An Overlap Presentation of Immune Reconstitution Inflammatory Syndrome and Hemophagocytic Lymphohistiocytosis in a Patient with Advanced HIV

An Overlap Presentation of Immune Reconstitution Inflammatory Syndrome and Hemophagocytic Lymphohistiocytosis in a Patient with Advanced HIV | 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 An Overlap Presentation of Immune Reconstitution Inflammatory Syndrome and Hemophagocytic Lymphohistiocytosis in a Patient with Advanced HIV Qazi Syed Abdullah, Reva Saddi, Venkat Ramesh, Srikar Tadikonda, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9627217/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 fatal hyperinflammatory syndrome frequently triggered by infections in immunocompromised hosts. In HIV patients, upon initiation of antiretroviral therapy (ART), tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) can overlap and present with fever, cytopenias, and hepatosplenomegaly. Case Presentation: A 44-year-old male, a known case of HIV with poor ART adherence, presented with four weeks of cough, fever, and weight loss. He had completed treatment for disseminated TB three years prior. Cervical lymph node biopsy GeneXpert was positive for rifampicin-sensitive Mycobacterium tuberculosis . PET-CT showed pulmonary, nodal, marrow, and splenic involvement. He was restarted on anti-tubercular therapy (ATT) and ART. After initial improvement, he deteriorated with persistent fever, worsening respiratory symptoms, severe pancytopenia, hepatosplenomegaly, hyperferritinemia, and hypertriglyceridemia. Bone marrow studies showed florid hemophagocytosis and non-caseating granulomas. He met six of eight HLH-2004 criteria and had an HScore of 237 (98%-99%), establishing a diagnosis of secondary HLH overlapping with paradoxical TB-IRIS. He was managed with an Etoposide-Dexamethasone combination alongside ATT and ART. Conclusion This case highlights the importance of maintaining a high index of suspicion when managing HIV patients in TB-endemic regions for HLH-IRIS overlap. Early suspicion, application of the HLH criteria/HScore, bone marrow evaluation, and initiation of timely treatment are necessary for improving patient survival. Hemophagocytic lymphohistiocytosis Immune reconstitution inflammatory syndrome HIV Tuberculosis Etoposide Introduction Hemophagocytic Lymphohistiocytosis (HLH) is an aberrant hyperinflammatory, hyperferritinemic immune response syndrome driven by T-cells and associated with a potentially fatal cytokine storm [ 1 , 2 ] . It can be categorised as primary and secondary HLH. Secondary HLH is an acquired immune dysfunction that occurs mainly in response to infections, autoimmune disorders, and malignancies [ 3 ] . HLH poses significant morbidity and mortality due to a combination of delayed diagnosis and delayed initiation of treatment. Individuals with HIV on antiretroviral therapy are at risk of developing TB-associated immune reconstitution inflammatory syndrome (TB-IRIS), an inflammatory complication due to rapid restoration of immune response following ART, leading to an exaggerated inflammatory response to Mycobacterium tuberculosis antigens [ 4 ] . HLH and TB-IRIS share overlapping manifestations such as fever, cytopenias, organomegaly, and systemic inflammation. Therefore, distinguishing them is often difficult and a high index of suspicion is frequently needed. The overlapping presentation of TB-IRIS and HLH is peculiar, making this case noteworthy for clinicians in order to recognise and manage such presentations. This report presents a rare case of overlapping TB-IRIS and secondary HLH successfully managed with steroids and etoposide therapy. Case Presentation This patient is a 44-year-old male farmer who is a known case of HIV-1 for the past nine years and is non-compliant with medication. He presented with complaints of four weeks of cough, fever, and weight loss of seven kilograms over the past one month. He had similar complaints three years prior and was diagnosed with disseminated tuberculosis (TB) sensitive to rifampicin, for which he was started on an HRZE regimen, which he completed. His vitals on admission were as follows: Temperature 104°F, HR 130 bpm, BP 130/90 mmHg, RR 26 cpm, and oxygen saturation 92% on room air. He was admitted to the Department of General Medicine for further evaluation. His initial workup is summarised in Table 1 . Table 1 – Initial workup of the patient on admission. Parameter Value Reference Range AST 250 IU/L 10–40 IU/L ALT 129 IU/L 7–56 IU/L CRP 130 mg/L < 5 mg/L Haemoglobin (Hb) 8.7 g/dL 12–16 g/dL Platelets 215 ×10³/µL 150–450 ×10³/µL Total Leukocyte Count (TLC) 4.39 ×10³/µL 4–11 ×10³/µL Creatinine 1.34 mg/dL 0.6–1.2 mg/dL CD8 860 cells/µL 150–1000 cells/µL CD4 70 cells/µL 500–1500 cells/µL A bronchoalveolar lavage GeneXpert was negative for TB; however, an ultrasound-guided cervical lymph node aspiration GeneXpert was positive for Mycobacterium tuberculosis with rifampicin sensitivity. PET-CT was suggestive of disseminated tuberculosis with pulmonary, lymph node, bone marrow, and spleen involvement. The patient was started on HRZE followed by the TLD regimen (Tenofovir–Lamivudine–Dolutegravir). The patient initially showed some signs of clinical improvement over one week. However, his condition began to deteriorate with persistent fever spikes and worsening cough. His laboratory parameters are shown in Table 2 . Table 2 – Pancytopenia with elevated ESR, CRP, ferritin, and triglycerides. Parameter Value Normal Range ESR 93 mm/hr 0–20 mm/hr C-reactive protein (CRP) 130 mg/L < 5 mg/L Procalcitonin 19 ng/mL < 0.05 ng/mL Serum lactate 3.3 mmol/L 0.5–2.2 mmol/L Serum creatinine 2.0 mg/dL 0.6–1.2 mg/dL Total serum bilirubin (TSB) 0.3 mg/dL 0.2–1.2 mg/dL Alkaline phosphatase (ALP) 148 IU/L 40–120 IU/L Gamma-glutamyl transferase (GGT) 266 IU/L 9–48 IU/L Aspartate aminotransferase (AST) 52 IU/L 5–40 IU/L Alanine aminotransferase (ALT) 65 IU/L 7–56 IU/L Serum albumin 2.5 g/dL 3.5–5.0 g/dL Serum globulin 5.3 g/dL 2.0–3.5 g/dL Ferritin 1650 ng/mL 30–400 ng/mL Triglycerides 340 mg/dL < 150 mg/dL His blood counts demonstrated pancytopenia: haemoglobin 7.3 g/dL, white blood cell count 4,250 cells/µL, and platelets 7,000 cells/µL. Blood and urine cultures showed no growth. Serum cryptococcal antigen was negative. Ultrasound of the abdomen showed hepatosplenomegaly with splenic microabscesses. HRCT chest showed patchy consolidation in the right lower lobe. The progressive pancytopenia in a patient with HIV, in the presence of raised ferritin, triglycerides, and hepatosplenomegaly, prompted bone marrow aspiration and biopsy. Marrow aspiration revealed plasma cell predominance with florid hemophagocytes, engulfed platelets, and nucleated erythrocytes. Marrow biopsy showed a normocellular marrow with well-defined epithelioid cells, non-caseating granulomas, and Langhans giant cells. Reticulin stain showed grade II fibrosis (0 to III). Acid-fast staining did not reveal any acid-fast bacilli. The patient presented with six of the eight HLH-2004 diagnostic criteria: an elevated ferritin of 1,650 ng/mL, triglycerides of 340 mg/dL, pancytopenia, high fevers, hepatosplenomegaly on ultrasound, and evidence of hemophagocytosis on bone marrow aspiration. The patient had an HScore of 237, predicting a 98–99% probability of HLH, and we arrived at a final diagnosis of secondary hemophagocytic lymphohistiocytosis with paradoxical TB-immune reconstitution inflammatory syndrome (IRIS). The patient was started on etoposide and dexamethasone for HLH and IRIS, and the infections were treated with the TLD regimen and anti-tubercular therapy consisting of rifampicin, moxifloxacin, isoniazid, and ethambutol. Etoposide was administered on days 1, 4, 8, and 15, followed by a weekly dose for a total duration of eight weeks. The patient's clinical status improved significantly, and his blood counts showed improvement within two weeks: haemoglobin 8.4 g/dL, white blood cell count 3,080 cells/µL, and platelets 142,000 cells/µL. He was subsequently discharged and continued follow-up with medical oncology. Informed consent was obtained from this patient for this study. Discussion Secondary HLH is a serious haematologic condition elicited by immune hyperactivation in response to different triggers, including autoimmune and autoinflammatory diseases, persistent infections, and malignancies [ 5 ] . Based on the available literature on TB-associated HLH, consisting of 115 cases, the overall mortality rate was higher in patients with TB-associated HLH compared to other infection-induced HLH [ 6 , 7 , 8 ] . A high proportion of TB-triggered HLH cases have extrapulmonary TB, mainly involving the bone marrow. In our case, M. tuberculosis was detected from the GeneXpert sample, and bone marrow showed changes suggestive of TB. However, no bacilli could be isolated from the marrow, as the patient had already been receiving anti-tubercular therapy. TB-IRIS is a paradoxical worsening or recurrence of pre-existing tuberculous lesions, or development of new lesions, in patients on effective antituberculosis treatment. There are two forms of IRIS: paradoxical and unmasking. Paradoxical IRIS is defined as recurrent, new, or worsening symptoms in a previously treated case [ 9 ] . In our case, the patient had disseminated tuberculosis three years prior and had completed the full course of ATT. Following initiation of ART, he experienced progressive deterioration, which was consistent with a classification of paradoxical TB-IRIS. Current available literature recognises that severe TB-IRIS has an overlapping phenotype with HLH, owing to their shared pathogenesis involving IFN-γ and unopposed T-cell activation, causing severe inflammatory disease. Patients with a dual diagnosis of IRIS-HLH had a more severe clinical course requiring more steroids and a longer duration of immunosuppression, with many requiring additional therapies beyond steroids due to refractory symptoms or steroid intolerance [ 10 , 11 ] . Our patient fulfilled six of the eight Henter et al. validated HLH-2004 diagnostic criteria [ 12 ] : Fever ≥ 38.5°C Splenomegaly Cytopenias affecting at least two of three peripheral blood lineages: haemoglobin < 9 g/dL, platelets < 100 × 10³/mL, neutrophils 265 mg/dL) and/or hypofibrinogenaemia ( 500 ng/mL NK-cell activity and IL-2 receptor levels were not measured due to limited resources. However, bone marrow findings of florid hemophagocytosis, plasma cell predominance, non-caseating granulomas, Langhans giant cells, and grade II reticulin fibrosis — despite a negative AFB stain — combined with an HScore of 237, further solidified the clinical probability of HLH [ 13 ] . Based on available literature, there is limited information on the mortality of HLH-IRIS specifically; however, a systematic review of 116 cases reports a 45% mortality rate in patients with TB-associated HLH, underscoring the importance of prompt recognition and initiation of ATT and immunomodulatory therapies to improve patient outcomes [ 7 ] . In our case, the patient was initially worked up for sepsis, which was excluded. Paradoxical IRIS was considered and confirmed based on the patient's clinical timeline and paradoxical worsening following ART initiation, and steroids were commenced immediately. Given the pancytopenia and markedly elevated ferritin, we maintained a low threshold for bone marrow histopathological evaluation. The patient was started on etoposide (150 mg/m² on days 1, 4, 8, and 15, then weekly for eight weeks) combined with dexamethasone, which effectively controlled HLH features. Rapid improvement in fever, cytopenias, and clinical status was observed within two weeks. Concurrent ATT and ART were continued to address the underlying TB and HIV [ 14 ] . Conclusion This case highlights the importance of considering HLH in patients with advanced HIV presenting with persistent fever and cytopenias after ART initiation. Early recognition and initiation of combined immunosuppressive and antimicrobial therapy can significantly improve outcomes. Abbreviations HLH Hemophagocytic lymphohistiocytosis TB Tuberculosis HIV Human Immunodeficiency Virus IRIS Immune Reconstitution Inflammatory Syndrome ART Antiretroviral therapy ATT Antitubercular therapy TLD Tenofovir–Lamivudine–Dolutegravir. Declarations Ethics approval and consent to participate: Ethics approval was not required for this study, as this is a single-patient case report and did not involve and experimental intervention or research on human subjects. Informed consent was obtained from the patient for the publication of this case report and any accompanying images and data, in accordance with the Declaration of Helsinki. Consent for publication: Informed consent obtained from the patient. Competing interests: The authors declare that they have no competing interests. Authors' contributions: All authors contributed to the management of the patient, data collection, drafting, and revision of this manuscript, and approved the final version for submission. Funding: No funding was received for this work. Availability of data and materials: Not applicable. References Brisse E, Wouters CH, Matthys P. Hemophagocytic lymphohistiocytosis (HLH): A heterogeneous spectrum of cytokine-driven immune disorders. Cytokine Growth Factor Rev. 2015;26(3):263–80. https://doi.org/10.1016/j.cytgfr.2014.10.001 . Memon F, Ahmed J, Malik F, Ahmad J, Memon DA. Adult-onset Primary Hemophagocytic Lymphohistiocytosis: Reporting a Rare Case with Review of Literature. Cureus. 2020;12(1):e6723. https://doi.org/10.7759/cureus.6723 . Allen CE, McClain KL. Pathophysiology and epidemiology of hemophagocytic lymphohistiocytosis. Hematol Am Soc Hematol Educ Program. 2015;2015:177–82. https://doi.org/10.1182/asheducation-2015.1.177 . Vignesh R, Balakrishnan P, Tan HY, Yong YK, Velu V, Larsson M, et al. Tuberculosis-associated immune reconstitution inflammatory syndrome — an extempore game of misfiring with defence arsenals. Pathogens. 2023;12(2):210. https://doi.org/10.3390/pathogens12020210 . Allen CE, McClain KL. Pathophysiology and epidemiology of hemophagocytic lymphohistiocytosis. Hematol Am Soc Hematol Educ Program. 2015;2015:177–82. Kurver L, Seers T, van Dorp S, van Crevel R, Pollara G, van Laarhoven A. Tuberculosis-associated hemophagocytic lymphohistiocytosis: diagnostic challenges and determinants of outcome. Open Forum Infect Dis. 2024;11(4):ofad697. https://doi.org/10.1093/ofid/ofad697 . Fauchald T, Blomberg B, Reikvam H. Tuberculosis-associated hemophagocytic lymphohistiocytosis: a review of current literature. J Clin Med. 2023;12(16):5366. https://doi.org/10.3390/jcm12165366 . Kurver L, Seers T, van Dorp S, van Crevel R, Pollara G, van Laarhoven A. Tuberculosis-associated hemophagocytic lymphohistiocytosis: diagnostic challenges and determinants of outcome. Open Forum Infect Dis. 2024;11(4):ofad697. https://doi.org/10.1093/ofid/ofad697 . Lanzafame M, Vento S. Tuberculosis-immune reconstitution inflammatory syndrome. J Clin Tuberc Other Mycobact Dis. 2016;3:6–9. https://doi.org/10.1016/j.jctube.2016.03.002 . Rocco JM, Laidlaw E, Galindo F, Anderson M, Rupert A, Higgins J, et al. Severe mycobacterial immune reconstitution inflammatory syndrome (IRIS) in advanced human immunodeficiency virus (HIV) has features of hemophagocytic lymphohistiocytosis and requires prolonged immune suppression. Clin Infect Dis. 2023;76(3):e561–70. https://doi.org/10.1093/cid/ciac717 . Patel N, Chastain C. Overlap syndrome of immune reconstitution inflammatory syndrome secondary to disseminated mycobacterial infection and hemophagocytic lymphohistiocytosis in a patient with newly diagnosed HIV/AIDS. Cureus. 2024;16(2):e53410. https://doi.org/10.7759/cureus.53410 . Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124–31. https://doi.org/10.1002/pbc.21039 . Fardet L, Galicier L, Lambotte O, Marzac C, Aumont C, Chahwan D, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014;66(9):2613–20. https://doi.org/10.1002/art.38690 . Bergsten E, Horne A, Aricó M, Astigarraga I, Egeler RM, Filipovich AH, et al. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017;130(25):2728–38. https://doi.org/10.1182/blood-2017-06-788349 . Rocco JM, Laidlaw E, Galindo F, Anderson M, Rupert A, Higgins J, et al. Severe mycobacterial immune reconstitution inflammatory syndrome (IRIS) in advanced human immunodeficiency virus (HIV) has features of hemophagocytic lymphohistiocytosis and requires prolonged immune suppression. Clin Infect Dis. 2023;76(3):e561–70. https://doi.org/10.1093/cid/ciac717 . Additional Declarations No competing interests reported. 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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-9627217","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":638111037,"identity":"73710dac-7945-44fe-bb82-6e52bdb6dc72","order_by":0,"name":"Qazi Syed Abdullah","email":"data:image/png;base64,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","orcid":"","institution":"Apollo Institute of Medical Sciences and Research, Hyderabad","correspondingAuthor":true,"prefix":"","firstName":"Qazi","middleName":"Syed","lastName":"Abdullah","suffix":""},{"id":638111038,"identity":"b8141df1-3103-4ba8-92e5-b637655fa8be","order_by":1,"name":"Reva Saddi","email":"","orcid":"","institution":"Apollo Institute of Medical Sciences and Research, Hyderabad","correspondingAuthor":false,"prefix":"","firstName":"Reva","middleName":"","lastName":"Saddi","suffix":""},{"id":638111039,"identity":"93731cf2-4e66-41b2-8c50-8175dab2ce2d","order_by":2,"name":"Venkat Ramesh","email":"","orcid":"","institution":"Apollo Institute of Medical Sciences and Research, Hyderabad","correspondingAuthor":false,"prefix":"","firstName":"Venkat","middleName":"","lastName":"Ramesh","suffix":""},{"id":638111040,"identity":"af7a6297-3722-49a0-bbed-be59e2a77327","order_by":3,"name":"Srikar Tadikonda","email":"","orcid":"","institution":"Apollo Institute of Medical Sciences and Research, Hyderabad","correspondingAuthor":false,"prefix":"","firstName":"Srikar","middleName":"","lastName":"Tadikonda","suffix":""},{"id":638111041,"identity":"b25f8dfd-44d0-48bc-ae38-24515104935b","order_by":4,"name":"Arafath Hussna Shaik","email":"","orcid":"","institution":"Apollo Institute of Medical Sciences and Research, Hyderabad","correspondingAuthor":false,"prefix":"","firstName":"Arafath","middleName":"Hussna","lastName":"Shaik","suffix":""},{"id":638111042,"identity":"189993d3-39e7-4ae3-8290-6e116c0c4444","order_by":5,"name":"Nagendar Devulapally","email":"","orcid":"","institution":"Apollo Institute of Medical Sciences and Research, Hyderabad","correspondingAuthor":false,"prefix":"","firstName":"Nagendar","middleName":"","lastName":"Devulapally","suffix":""}],"badges":[],"createdAt":"2026-05-06 08:24:00","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9627217/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9627217/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":109057372,"identity":"eed0ca80-6efc-4810-b355-c0948c3c7c95","added_by":"auto","created_at":"2026-05-12 07:48:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":204990,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9627217/v1/cdeb02f2-6016-4498-8120-84a62b242437.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"An Overlap Presentation of Immune Reconstitution Inflammatory Syndrome and Hemophagocytic Lymphohistiocytosis in a Patient with Advanced HIV","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHemophagocytic Lymphohistiocytosis (HLH) is an aberrant hyperinflammatory, hyperferritinemic immune response syndrome driven by T-cells and associated with a potentially fatal cytokine storm \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. It can be categorised as primary and secondary HLH.\u003c/p\u003e \u003cp\u003eSecondary HLH is an acquired immune dysfunction that occurs mainly in response to infections, autoimmune disorders, and malignancies \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. HLH poses significant morbidity and mortality due to a combination of delayed diagnosis and delayed initiation of treatment.\u003c/p\u003e \u003cp\u003eIndividuals with HIV on antiretroviral therapy are at risk of developing TB-associated immune reconstitution inflammatory syndrome (TB-IRIS), an inflammatory complication due to rapid restoration of immune response following ART, leading to an exaggerated inflammatory response to \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e antigens \u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. HLH and TB-IRIS share overlapping manifestations such as fever, cytopenias, organomegaly, and systemic inflammation. Therefore, distinguishing them is often difficult and a high index of suspicion is frequently needed. The overlapping presentation of TB-IRIS and HLH is peculiar, making this case noteworthy for clinicians in order to recognise and manage such presentations. This report presents a rare case of overlapping TB-IRIS and secondary HLH successfully managed with steroids and etoposide therapy.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eThis patient is a 44-year-old male farmer who is a known case of HIV-1 for the past nine years and is non-compliant with medication. He presented with complaints of four weeks of cough, fever, and weight loss of seven kilograms over the past one month. He had similar complaints three years prior and was diagnosed with disseminated tuberculosis (TB) sensitive to rifampicin, for which he was started on an HRZE regimen, which he completed. His vitals on admission were as follows: Temperature 104\u0026deg;F, HR 130 bpm, BP 130/90 mmHg, RR 26 cpm, and oxygen saturation 92% on room air. He was admitted to the Department of General Medicine for further evaluation. His initial workup is summarised in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\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\u003e\u003cem\u003e\u0026ndash; Initial workup of the patient on admission.\u003c/em\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\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 \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\u003eValue\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReference Range\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e250 IU/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u0026ndash;40 IU/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e129 IU/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7\u0026ndash;56 IU/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e130 mg/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;5 mg/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHaemoglobin (Hb)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.7 g/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12\u0026ndash;16 g/dL\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelets\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e215 \u0026times;10\u0026sup3;/\u0026micro;L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e150\u0026ndash;450 \u0026times;10\u0026sup3;/\u0026micro;L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal Leukocyte Count (TLC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.39 \u0026times;10\u0026sup3;/\u0026micro;L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u0026ndash;11 \u0026times;10\u0026sup3;/\u0026micro;L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCreatinine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.34 mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.6\u0026ndash;1.2 mg/dL\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e860 cells/\u0026micro;L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e150\u0026ndash;1000 cells/\u0026micro;L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70 cells/\u0026micro;L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e500\u0026ndash;1500 cells/\u0026micro;L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eA bronchoalveolar lavage GeneXpert was negative for TB; however, an ultrasound-guided cervical lymph node aspiration GeneXpert was positive for \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e with rifampicin sensitivity. PET-CT was suggestive of disseminated tuberculosis with pulmonary, lymph node, bone marrow, and spleen involvement. The patient was started on HRZE followed by the TLD regimen (Tenofovir\u0026ndash;Lamivudine\u0026ndash;Dolutegravir). The patient initially showed some signs of clinical improvement over one week. However, his condition began to deteriorate with persistent fever spikes and worsening cough. His laboratory parameters are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cem\u003e\u0026ndash; Pancytopenia with elevated ESR, CRP, ferritin, and triglycerides.\u003c/em\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\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 \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\u003eValue\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNormal Range\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eESR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e93 mm/hr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u0026ndash;20 mm/hr\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-reactive protein (CRP)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e130 mg/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;5 mg/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProcalcitonin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 ng/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.05 ng/mL\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum lactate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.3 mmol/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.5\u0026ndash;2.2 mmol/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum creatinine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.0 mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.6\u0026ndash;1.2 mg/dL\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal serum bilirubin (TSB)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.3 mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.2\u0026ndash;1.2 mg/dL\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlkaline phosphatase (ALP)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e148 IU/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40\u0026ndash;120 IU/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGamma-glutamyl transferase (GGT)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e266 IU/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u0026ndash;48 IU/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAspartate aminotransferase (AST)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52 IU/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u0026ndash;40 IU/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlanine aminotransferase (ALT)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65 IU/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7\u0026ndash;56 IU/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum albumin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.5 g/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.5\u0026ndash;5.0 g/dL\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum globulin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.3 g/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.0\u0026ndash;3.5 g/dL\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFerritin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1650 ng/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30\u0026ndash;400 ng/mL\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTriglycerides\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e340 mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;150 mg/dL\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eHis blood counts demonstrated pancytopenia: haemoglobin 7.3 g/dL, white blood cell count 4,250 cells/\u0026micro;L, and platelets 7,000 cells/\u0026micro;L. Blood and urine cultures showed no growth. Serum cryptococcal antigen was negative.\u003c/p\u003e \u003cp\u003eUltrasound of the abdomen showed hepatosplenomegaly with splenic microabscesses. HRCT chest showed patchy consolidation in the right lower lobe.\u003c/p\u003e \u003cp\u003eThe progressive pancytopenia in a patient with HIV, in the presence of raised ferritin, triglycerides, and hepatosplenomegaly, prompted bone marrow aspiration and biopsy. Marrow aspiration revealed plasma cell predominance with florid hemophagocytes, engulfed platelets, and nucleated erythrocytes. Marrow biopsy showed a normocellular marrow with well-defined epithelioid cells, non-caseating granulomas, and Langhans giant cells. Reticulin stain showed grade II fibrosis (0 to III). Acid-fast staining did not reveal any acid-fast bacilli.\u003c/p\u003e \u003cp\u003eThe patient presented with six of the eight HLH-2004 diagnostic criteria: an elevated ferritin of 1,650 ng/mL, triglycerides of 340 mg/dL, pancytopenia, high fevers, hepatosplenomegaly on ultrasound, and evidence of hemophagocytosis on bone marrow aspiration. The patient had an HScore of 237, predicting a 98\u0026ndash;99% probability of HLH, and we arrived at a final diagnosis of secondary hemophagocytic lymphohistiocytosis with paradoxical TB-immune reconstitution inflammatory syndrome (IRIS).\u003c/p\u003e \u003cp\u003eThe patient was started on etoposide and dexamethasone for HLH and IRIS, and the infections were treated with the TLD regimen and anti-tubercular therapy consisting of rifampicin, moxifloxacin, isoniazid, and ethambutol. Etoposide was administered on days 1, 4, 8, and 15, followed by a weekly dose for a total duration of eight weeks. The patient's clinical status improved significantly, and his blood counts showed improvement within two weeks: haemoglobin 8.4 g/dL, white blood cell count 3,080 cells/\u0026micro;L, and platelets 142,000 cells/\u0026micro;L. He was subsequently discharged and continued follow-up with medical oncology. Informed consent was obtained from this patient for this study.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSecondary HLH is a serious haematologic condition elicited by immune hyperactivation in response to different triggers, including autoimmune and autoinflammatory diseases, persistent infections, and malignancies \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Based on the available literature on TB-associated HLH, consisting of 115 cases, the overall mortality rate was higher in patients with TB-associated HLH compared to other infection-induced HLH \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. A high proportion of TB-triggered HLH cases have extrapulmonary TB, mainly involving the bone marrow. In our case, \u003cem\u003eM. tuberculosis\u003c/em\u003e was detected from the GeneXpert sample, and bone marrow showed changes suggestive of TB. However, no bacilli could be isolated from the marrow, as the patient had already been receiving anti-tubercular therapy.\u003c/p\u003e \u003cp\u003eTB-IRIS is a paradoxical worsening or recurrence of pre-existing tuberculous lesions, or development of new lesions, in patients on effective antituberculosis treatment. There are two forms of IRIS: paradoxical and unmasking. Paradoxical IRIS is defined as recurrent, new, or worsening symptoms in a previously treated case \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. In our case, the patient had disseminated tuberculosis three years prior and had completed the full course of ATT. Following initiation of ART, he experienced progressive deterioration, which was consistent with a classification of paradoxical TB-IRIS.\u003c/p\u003e \u003cp\u003eCurrent available literature recognises that severe TB-IRIS has an overlapping phenotype with HLH, owing to their shared pathogenesis involving IFN-γ and unopposed T-cell activation, causing severe inflammatory disease. Patients with a dual diagnosis of IRIS-HLH had a more severe clinical course requiring more steroids and a longer duration of immunosuppression, with many requiring additional therapies beyond steroids due to refractory symptoms or steroid intolerance \u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOur patient fulfilled six of the eight Henter \u003cem\u003eet al.\u003c/em\u003e validated HLH-2004 diagnostic criteria \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eFever\u0026thinsp;\u0026ge;\u0026thinsp;38.5\u0026deg;C\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSplenomegaly\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eCytopenias affecting at least two of three peripheral blood lineages: haemoglobin\u0026thinsp;\u0026lt;\u0026thinsp;9 g/dL, platelets\u0026thinsp;\u0026lt;\u0026thinsp;100 \u0026times; 10\u0026sup3;/mL, neutrophils\u0026thinsp;\u0026lt;\u0026thinsp;1 \u0026times; 10\u0026sup3;/mL\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eHypertriglyceridaemia (fasting\u0026thinsp;\u0026gt;\u0026thinsp;265 mg/dL) and/or hypofibrinogenaemia (\u0026lt;\u0026thinsp;150 mg/dL)\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eHemophagocytosis in bone marrow, spleen, lymph nodes, or liver\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eFerritin\u0026thinsp;\u0026gt;\u0026thinsp;500 ng/mL\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eNK-cell activity and IL-2 receptor levels were not measured due to limited resources. However, bone marrow findings of florid hemophagocytosis, plasma cell predominance, non-caseating granulomas, Langhans giant cells, and grade II reticulin fibrosis \u0026mdash; despite a negative AFB stain \u0026mdash; combined with an HScore of 237, further solidified the clinical probability of HLH \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eBased on available literature, there is limited information on the mortality of HLH-IRIS specifically; however, a systematic review of 116 cases reports a 45% mortality rate in patients with TB-associated HLH, underscoring the importance of prompt recognition and initiation of ATT and immunomodulatory therapies to improve patient outcomes \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. In our case, the patient was initially worked up for sepsis, which was excluded. Paradoxical IRIS was considered and confirmed based on the patient's clinical timeline and paradoxical worsening following ART initiation, and steroids were commenced immediately. Given the pancytopenia and markedly elevated ferritin, we maintained a low threshold for bone marrow histopathological evaluation. The patient was started on etoposide (150 mg/m\u0026sup2; on days 1, 4, 8, and 15, then weekly for eight weeks) combined with dexamethasone, which effectively controlled HLH features. Rapid improvement in fever, cytopenias, and clinical status was observed within two weeks. Concurrent ATT and ART were continued to address the underlying TB and HIV \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case highlights the importance of considering HLH in patients with advanced HIV presenting with persistent fever and cytopenias after ART initiation. Early recognition and initiation of combined immunosuppressive and antimicrobial therapy can significantly improve outcomes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eHLH\u003c/b\u003e\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\"\u003e\u003cb\u003eTB\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTuberculosis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eHIV\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHuman Immunodeficiency Virus\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eIRIS\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eImmune Reconstitution Inflammatory Syndrome\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eART\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAntiretroviral therapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eATT\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAntitubercular therapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eTLD\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTenofovir\u0026ndash;Lamivudine\u0026ndash;Dolutegravir.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003eEthics approval was not required for this study, as this is a single-patient case report and did not involve and experimental intervention or research on human subjects. Informed consent was obtained from the patient for the publication of this case report and any accompanying images and data, in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eInformed consent obtained from the patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions:\u0026nbsp;\u003c/strong\u003eAll authors contributed to the management of the patient, data collection, drafting, and revision of this manuscript, and approved the final version for submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eNo funding was received for this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBrisse E, Wouters CH, Matthys P. 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Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014;66(9):2613\u0026ndash;20. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/art.38690\u003c/span\u003e\u003cspan address=\"10.1002/art.38690\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBergsten E, Horne A, Aric\u0026oacute; M, Astigarraga I, Egeler RM, Filipovich AH, et al. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017;130(25):2728\u0026ndash;38. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1182/blood-2017-06-788349\u003c/span\u003e\u003cspan address=\"10.1182/blood-2017-06-788349\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRocco JM, Laidlaw E, Galindo F, Anderson M, Rupert A, Higgins J, et al. Severe mycobacterial immune reconstitution inflammatory syndrome (IRIS) in advanced human immunodeficiency virus (HIV) has features of hemophagocytic lymphohistiocytosis and requires prolonged immune suppression. Clin Infect Dis. 2023;76(3):e561\u0026ndash;70. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/cid/ciac717\u003c/span\u003e\u003cspan address=\"10.1093/cid/ciac717\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\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, Immune reconstitution inflammatory syndrome, HIV, Tuberculosis, Etoposide","lastPublishedDoi":"10.21203/rs.3.rs-9627217/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9627217/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eHemophagocytic lymphohistiocytosis (HLH) is a fatal hyperinflammatory syndrome frequently triggered by infections in immunocompromised hosts. In HIV patients, upon initiation of antiretroviral therapy (ART), tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) can overlap and present with fever, cytopenias, and hepatosplenomegaly.\u003c/p\u003e\u003ch2\u003eCase Presentation:\u003c/h2\u003e \u003cp\u003eA 44-year-old male, a known case of HIV with poor ART adherence, presented with four weeks of cough, fever, and weight loss. He had completed treatment for disseminated TB three years prior. Cervical lymph node biopsy GeneXpert was positive for rifampicin-sensitive \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e. PET-CT showed pulmonary, nodal, marrow, and splenic involvement. He was restarted on anti-tubercular therapy (ATT) and ART. After initial improvement, he deteriorated with persistent fever, worsening respiratory symptoms, severe pancytopenia, hepatosplenomegaly, hyperferritinemia, and hypertriglyceridemia. Bone marrow studies showed florid hemophagocytosis and non-caseating granulomas. He met six of eight HLH-2004 criteria and had an HScore of 237 (98%-99%), establishing a diagnosis of secondary HLH overlapping with paradoxical TB-IRIS. He was managed with an Etoposide-Dexamethasone combination alongside ATT and ART.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis case highlights the importance of maintaining a high index of suspicion when managing HIV patients in TB-endemic regions for HLH-IRIS overlap. Early suspicion, application of the HLH criteria/HScore, bone marrow evaluation, and initiation of timely treatment are necessary for improving patient survival.\u003c/p\u003e","manuscriptTitle":"An Overlap Presentation of Immune Reconstitution Inflammatory Syndrome and Hemophagocytic Lymphohistiocytosis in a Patient with Advanced HIV","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-12 07:47:57","doi":"10.21203/rs.3.rs-9627217/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":"05bff4e7-6b6e-4c4e-8693-d7774d3adfbf","owner":[],"postedDate":"May 12th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Rejected","date":"2026-05-11T09:28:44+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-05-08T16:37:44+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-05-08T16:36:51+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Infectious Diseases","date":"2026-05-06T08:17:45+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-12T07:48:00+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-12 07:47:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9627217","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9627217","identity":"rs-9627217","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}