activation and excessive release of cytokines [ 1 ]. Hemophagocytosis, by activated histiocytes, constitutes a self-perpetuating circle of inflammation, culminating in multiorgan damage [ 2 ]. HLH is primary (genetic) or secondary (acquired). Primary HLH, classically autosomal recessive, is associated with mutations in PRF1, UNC13D, STX11, and STXBP2, genes implicated in cytotoxic granule exocytosis [ 3 ]. Secondary HLH results from infection (most frequently Epstein-Barr virus and Dengue virus), malignancy, or autoimmune disease, with a mortality of over 40% if left untreated [ 4 ]. The diagnosis of HLH is highly challenging. Clinically, it is mainly diagnosed using the HLH 2004 diagnostic criteria, which requires five out of eight clinical and laboratory findings, or via identification of a pathogenic genetic mutation in familial cases. The HScore is also frequently used to assess the possibility of HLH in adult patients. Treatment is focused on suppressing the hyperinflammatory response and handling the underlying cause. Standard first-line therapy includes dexamethasone, cyclosporine, and etoposide on the basis of HLH-94/HLH-2004 protocols. Hematopoietic stem cell transplantation is recommended in primary (familial) cases, while therapy in secondary (acquired) cases is tailored to the triggering factor [ 1 ]. We present a 9-year-old girl with secondary HLH who was initially diagnosed with refractory enteric fever, demonstrating infection-mimicking HLH diagnostic traps. She developed recurrent fever (104°F), hepatosplenomegaly, and characteristic laboratory findings: hyperferritinemia (1144 ng/mL), hypofibrinogenemia (107 mg/dL), and cytopenias despite prolonged meropenem therapy. This case highlights the importance of diagnosing HLH in febrile antimicrobial-resistant patients, where hyperferritinemia and coagulopathy are diagnostic clues [ 1 , 4 ]. Case Report A 9-year-old female patient, weighing around 25 kg, reported to our tertiary care centre with a history of high-grade fever, up to 104°F, persisting for more than two weeks' duration. This prolonged fever had been associated with a long-standing cough, chest congestion, poor oral tolerance, generalised weakness, and pallor. Earlier, the illness had been preceded by an even longer intermittent febrile disease of one to two months' duration, indicative of a severe systemic process. Her treatment had begun with an empirical strategy in the form of a case of enteric fever with complications; therefore, she had been administered a prolonged course of intravenous broad-spectrum antibiotics, such as Meropenem, Piperacillin-Tazobactam, Linezolid, and Vancomycin, for over three weeks. Irrespective of these interventions, her fever remained refractory, and a reassessment of the underlying cause was warranted. On clinical examination, the patient was unresponsive but alert. She was also febrile and irritable and had mild pedal oedema. The abdominal examination showed hepatosplenomegaly with hepatomegaly 3–4 cm below the costal margin and splenomegaly 4–5 cm below the costal margin. Bilateral crepitations were present on auscultation of the chest; however, there was no evidence of any clinical or radiological pleural effusion. The neurological examination was routine during the entire stay in the hospital. Serial ultrasound scans established the presence of mild pericholecystic and pelvic free fluid and also the presence of hepatosplenomegaly. MRI showed mild cerebral atrophic changes along with extensive sinus inflammatory disease, which is indicative of subclinical central nervous system involvement. Laboratory findings showed prominent hematologic abnormalities like anaemia, thrombocytopenia, and neutropenia. Patients' inflammatory markers were significantly elevated with hyperferritinemia, hypertriglyceridemia, and hypofibrinogenemia, which was characteristic of systemic hyperinflammation. Electrolyte imbalance in the form of hyponatremia and a mild increase in liver enzymes were observed. Blood culture was positive for non-Aureus Staphylococcus species. Antinuclear antibodies and Brucella serologies were negative. The first hypothesis for complicated enteric fever was prolonged high-grade fever, endemicity, and hepatosplenomegaly. However, the finding of negative blood cultures and failure to respond to prolonged broad-spectrum antibiotics made this diagnosis suspect. Hematologic malignancies in the form of lymphoma or leukaemia were considered on the basis of the presence of organomegaly and cytopenias; however, the absence of blasts in peripheral blood smears and the lack of bone marrow examination made this hypothesis unproven. Macrophage Activation Syndrome, an HLH-like complication of systemic juvenile idiopathic arthritis, was another strong possibility. However, a lack of rash, arthritis, or autoimmune markers reduced the probability of this diagnosis. Viral infections, especially Epstein-Barr virus (EBV), were a strong probable trigger, with the presence of hyperferritinemia and systemic inflammation; however, no viral PCR was noted. Disseminated tuberculosis and brucellosis were also ruled out, both serologically and clinically. Although primary (familial) HLH is less probable with the patient's age and lack of familial history, it cannot be ruled out altogether without the help of a genetic workup. Autoimmune illnesses like systemic lupus erythematosus were less probable due to a negative antinuclear antibody and lack of supportive clinical findings. The findings collectively highly point towards a diagnosis of secondary HLH, most probably triggered by an occult viral infection or a hidden underlying hematologic malignancy. Based on HLH-2004 diagnostic criteria, the patient met at least five of the eight required parameters to diagnose [ 1 ]. These results confirm the diagnosis of hematophagocytic lymphohistiocytosis (see Table 1 ). Despite supportive interventions like albumin infusion, antipyretics, and intravenous fluids, her fever remained largely intractable, thus confirming the inflammatory nature of the disease. Figures 1 , 2 and 3 shows a chest X-ray (PA view) of the patient, with normal lung fields, absence of cardiomegaly, and absence of pleural effusion or widening of the mediastinum. These results exclude pulmonary infection or malignancy, further confirming the systemic nature of HLH. This case emphasises the subtle diagnostic presentation of HLH, especially in children with features that overlap with infection. Suspecting early, recognising diagnostic clues on time, and starting HLH-directed treatment immediately are extremely important to enhance outcomes. Secondary triggering workup for malignancy or autoimmune disease is strongly advised in this situation. Table 1 Primary lab data of Patient Parameter Result Normal Range Interpretation Hemoglobin (Hb) 8.4 g/dL 11.5–15.5 g/dL Severe anemia Hematocrit (HCT) 26.2% 35.0–45.0% Low RBC Count 3.93 ×10¹²/L 4.0-5.2 ×10¹²/L Mildly reduced MCV 66.7 fL 77–95 fL Microcytic MCH 21.4 pg 25–33 pg Hypochromic MCHC 32.1 g/dL 31–37 g/dL Normal RDW 22.3% 12.1–16.9% High (anisocytosis) WBC Count 8.5 ×10⁹/L 5.0–13.0 ×10⁹/L Normal Neutrophils 7.3% 40–75% Severe neutropenia Lymphocytes 39.2% 20–45% Normal Monocytes 53.4% 2–10% Marked monocytosis Eosinophils 0.0% 1–6% Absent Basophils 0.1% 0–1% Normal Platelets 114 ×10⁹/L 180–400 ×10⁹/L Thrombocytopenia Discussion In our patient's situation, a 9-year-old girl, the disease was characterised by chronic high-grade fever, hepatosplenomegaly, cytopenia, hyperferritinemia and hypertriglyceridemia, and decreased fibrinogen—features that fulfil at least five of the eight HLH-2004 diagnostic criteria [ 1 ]. The patient was initially treated on the suspected diagnosis of complicated enteric fever, a plausible one in the clinical context and presenting features. However, the failure to respond to almost three weeks of intravenous broad-spectrum antibiotics, including Meropenem, Tanzo, Colomycin, and Linezolid, made rethinking the diagnosis essential. In the context of adequate antibiotic cover, refractory fever in children must continually raise the suspicion of hyperinflammatory syndromes like hemophagocytic lymphohistiocytosis (HLH) [ 5 , 6 ]. In the current case, prolonged fever over 38.5°C, despite antipyretics administered every four hours and sponging, was one of the most recalcitrant clinical features. Hepatosplenomegaly was documented by clinical examination and radiologic study, in which the spleen size was 15.9 cm. Organ enlargement and hematologic disturbances—haemoglobin consistently less than 9 g/dL and platelets falling to a level as low as 25,000—complete the cytopenia requirement for Hemophagocytic Lymphohistiocytosis. The absolute neutrophil count was less than 1.0 × 10^9/L, thus again completing the requirement for cytopenia in at least two hemopoietic lineages [ 1 , 7 ]. Inflammatory markers were also high. Serum ferritin was 1144 ng/mL. Triglycerides were 349 mg/dL, and fibrinogen fell to 107 mg/dL, qualifying for HLH criteria for metabolic dysregulation [ 1 , 8 ]. The findings indicate a cytokine-mediated process rather than infectious aetiology. The negative ANA panel and Brucella serologies excluded autoimmune and other infectious mimics [ 6 , 7 ]. The patient had no focal deficits; however, MRI was positive for mild atrophic changes in the brain with evidence of sinus inflammatory disease. These findings could indicate central nervous system involvement, a known complication occurring in 25–50% of HLH cases [ 9 ]. The elevation of liver enzymes and requirement for albumin transfusion suggested hepatic involvement. Despite the lack of assessment of bone marrow biopsy, natural killer (NK) cell activity, and soluble interleukin-2 receptor levels, clinical diagnosis of HLH is still justified with the available data [ 1 , 4 ]. One major limitation is the absence of reported therapy for hemophagocytic lymphohistiocytosis, such as dexamethasone or etoposide, which are routine in treatment protocols such as HLH-94 or HLH-2004 [ 1 , 10 ]. Prompt therapeutic intervention is necessary to avoid irreversible organ damage and improve survival [ 8 , 11 ]. In many settings, however, the absence of specific diagnostic methods and targeted therapies may lead to delayed use of appropriate treatment. Conclusion This case illustrates the diagnostic and therapeutic dilemma of Hemophagocytic Lymphohistiocytosis, especially in pediatric patients with an ill-defined febrile illness initially mistaken for having the usual causes of infection. Patient's chronic fever, multi-lineage cytopenias, organomegaly, and raised inflammatory markers highlight the requirement to keep a high level of suspicion for HLH when usual management does not yield an improvement. The early recognition and utilisation of the HLH-2004 diagnostic criteria were crucial to making a presumptive diagnosis despite the lack of molecular or histopathological evidence. Clinicians need to be more alert to hyperinflammatory syndromes like Hemophagocytic Lymphohistiocytosis, which masquerade as more common infections but require essentially different treatment. This case supports the idea that refractory fever and systemic inflammation, particularly when accompanied by specific haematological and biochemical profiles, should lead to early suspicion of HLH. Prompt diagnosis and treatment are necessary for optimal patient outcomes, and this case is educational about the complicated and dynamic nature of pediatric presentations of HLH. Abbreviations HLH Hemophagocytic Lymphohistiocytosis CBC Complete Blood Count CT Computed Tomography ICU Intensive Care Unit IVIG Intravenous Immunoglobulin ESR Erythrocyte Sedimentation Rate CRP C-reactive Protein NK cells Natural Killer Cells AST Aspartate Aminotransferase ALT Alanine Aminotransferase LDH Lactate Dehydrogenase INR International Normalized Ratio PT Prothrombin Time APTT Activated Partial Thromboplastin Time EBV Epstein–Barr Virus PCR Polymerase Chain Reaction CNS Central Nervous System FIP1L1 Factor Interacting with PAPOLA and CPSF1-Like 1 UNC13D Unc-13 Homolog D STX11 Syntaxin 11 STXBP2 Syntaxin Binding Protein 2 Declarations Funding Not applicable. Conflicts of interest / Competing interests The authors declare no conflicts of interest. Ethics approval This case report was conducted in accordance with institutional ethical standards. Ethical approval was waived due to the nature of the case report. Consent to participate Informed consent was obtained from the patient’s parent(s) for participation in this study. Written consent for publication Written informed consent was obtained from the patient’s parent(s) for publication of this case report and any accompanying images. Availability of data and material Not applicable. Code availability Not applicable. References Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G (2007) HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. ;48(2):124 – 31. 10.1002/pbc.21039 . PMID: 16937360 Filipovich AH (2006) Hemophagocytic lymphohistiocytosis and related disorders. Curr Opin Allergy Clin Immunol. ;6(6):410-5. 10.1097/01.all.0000246626.57118.d9 . PMID: 17088644 Canna SW, Marsh RA (2020) Pediatric hemophagocytic lymphohistiocytosis. Blood 135(16):1332–1343. 10.1182/blood.2019000936 PMID: 32107531; PMCID: PMC8212354 Ramos-Casals M, Brito-Zerón P, López-Guillermo A, Khamashta MA, Bosch X (2014) Adult haemophagocytic syndrome. Lancet. ;383(9927):1503–1516. doi: 10.1016/S0140-6736(13)61048-X. Epub 2013 Nov 27. Erratum in: Lancet. 2014;383(9927):1464. PMID: 24290661 Janka G (2009) Hemophagocytic lymphohistiocytosis: when the immune system runs amok. Klin Padiatr. ;221(5):278 – 85. doi: 10.1055/s-0029-1237386. Epub 2009 Aug 25. PMID: 19707989 Rosado FG, Kim AS (2013) Hemophagocytic lymphohistiocytosis: an update on diagnosis and pathogenesis. Am J Clin Pathol. ;139(6):713 – 27. 10.1309/AJCP4ZDKJ4ICOUAT . PMID: 23690113 Otrock ZK, Eby CS (2015) Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis. Am J Hematol 90(3):220–224. 10.1002/ajh.23911 Epub 2015 Jan 16. PMID: 25469675 Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL (2011) How I treat hemophagocytic lymphohistiocytosis. Blood. ;118(15):4041-52. doi: 10.1182/blood-2011-03-278127. Epub 2011 Aug 9. PMID: 21828139; PMCID: PMC3204727 Lehmberg K, Nichols KE, Henter JI, Girschikofsky M, Greenwood T, Jordan M, Kumar A, Minkov M, La Rosée P, Weitzman S, Study Group on Hemophagocytic Lymphohistiocytosis Subtypes of the Histiocyte Society (2015) Consensus recommendations for the diagnosis and management of hemophagocytic lymphohistiocytosis associated with malignancies. Haematologica 100(8):997–1004 PMID: 26314082; PMCID: PMC5004414 La Rosée P, Horne A, Hines M, von Bahr Greenwood T, Machowicz R, Berliner N, Birndt S, Gil-Herrera J, Girschikofsky M, Jordan MB, Kumar A, van Laar JAM, Lachmann G, Nichols KE, Ramanan AV, Wang Y, Wang Z, Janka G, Henter JI (2019) Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood 133(23):2465–2477. 10.1182/blood.2018894618 Epub 2019 Apr 16. PMID: 30992265 Allen CE, Yu X, Kozinetz CA, McClain KL (2008) Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. ;50(6):1227-35. 10.1002/pbc.21423 . PMID: 18085676 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7235912","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":497211323,"identity":"4a6b8bf1-579f-42e4-980a-9456e7164b8a","order_by":0,"name":"Muhammad Taaha Siddiqui","email":"data:image/png;base64,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","orcid":"","institution":"Continental Medical College","correspondingAuthor":true,"prefix":"","firstName":"Muhammad","middleName":"Taaha","lastName":"Siddiqui","suffix":""},{"id":497211324,"identity":"b18e6c7c-00e8-4cff-b748-241e919f7376","order_by":1,"name":"Nawal Fatima","email":"","orcid":"","institution":"Continental Medical College","correspondingAuthor":false,"prefix":"","firstName":"Nawal","middleName":"","lastName":"Fatima","suffix":""},{"id":497211325,"identity":"c42e674a-dede-4c64-b160-ea0d2c8e7583","order_by":2,"name":"Khola Qazi","email":"","orcid":"","institution":"Jinnah Sindh Medical University","correspondingAuthor":false,"prefix":"","firstName":"Khola","middleName":"","lastName":"Qazi","suffix":""}],"badges":[],"createdAt":"2025-07-28 16:23:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7235912/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7235912/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":88646963,"identity":"42394076-1ebc-4c7c-baa1-ab397bef0bf3","added_by":"auto","created_at":"2025-08-08 16:36:35","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":95117,"visible":true,"origin":"","legend":"\u003cp\u003eshows a chest X-ray (PA view) of the patient, with normal lung fields, absence of cardiomegaly, and absence of pleural effusion or widening of the mediastinum.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7235912/v1/c6d4fb219c5db9b2958bd6db.jpg"},{"id":88646962,"identity":"b9a99594-ab40-492e-b3ec-608661901e53","added_by":"auto","created_at":"2025-08-08 16:36:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":65848,"visible":true,"origin":"","legend":"\u003cp\u003eThe bar graph below illustrates key laboratory findings in the patient. Parameters falling outside the normal reference ranges are highlighted in red.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7235912/v1/ea967b488114e004a403b994.png"},{"id":88646964,"identity":"4c5969e2-3de3-4667-8810-61804abd9c87","added_by":"auto","created_at":"2025-08-08 16:36:35","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":178221,"visible":true,"origin":"","legend":"\u003cp\u003eThis radar chart provides a visual representation of the severity of deviation from normal ranges across key hematologic parameters in the HLH patient.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7235912/v1/b788622bbf3bc698fbfa29e2.png"},{"id":88647514,"identity":"ab92974a-813c-4ab8-b269-81f4b411a769","added_by":"auto","created_at":"2025-08-08 16:44:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":838544,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7235912/v1/2bb36d2b-fec8-4963-8ce6-cb2e78c5840c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pediatric Hemophagocytic Lymphohistiocytosis Presenting as a Refractory Febrile Illness: A CASE REPORT","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory, hyperferritinemic syndrome caused by uncontrolled cytotoxic T lymphocyte and macrophage activation and excessive release of cytokines [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Hemophagocytosis, by activated histiocytes, constitutes a self-perpetuating circle of inflammation, culminating in multiorgan damage [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. HLH is primary (genetic) or secondary (acquired). Primary HLH, classically autosomal recessive, is associated with mutations in PRF1, UNC13D, STX11, and STXBP2, genes implicated in cytotoxic granule exocytosis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Secondary HLH results from infection (most frequently Epstein-Barr virus and Dengue virus), malignancy, or autoimmune disease, with a mortality of over 40% if left untreated [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The diagnosis of HLH is highly challenging. Clinically, it is mainly diagnosed using the HLH 2004 diagnostic criteria, which requires five out of eight clinical and laboratory findings, or via identification of a pathogenic genetic mutation in familial cases. The HScore is also frequently used to assess the possibility of HLH in adult patients. Treatment is focused on suppressing the hyperinflammatory response and handling the underlying cause. Standard first-line therapy includes dexamethasone, cyclosporine, and etoposide on the basis of HLH-94/HLH-2004 protocols. Hematopoietic stem cell transplantation is recommended in primary (familial) cases, while therapy in secondary (acquired) cases is tailored to the triggering factor [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. We present a 9-year-old girl with secondary HLH who was initially diagnosed with refractory enteric fever, demonstrating infection-mimicking HLH diagnostic traps. She developed recurrent fever (104°F), hepatosplenomegaly, and characteristic laboratory findings: hyperferritinemia (1144 ng/mL), hypofibrinogenemia (107 mg/dL), and cytopenias despite prolonged meropenem therapy. This case highlights the importance of diagnosing HLH in febrile antimicrobial-resistant patients, where hyperferritinemia and coagulopathy are diagnostic clues [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Case Report","content":"\u003cp\u003eA 9-year-old female patient, weighing around 25 kg, reported to our tertiary care centre with a history of high-grade fever, up to 104°F, persisting for more than two weeks' duration. This prolonged fever had been associated with a long-standing cough, chest congestion, poor oral tolerance, generalised weakness, and pallor. Earlier, the illness had been preceded by an even longer intermittent febrile disease of one to two months' duration, indicative of a severe systemic process. Her treatment had begun with an empirical strategy in the form of a case of enteric fever with complications; therefore, she had been administered a prolonged course of intravenous broad-spectrum antibiotics, such as Meropenem, Piperacillin-Tazobactam, Linezolid, and Vancomycin, for over three weeks. Irrespective of these interventions, her fever remained refractory, and a reassessment of the underlying cause was warranted.\u003c/p\u003e\u003cp\u003eOn clinical examination, the patient was unresponsive but alert. She was also febrile and irritable and had mild pedal oedema. The abdominal examination showed hepatosplenomegaly with hepatomegaly 3–4 cm below the costal margin and splenomegaly 4–5 cm below the costal margin. Bilateral crepitations were present on auscultation of the chest; however, there was no evidence of any clinical or radiological pleural effusion. The neurological examination was routine during the entire stay in the hospital. Serial ultrasound scans established the presence of mild pericholecystic and pelvic free fluid and also the presence of hepatosplenomegaly. MRI showed mild cerebral atrophic changes along with extensive sinus inflammatory disease, which is indicative of subclinical central nervous system involvement.\u003c/p\u003e\u003cp\u003eLaboratory findings showed prominent hematologic abnormalities like anaemia, thrombocytopenia, and neutropenia. Patients' inflammatory markers were significantly elevated with hyperferritinemia, hypertriglyceridemia, and hypofibrinogenemia, which was characteristic of systemic hyperinflammation. Electrolyte imbalance in the form of hyponatremia and a mild increase in liver enzymes were observed. Blood culture was positive for non-Aureus Staphylococcus species. Antinuclear antibodies and Brucella serologies were negative. The first hypothesis for complicated enteric fever was prolonged high-grade fever, endemicity, and hepatosplenomegaly. However, the finding of negative blood cultures and failure to respond to prolonged broad-spectrum antibiotics made this diagnosis suspect. Hematologic malignancies in the form of lymphoma or leukaemia were considered on the basis of the presence of organomegaly and cytopenias; however, the absence of blasts in peripheral blood smears and the lack of bone marrow examination made this hypothesis unproven.\u003c/p\u003e\u003cp\u003eMacrophage Activation Syndrome, an HLH-like complication of systemic juvenile idiopathic arthritis, was another strong possibility. However, a lack of rash, arthritis, or autoimmune markers reduced the probability of this diagnosis. Viral infections, especially Epstein-Barr virus (EBV), were a strong probable trigger, with the presence of hyperferritinemia and systemic inflammation; however, no viral PCR was noted. Disseminated tuberculosis and brucellosis were also ruled out, both serologically and clinically. Although primary (familial) HLH is less probable with the patient's age and lack of familial history, it cannot be ruled out altogether without the help of a genetic workup. Autoimmune illnesses like systemic lupus erythematosus were less probable due to a negative antinuclear antibody and lack of supportive clinical findings. The findings collectively highly point towards a diagnosis of secondary HLH, most probably triggered by an occult viral infection or a hidden underlying hematologic malignancy.\u003c/p\u003e\u003cp\u003eBased on HLH-2004 diagnostic criteria, the patient met at least five of the eight required parameters to diagnose [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. These results confirm the diagnosis of hematophagocytic lymphohistiocytosis (see Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Despite supportive interventions like albumin infusion, antipyretics, and intravenous fluids, her fever remained largely intractable, thus confirming the inflammatory nature of the disease. Figures\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows a chest X-ray (PA view) of the patient, with normal lung fields, absence of cardiomegaly, and absence of pleural effusion or widening of the mediastinum. These results exclude pulmonary infection or malignancy, further confirming the systemic nature of HLH.\u003c/p\u003e\u003cp\u003eThis case emphasises the subtle diagnostic presentation of HLH, especially in children with features that overlap with infection. Suspecting early, recognising diagnostic clues on time, and starting HLH-directed treatment immediately are extremely important to enhance outcomes. Secondary triggering workup for malignancy or autoimmune disease is strongly advised in this situation.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePrimary lab data of Patient\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eParameter\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eResult\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNormal Range\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eInterpretation\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHemoglobin (Hb)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8.4 g/dL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11.5–15.5 g/dL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSevere anemia\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHematocrit (HCT)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e26.2%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e35.0–45.0%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRBC Count\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.93 ×10¹²/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.0-5.2 ×10¹²/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMildly reduced\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMCV\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e66.7 fL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e77–95 fL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMicrocytic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMCH\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e21.4 pg\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e25–33 pg\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHypochromic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMCHC\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e32.1 g/dL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e31–37 g/dL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRDW\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22.3%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12.1–16.9%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHigh (anisocytosis)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eWBC Count\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8.5 ×10⁹/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.0–13.0 ×10⁹/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNeutrophils\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7.3%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e40–75%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSevere neutropenia\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLymphocytes\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e39.2%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20–45%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMonocytes\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e53.4%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2–10%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMarked monocytosis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eEosinophils\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.0%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1–6%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAbsent\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBasophils\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.1%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0–1%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePlatelets\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e114 ×10⁹/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e180–400 ×10⁹/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eThrombocytopenia\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn our patient's situation, a 9-year-old girl, the disease was characterised by chronic high-grade fever, hepatosplenomegaly, cytopenia, hyperferritinemia and hypertriglyceridemia, and decreased fibrinogen\u0026mdash;features that fulfil at least five of the eight HLH-2004 diagnostic criteria [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe patient was initially treated on the suspected diagnosis of complicated enteric fever, a plausible one in the clinical context and presenting features. However, the failure to respond to almost three weeks of intravenous broad-spectrum antibiotics, including Meropenem, Tanzo, Colomycin, and Linezolid, made rethinking the diagnosis essential. In the context of adequate antibiotic cover, refractory fever in children must continually raise the suspicion of hyperinflammatory syndromes like hemophagocytic lymphohistiocytosis (HLH) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In the current case, prolonged fever over 38.5\u0026deg;C, despite antipyretics administered every four hours and sponging, was one of the most recalcitrant clinical features.\u003c/p\u003e\u003cp\u003eHepatosplenomegaly was documented by clinical examination and radiologic study, in which the spleen size was 15.9 cm. Organ enlargement and hematologic disturbances\u0026mdash;haemoglobin consistently less than 9 g/dL and platelets falling to a level as low as 25,000\u0026mdash;complete the cytopenia requirement for Hemophagocytic Lymphohistiocytosis. The absolute neutrophil count was less than 1.0 \u0026times; 10^9/L, thus again completing the requirement for cytopenia in at least two hemopoietic lineages [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eInflammatory markers were also high. Serum ferritin was 1144 ng/mL. Triglycerides were 349 mg/dL, and fibrinogen fell to 107 mg/dL, qualifying for HLH criteria for metabolic dysregulation [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The findings indicate a cytokine-mediated process rather than infectious aetiology. The negative ANA panel and Brucella serologies excluded autoimmune and other infectious mimics [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe patient had no focal deficits; however, MRI was positive for mild atrophic changes in the brain with evidence of sinus inflammatory disease. These findings could indicate central nervous system involvement, a known complication occurring in 25\u0026ndash;50% of HLH cases [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The elevation of liver enzymes and requirement for albumin transfusion suggested hepatic involvement. Despite the lack of assessment of bone marrow biopsy, natural killer (NK) cell activity, and soluble interleukin-2 receptor levels, clinical diagnosis of HLH is still justified with the available data [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOne major limitation is the absence of reported therapy for hemophagocytic lymphohistiocytosis, such as dexamethasone or etoposide, which are routine in treatment protocols such as HLH-94 or HLH-2004 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Prompt therapeutic intervention is necessary to avoid irreversible organ damage and improve survival [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In many settings, however, the absence of specific diagnostic methods and targeted therapies may lead to delayed use of appropriate treatment.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case illustrates the diagnostic and therapeutic dilemma of Hemophagocytic Lymphohistiocytosis, especially in pediatric patients with an ill-defined febrile illness initially mistaken for having the usual causes of infection. Patient's chronic fever, multi-lineage cytopenias, organomegaly, and raised inflammatory markers highlight the requirement to keep a high level of suspicion for HLH when usual management does not yield an improvement. The early recognition and utilisation of the HLH-2004 diagnostic criteria were crucial to making a presumptive diagnosis despite the lack of molecular or histopathological evidence.\u003c/p\u003e\u003cp\u003eClinicians need to be more alert to hyperinflammatory syndromes like Hemophagocytic Lymphohistiocytosis, which masquerade as more common infections but require essentially different treatment. This case supports the idea that refractory fever and systemic inflammation, particularly when accompanied by specific haematological and biochemical profiles, should lead to early suspicion of HLH. Prompt diagnosis and treatment are necessary for optimal patient outcomes, and this case is educational about the complicated and dynamic nature of pediatric presentations of HLH.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHLH\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eHemophagocytic Lymphohistiocytosis\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCBC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eComplete Blood Count\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eComputed Tomography\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eICU\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eIntensive Care Unit\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIVIG\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eIntravenous Immunoglobulin\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eESR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eErythrocyte Sedimentation Rate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCRP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eC-reactive Protein\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNK cells\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNatural Killer Cells\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAST\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAspartate Aminotransferase\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eALT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAlanine Aminotransferase\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eLDH\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eLactate Dehydrogenase\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eINR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eInternational Normalized Ratio\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eProthrombin Time\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAPTT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eActivated Partial Thromboplastin Time\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eEBV\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eEpstein\u0026ndash;Barr Virus\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePCR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePolymerase Chain Reaction\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCNS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCentral Nervous System\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eFIP1L1\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eFactor Interacting with PAPOLA and CPSF1-Like 1\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eUNC13D\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eUnc-13 Homolog D\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSTX11\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSyntaxin 11\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSTXBP2\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSyntaxin Binding Protein 2\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest / Competing interests \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis case report was conducted in accordance with institutional ethical standards. Ethical approval was waived due to the nature of the case report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from the patient’s parent(s) for participation in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWritten consent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient’s parent(s) for publication of this case report and any accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHenter JI, Horne A, Aric\u0026oacute; M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G (2007) HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. ;48(2):124\u0026thinsp;\u0026ndash;\u0026thinsp;31. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/pbc.21039\u003c/span\u003e\u003cspan address=\"10.1002/pbc.21039\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 16937360\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFilipovich AH (2006) Hemophagocytic lymphohistiocytosis and related disorders. Curr Opin Allergy Clin Immunol. ;6(6):410-5. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/01.all.0000246626.57118.d9\u003c/span\u003e\u003cspan address=\"10.1097/01.all.0000246626.57118.d9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 17088644\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCanna SW, Marsh RA (2020) Pediatric hemophagocytic lymphohistiocytosis. Blood 135(16):1332\u0026ndash;1343. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1182/blood.2019000936\u003c/span\u003e\u003cspan address=\"10.1182/blood.2019000936\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003ePMID: 32107531; PMCID: PMC8212354\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRamos-Casals M, Brito-Zer\u0026oacute;n P, L\u0026oacute;pez-Guillermo A, Khamashta MA, Bosch X (2014) Adult haemophagocytic syndrome. Lancet. ;383(9927):1503\u0026ndash;1516. doi: 10.1016/S0140-6736(13)61048-X. Epub 2013 Nov 27. Erratum in: Lancet. 2014;383(9927):1464. PMID: 24290661\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJanka G (2009) Hemophagocytic lymphohistiocytosis: when the immune system runs amok. Klin Padiatr. ;221(5):278\u0026thinsp;\u0026ndash;\u0026thinsp;85. doi: 10.1055/s-0029-1237386. Epub 2009 Aug 25. PMID: 19707989\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRosado FG, Kim AS (2013) Hemophagocytic lymphohistiocytosis: an update on diagnosis and pathogenesis. Am J Clin Pathol. ;139(6):713\u0026thinsp;\u0026ndash;\u0026thinsp;27. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1309/AJCP4ZDKJ4ICOUAT\u003c/span\u003e\u003cspan address=\"10.1309/AJCP4ZDKJ4ICOUAT\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 23690113\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOtrock ZK, Eby CS (2015) Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis. Am J Hematol 90(3):220\u0026ndash;224. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/ajh.23911\u003c/span\u003e\u003cspan address=\"10.1002/ajh.23911\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003eEpub 2015 Jan 16. PMID: 25469675\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL (2011) How I treat hemophagocytic lymphohistiocytosis. Blood. ;118(15):4041-52. doi: 10.1182/blood-2011-03-278127. Epub 2011 Aug 9. PMID: 21828139; PMCID: PMC3204727\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLehmberg K, Nichols KE, Henter JI, Girschikofsky M, Greenwood T, Jordan M, Kumar A, Minkov M, La Ros\u0026eacute;e P, Weitzman S, Study Group on Hemophagocytic Lymphohistiocytosis Subtypes of the Histiocyte Society (2015) Consensus recommendations for the diagnosis and management of hemophagocytic lymphohistiocytosis associated with malignancies. Haematologica 100(8):997\u0026ndash;1004 PMID: 26314082; PMCID: PMC5004414\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLa Ros\u0026eacute;e P, Horne A, Hines M, von Bahr Greenwood T, Machowicz R, Berliner N, Birndt S, Gil-Herrera J, Girschikofsky M, Jordan MB, Kumar A, van Laar JAM, Lachmann G, Nichols KE, Ramanan AV, Wang Y, Wang Z, Janka G, Henter JI (2019) Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood 133(23):2465\u0026ndash;2477. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1182/blood.2018894618\u003c/span\u003e\u003cspan address=\"10.1182/blood.2018894618\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003eEpub 2019 Apr 16. PMID: 30992265\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAllen CE, Yu X, Kozinetz CA, McClain KL (2008) Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. ;50(6):1227-35. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/pbc.21423\u003c/span\u003e\u003cspan address=\"10.1002/pbc.21423\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 18085676\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Hemophagocytic lymphohistiocytosis, cytopenia, hyperferritinemia, pediatric, hyperinflammation, fever of unknown origin","lastPublishedDoi":"10.21203/rs.3.rs-7235912/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7235912/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003eHemophagocytic Lymphohistiocytosis (HLH) is a life-threatening, exceedingly rare hyperinflammatory syndrome that typically presents with nonspecific symptoms such as fever and cytopenias. An early diagnosis of HLH is a significant clinical challenge, especially in children with presentations mimicking common infectious diseases.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation\u003c/strong\u003eA 9-year-old Pakistani girl came with a 2-week history of intractable high-grade fever, cough, and generalised weakness, unresponsive to broad-spectrum antibiotics. Physical examination showed hepatosplenomegaly and pallor. Laboratory tests showed pancytopenia, significantly elevated serum ferritin (1144 ng/ml), hypertriglyceridemia (349 mg/dL), and hypofibrinogenemia (107 mg/dL). Imaging showed hepatosplenomegaly and mild brain atrophic changes. Despite treatment with multiple antimicrobial therapies, the fever persisted, and thus, suspicion of HLH arose. She met five out of eight HLH-2004 diagnostic criteria, and on this basis, a presumptive diagnosis was established. Treatment consisted of supportive care, antipyretics, transfusions, and continued observation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003eThis case underscores the need to keep HLH in mind in children with chronic, treatment-resistant febrile illness, particularly in the setting of cytopenias and organomegaly. Early diagnosis and application of well-established diagnostic criteria are crucial to intervene early and enhance prognosis.\u003c/p\u003e","manuscriptTitle":"Pediatric Hemophagocytic Lymphohistiocytosis Presenting as a Refractory Febrile Illness: A CASE REPORT","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-08 16:36:30","doi":"10.21203/rs.3.rs-7235912/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0adeb1a3-03f3-4d83-bbf6-ad5b75cd9b83","owner":[],"postedDate":"August 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-08-08T16:36:31+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-08 16:36:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7235912","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7235912","identity":"rs-7235912","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}