Human Metapneumovirus-Associated Secondary Hemophagocytic Syndrome in an Immunocompetent Adult: A Rapid-Response Case Report

Human Metapneumovirus-Associated Secondary Hemophagocytic Syndrome in an Immunocompetent Adult: A Rapid-Response 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 Human Metapneumovirus-Associated Secondary Hemophagocytic Syndrome in an Immunocompetent Adult: A Rapid-Response Case Report Liting Zhang, Guannan Ma, Mingzhu Ling, Wenbing Chen, Cuiting Shan, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8610490/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background Human metapneumovirus (HMPV) commonly causes severe lower respiratory tract infection in adults, but HMPV-triggered secondary hemophagocytic lymphohistiocytosis (HLH) is exceedingly rare. Case presentation: A previously healthy 44-year-old woman presented with 4 days of fever and cough. On admission she had pancytopenia (white blood cells 2.9×10⁹/L, hemoglobin 64 g/L, platelets 39×10⁹/L). Bone-marrow smears showed hemophagocytosis and NK-cell cytotoxicity was reduced (8.6%). Metagenomic next-generation sequencing (mNGS) of bronchoalveolar-lavage fluid (BALF) identified HMPV (38,433 reads) as the predominant pathogen; cerebrospinal fluid (CSF) mNGS was negative. She met 7/8 HLH-2004 criteria (persistent fever, ≥ 2-line cytopenias, hemophagocytosis, low NK activity, hypofibrinogenemia, elevated ferritin, and elevated sCD25) and was diagnosed with HMPV-associated secondary HLH. Management included ganciclovir for antiviral coverage, a short taper of methylprednisolone for cytokine control, empiric voriconazole under steroid exposure (Day 6–12), high-flow oxygen, and osmotherapy for intracranial hypertension. Defervescence occurred by Day 5 with rapid hematologic and neurologic recovery; she was discharged on Day 11 and remained well at follow-up. Conclusions HMPV can precipitate HLH in immunocompetent adults. In severe viral pneumonia with otherwise unexplained cytopenias, early bone-marrow evaluation and HLH assessment are essential. Pathogen-directed therapy guided by respiratory-sample mNGS, combined with measured immunomodulation, may improve outcomes. human metapneumovirus hemophagocytic lymphohistiocytosis metagenomic next-generation sequencing severe viral pneumonia case report Figures Figure 1 Figure 2 Figure 3 Introduction Hemophagocytic lymphohistiocytosis (HLH) is a rare yet highly lethal syndrome of pathological immune activation characterized by high fever, hepatosplenomegaly, cytopenias, hyperferritinemia, and macrophage hemophagocytosis in involved tissues 1,2 . HLH is broadly classified as primary (familial) or secondary; the latter is most often triggered by infections, malignancies, or autoimmune diseases 1,3 . Among human respiratory viruses, human metapneumovirus (HMPV), a member of the family Paramyxoviridae , is an important cause of lower respiratory tract infection in children and in immunocompromised hosts; in adults, it can also lead to severe disease necessitating hospitalization and, at times, intensive care 4 . Although HMPV infection typically presents with bronchitis or pneumonia, HMPV-induced HLH is exceedingly rare in clinical practice, and related reports remain very limited 5 . To date, only sporadic cases of HMPV-associated HLH have been documented, and the clinical presentation, diagnostic pathway, therapeutic strategies, and outcomes have not been systematically summarized 2,5 . Here, we present a case of HLH precipitated by HMPV infection. By detailing the patient’s clinical course, laboratory findings, and response to treatment, we aim to increase clinicians’ awareness of this uncommon etiology, promote earlier recognition and intervention, and ultimately improve patient outcomes. Case Presentation A previously healthy 44-year-old woman presented with 4 days of fever (peak 39.6°C), cough with scant yellow sputum, chills, and dizziness. At an outside facility, laboratory tests showed WBC 3.4 × 10⁹/L, hemoglobin (HGB) 72 g/L, and high-sensitivity C-reactive protein (hs-CRP) 76.12 mg/L. Chest CT demonstrated bronchitic changes, a small patchy opacity in the right upper lobe, and small bilateral pleural effusions. Empiric oral levofloxacin/cephalosporin, ambroxol, and antipyretics yielded no improvement. On evaluation at our clinic, repeat testing showed WBC 2.9 × 10⁹/L, platelets (PLT) 39 × 10⁹/L, HGB 64 g/L, and CRP 126.8 mg/L. She was admitted with the working diagnoses of suspected pneumonia, infectious fever, and trilineage cytopenia. Admission vitals were: temperature 37.0°C, heart rate 107/min, respiratory rate 20/min, blood pressure 107/56 mmHg, and SpO₂ 97% on room air. Omadacycline 0.1 g once daily was initiated (first dose doubled as a loading dose). Later on the day of admission, SpO₂ declined to 94% and expiratory wheeze was noted. CT pulmonary angiography revealed no pulmonary embolism but showed predominant interstitial changes, small bilateral pleural effusions, and subcarinal lymphadenopathy. Transthoracic echocardiography and B-type natriuretic peptide were not suggestive of heart failure. On hospital Day 2, fever recrudesced and hypoxemia worsened (SpO₂ 80% on room air, 92% on 2 L/min via nasal cannula). Bone-marrow examination demonstrated active erythroid hyperplasia with iron deficiency, increased megakaryocytes with poor platelet production, and hemophagocytosis. Intravenous methylprednisolone 40 mg was added, and ferritin, fasting triglycerides, NK-cell cytotoxicity, and soluble interleukin-2 receptor (sCD25) were ordered. She experienced two seizure-like episodes accompanied by delirium/catatonia and was transferred to the respiratory intensive care unit (RICU). Representative laboratory data included IL-6 618.7 pg/mL, procalcitonin 0.57 ng/mL, ferritin 168.7 ng/mL, D-dimer 2.93 mg/L, albumin 36.4 g/L, γ-glutamyltransferase 214 U/L, triglycerides 2.33 mmol/L, ALT 71 U/L, and AST 29 U/L. Urinalysis showed ketones (++) and trace protein; EBV DNA was 6.01 × 10² copies/mL. Bedside EEG was mildly to moderately abnormal. Lumbar puncture revealed an opening pressure > 250 mmH₂O, with otherwise unremarkable CSF studies (glucose 4.50 mmol/L). Bronchoscopy showed white, viscous secretions and mucosal edema. On this basis, ceftriaxone 2.0 g twice daily, ganciclovir 250 mg every 12 h, methylprednisolone 40 mg daily, and mannitol 125 mL every 8 h were administered; she also received midazolam for sedation, high-flow nasal oxygen, and symptomatic olanzapine/tandospirone. Forty-antigen flow cytometry showed no abnormal clonal population. Microbiology: CSF mNGS (DNA + RNA) and cryptococcal antigen were negative. BALF mNGS (DNA + RNA) detected human metapneumovirus (HMPV) at high abundance (38,433 reads, dominant), along with lower reads for Pseudomonas aeruginosa (2,900), Haemophilus influenzae (1,360), Staphylococcus aureus (837), Candida albicans (1,022), Aspergillus flavus (46), and Aspergillus nidulans (7). GeneXpert MTB/RIF was negative. BALF cytology showed neutrophils 7.0%, macrophages 20.0%, and lymphocytes 73.0%. HMPV was judged the principal pathogen/trigger, with consideration of possible bacterial coinfection and steroid-related fungal risk. Omadacycline and ceftriaxone were discontinued; therapy was changed to cefoperazone–sulbactam 3 g every 8 h (Day 4–Day 12), with voriconazole 200 mg every 12 h added empirically (Day 6–Day 12). Ganciclovir was continued to Day 10. Methylprednisolone was tapered (Day 1–Day 4: 40 mg daily; Day 5–Day 8: 20 mg daily). Mannitol was given from Day 4 to Day 8. Days 5–8: the patient defervesced; after sedation weaning, consciousness cleared without further seizures. Peripheral counts rose and inflammatory markers declined. Anxiety/insomnia were managed with tandospirone 1 tablet three times daily and lorazepam 0.5 mg nightly; valproate was continued for seizure prophylaxis, with iron and potassium supplementation as needed. Oxygen support was de-escalated to nasal cannula, the urinary catheter was removed, and she was transferred out of the RICU. Bone-marrow biopsy with immunohistochemistry showed active trilineage hematopoiesis without dysplasia; NK-cell cytotoxicity was 8.6% (reference > 15%). Hematology favored infection-associated cytokine storm/HLH without evidence of hematologic malignancy. Days 10–11: brain MRI was normal; repeat lumbar puncture showed an opening pressure of 165 mmH₂O, and CSF routine/biochemistry and cultures remained unremarkable. The patient ambulated independently, maintained SpO₂ 98% off oxygen, and was discharged on Day 11 in stable condition. Follow-up Post-discharge chest CT demonstrated complete radiographic resolution (Fig. 2 ). Discussion This case highlights that (HMPV can serve as a potential trigger of sHLH even in immunocompetent adults. The patient presented with persistent high fever, pancytopenia, bone-marrow hemophagocytosis, and markedly reduced NK-cell activity.mNGS of BALF identified HMPV as the predominant pathogen, whereas CSF testing was negative, indicating that the infection was confined mainly to the lower respiratory tract. The clinical progression followed a characteristic pattern in which viral pneumonia precipitated systemic immune dysregulation culminating in HLH. From a mechanistic standpoint, sHLH represents a hyperinflammatory syndrome driven by impaired cytotoxic lymphocyte function, principally NK cells and CD8⁺ T cells, resulting in uncontrolled macrophage activation and cytokine storm. Previous studies have demonstrated that several HMPV-encoded proteins, including G, SH, and M2-2, can suppress the RIG-I/MAVS and NF-κB/IRF-3 signaling pathways, thereby attenuating type I interferon responses and prolonging viral replication and antigen exposure 6–8 . Such sustained antigenic stimulation, under conditions of compromised immune clearance, can lead to interferon-γ–driven monocyte–macrophage activation accompanied by elevated IL-6 and IL-1), forming the classical hyperinflammatory milieu observed in sHLH 9,10 . The patient’s reduced NK-cell cytotoxicity, increased serum IL-6, and bone-marrow hemophagocytosis were consistent with this pathogenic framework. From a diagnostic perspective, this case underscores the importance of simultaneously screening for HLH and performing pathogen identification in adults presenting with severe viral pneumonia and unexplained cytopenias. mNGS of BALF offers a significant diagnostic advantage, particularly when viral replication is localized to the lower respiratory tract, as upper-airway swabs or blood samples may yield false-negative results. Parallel implementation of the HLH-2004 diagnostic criteria or the HScore together with mNGS facilitates early identification of infectious triggers and timely initiation of immunomodulatory therapy, which is critical for improving outcomes 11 3 . In adult HLH management, prompt recognition of the hyperinflammatory phenotype and dynamic monitoring of organ dysfunction remain key determinants of survival 9 . Therapeutically, there are currently no antiviral agents specifically approved for the treatment of HMPV infection. Although ribavirin has been used in select cases involving transplant or hematologic patients, evidence in immunocompetent adults remains limited 6 . In the present case, ganciclovir was administered prophylactically to prevent potential herpesvirus reactivation during corticosteroid therapy rather than to target HMPV directly. Moderate-dose, short-course methylpre dnisolone was employed to mitigate the cytokine storm, consistent with established adult HLH management protocols 12 . Considering the central role of IFN-γ in HLH pathogenesis, cytokine-targeted interventions such as the anti–IFN-γ monoclonal antibody emapalumab and JAK inhibitors (e.g., ruxolitinib) have shown promise in refractory or relapsing cases 13 ; however, prospective data in adults remain scarce. The favorable clinical response in this patient suggests that an integrated strategy combining pathogen control with immunomodulation may be both feasible and effective in cases without advanced multiorgan failure. This study has inherent limitations. As a single-case report, it cannot establish a definitive causal relationship between HMPV infection and HLH onset. The potential contribution of individual genetic susceptibility cannot be excluded. Future multicenter cohort studies focusing on HMPV-triggered sHLH in adults, incorporating immunophenotyping and molecular profiling, will be essential to delineate the pathogenic threshold and optimal timing for intervention in virus-associated HLH. Abbreviations HMPV Human Metapneumovirus HLH Hemophagocytic Lymphohistiocytosis mNGS Metagenomic next-generation Sequencing BALF Bronchoalveolar-lavage Fluid CSF Cerebrospinal Fluid HGB Hemoglobin hs-CRP High Sensitive C-reactive Protein PLT Platelets RICU Respiratory Intensive Care Unit Declarations Ethics approval and consent to participate Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Institutional approval was not required to publish the case details. Ethics Committee: Ethics Committee of The Second Affiliated Hospital of Zhejiang Chinese Medical University. Consent for publication Written informed consent was obtained from the patient. Competing interests The authors declare that they have no competing interests. Funding Statement This work was supported by fundings from Zhejiang Traditional Chinese Medicine Science and Technology Project (2024ZL513) and National Natural Science Foundation of China (82505433). Author Contribution Liting Zhang and Guannan Ma contributed to data collection and drafted the manuscript. Mingzhu Ling, Wenbin Cheng and Cuiting Shan were involved in data acquisition, analysis, interpretation and contributed to manuscript drafting. Ye Chen supervised the writing and guided the discussion of medical records. Acknowledgments None. Data Availability Data available on request from the Corresponding author. References Henter, J. I. et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatric blood & cancer 48 , 124–131, doi:10.1002/pbc.21039 (2007). Jordan, M. B., Allen, C. E., Weitzman, S., Filipovich, A. H. & McClain, K. L. How I treat hemophagocytic lymphohistiocytosis. Blood 118 , 4041–4052, doi:10.1182/blood-2011-03-278127 (2011). La Rosee, P. et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood 133 , 2465–2477, doi:10.1182/blood.2018894618 (2019). Barrera-Badillo, G. et al. Human Metapneumovirus: Etiological Agent of Severe Acute Respiratory Infections in Hospitalized and Deceased Patients with a Negative Diagnosis of Influenza. Pathogens 9 , doi:10.3390/pathogens9020085 (2020). Tamura, D., Inoue, S., Kawahara, Y., Mori, M. & Yamagata, T. Hypercytokinemia with hemophagocytic syndrome due to human metapneumovirus. Pediatrics international : official journal of the Japan Pediatric Society 60 , 974–976, doi:10.1111/ped.13665 (2018). Soto, J. A. et al. Human Metapneumovirus: Mechanisms and Molecular Targets Used by the Virus to Avoid the Immune System. Frontiers in immunology 9 , 2466, doi:10.3389/fimmu.2018.02466 (2018). Tanaka, Y., Morita, N., Kitagawa, Y., Gotoh, B. & Komatsu, T. Human metapneumovirus M2-2 protein inhibits RIG-I signaling by preventing TRIM25-mediated RIG-I ubiquitination. Frontiers in immunology 13 , 970750, doi:10.3389/fimmu.2022.970750 (2022). Bao, X. et al. Human metapneumovirus glycoprotein G inhibits innate immune responses. PLaoS pathogens 4 , e1000077, doi:10.1371/journal.ppat.1000077 (2008). Montrucchio, G. et al. Hemophagocytic Lymphohistiocytosis in the adult critically ill: a narrative review of case reports and case series. Frontiers in medicine 12 , 1622770, doi:10.3389/fmed.2025.1622770 (2025). Toumeh, N., Abu-Zeinah, K. F. & Godby, R. C. Hemophagocytic lymphohistiocytosis (HLH): a narrative review of the pathogenesis, clinical presentation, diagnosis, treatment, and prognosis. Annals of Blood 10 (2025). Notghi, A. A., Delahunty, J., Tattersall, R. S. & Stone, B. Haemophagocytic lymphohistiocytosis (HLH) secondary to measles in an adult with a loss of post-vaccination humoral immunity following rituximab. The Lancet. Infectious diseases 25 , e667-e675, doi:10.1016/S1473-3099(25)00223-3 (2025). Allen, C. E., Yu, X., Kozinetz, C. A. & McClain, K. L. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatric blood & cancer 50 , 1227–1235, doi:10.1002/pbc.21423 (2008). Orti, G. et al. Less frequent complications following CAR T-cell therapies: hemophagocytic lymphohistiocytosis, graft-versus-host disease, thrombotic microangiopathy, coagulation disorders and secondary malignancies: best practice recommendations from the EBMT Practice Harmonization and Guidelines Committee. Bone marrow transplantation 60 , 751–758, doi:10.1038/s41409-025-02567-5 (2025). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 25 Mar, 2026 Reviewers agreed at journal 16 Mar, 2026 Reviewers invited by journal 09 Mar, 2026 Editor assigned by journal 04 Mar, 2026 Editor invited by journal 09 Feb, 2026 Submission checks completed at journal 07 Feb, 2026 First submitted to journal 07 Feb, 2026 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-8610490","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":604436918,"identity":"a6ab6b14-e199-4551-ad0e-8d4dac918e0f","order_by":0,"name":"Liting Zhang","email":"","orcid":"","institution":"The Second Affiliated Hospital of Zhejiang Chinese Medical University","correspondingAuthor":false,"prefix":"","firstName":"Liting","middleName":"","lastName":"Zhang","suffix":""},{"id":604436920,"identity":"2bea5b68-d49e-4df6-bb7d-4ceebdf300dd","order_by":1,"name":"Guannan Ma","email":"","orcid":"","institution":"Zhejiang Key Laboratory of Digital Technology in Medical Diagnostics","correspondingAuthor":false,"prefix":"","firstName":"Guannan","middleName":"","lastName":"Ma","suffix":""},{"id":604436923,"identity":"e6b89029-5419-4f51-8cb9-1196f55a9e67","order_by":2,"name":"Mingzhu Ling","email":"","orcid":"","institution":"The Second Affiliated Hospital of Zhejiang Chinese Medical University","correspondingAuthor":false,"prefix":"","firstName":"Mingzhu","middleName":"","lastName":"Ling","suffix":""},{"id":604436926,"identity":"53b8020c-3bdd-4564-9df4-7dd7aee33b82","order_by":3,"name":"Wenbing Chen","email":"","orcid":"","institution":"The Second Affiliated Hospital of Zhejiang Chinese Medical University","correspondingAuthor":false,"prefix":"","firstName":"Wenbing","middleName":"","lastName":"Chen","suffix":""},{"id":604436930,"identity":"92e2fad6-f865-4a33-a2eb-fbab6fd4193b","order_by":4,"name":"Cuiting Shan","email":"","orcid":"","institution":"The Second Affiliated Hospital of Zhejiang Chinese Medical University","correspondingAuthor":false,"prefix":"","firstName":"Cuiting","middleName":"","lastName":"Shan","suffix":""},{"id":604436938,"identity":"50809caa-f2af-4f9b-aa85-d79831ee7888","order_by":5,"name":"Ye Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6UlEQVRIiWNgGAWjYBACfmbGxgcSBhJy/FABxgZCWiTbmw8bWFRYGEs2EKvF4MyxNImKMxWJGw4Qq4XhRo6ZxM02CcbN5w8/3czDYCO74QDzswf4dDDOyDG2nNkmwWx24JjZbR6GNOMNB9jMDfBpYZbIMbwt2SbBZnawhw2o5TDQhTxsEvi0sEnkGEj/bZPgMW7mAWn5T1gLD8+xJAmJMxISBmxgLQcIa5FgBwayRAUwZs6wmd2cY5BsPPMwmxleLfaHwVFZV9/ff/jZjTcVdrJ9x5uf4dWCBkBBxUyC+lEwCkbBKBgF2AEArDJIHDIVuGgAAAAASUVORK5CYII=","orcid":"","institution":"The Second Affiliated Hospital of Zhejiang Chinese Medical University","correspondingAuthor":true,"prefix":"","firstName":"Ye","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2026-01-15 12:39:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8610490/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8610490/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104557547,"identity":"377cdefb-7afe-43da-8862-aece85c97981","added_by":"auto","created_at":"2026-03-13 09:27:57","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":905326,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eHospital day–by–day timeline of clinical course, diagnostics, and therapy in the patient with HMPV-triggered HLH\u003c/strong\u003e. The orange line shows the oxygenation index (PaO₂/FiO₂, mmHg; left y-axis) and the blue line shows body temperature (°C; right y-axis) from Day 1 (D1) to Day 10 (D10). Key events are annotated: early trilineage cytopenias (RBCs/WBCs/PLTs), bone-marrow aspiration (HPS work-up), a seizure, lumbar puncture/bronchoscopy, and detection of HMPV (by BALF mNGS). Colored bars beneath the x-axis denote the start and duration of treatments. BALF, bronchoalveolar-lavage fluid; mNGS, metagenomic next-generation sequencing; HMPV, human metapneumovirus; HLH, hemophagocytic lymphohistiocytosis.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8610490/v1/96c1858403242ec6e4a57faf.png"},{"id":104557411,"identity":"e4dd3aa6-c6bd-43e2-b147-9b3c12a1c870","added_by":"auto","created_at":"2026-03-13 09:27:34","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":6479403,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSerial chest CT demonstrating radiologic evolution from admission to convalescence. \u003c/strong\u003eRows correspond to Day 1, Day 3, and Day 45. Lung-window images (columns 1–3) and a mediastinal-window image (column 4) are shown at comparable axial levels.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8610490/v1/6dd943af78c12ac95c76d651.png"},{"id":104557545,"identity":"a1c796b7-ce9a-4446-87f1-f002e53e98bf","added_by":"auto","created_at":"2026-03-13 09:27:56","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2608537,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBALF mNGS and Bone Marrow Smear Findings. \u003c/strong\u003e(A) The bar chart shows the relative number of reads detected in bronchoalveolar-lavage fluid (BALF) by metagenomic next-generation sequencing (mNGS). (B) A bone marrow smear demonstrates hemophagocytosis, with a lymphocyte, neutrophil, and platelet observed. The arrows highlight key features, including a lymphocyte, nuclear fragments, and a platelet, which are indicative of HLH.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8610490/v1/566ecbe4a3b49455654e22f5.png"},{"id":104557622,"identity":"b8a642a7-a95c-414a-86fc-358286eee730","added_by":"auto","created_at":"2026-03-13 09:28:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":10869927,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8610490/v1/e5ca8402-04ed-462b-927d-602a0d97c6e0.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Human Metapneumovirus-Associated Secondary Hemophagocytic Syndrome in an Immunocompetent Adult: A Rapid-Response Case Report","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHemophagocytic lymphohistiocytosis (HLH) is a rare yet highly lethal syndrome of pathological immune activation characterized by high fever, hepatosplenomegaly, cytopenias, hyperferritinemia, and macrophage hemophagocytosis in involved tissues \u003csup\u003e1,2\u003c/sup\u003e. HLH is broadly classified as primary (familial) or secondary; the latter is most often triggered by infections, malignancies, or autoimmune diseases \u003csup\u003e1,3\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAmong human respiratory viruses, human metapneumovirus (HMPV), a member of the family \u003cem\u003eParamyxoviridae\u003c/em\u003e, is an important cause of lower respiratory tract infection in children and in immunocompromised hosts; in adults, it can also lead to severe disease necessitating hospitalization and, at times, intensive care \u003csup\u003e4\u003c/sup\u003e. Although HMPV infection typically presents with bronchitis or pneumonia, HMPV-induced HLH is exceedingly rare in clinical practice, and related reports remain very limited \u003csup\u003e5\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTo date, only sporadic cases of HMPV-associated HLH have been documented, and the clinical presentation, diagnostic pathway, therapeutic strategies, and outcomes have not been systematically summarized \u003csup\u003e2,5\u003c/sup\u003e. Here, we present a case of HLH precipitated by HMPV infection. By detailing the patient\u0026rsquo;s clinical course, laboratory findings, and response to treatment, we aim to increase clinicians\u0026rsquo; awareness of this uncommon etiology, promote earlier recognition and intervention, and ultimately improve patient outcomes.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA previously healthy 44-year-old woman presented with 4 days of fever (peak 39.6\u0026deg;C), cough with scant yellow sputum, chills, and dizziness. At an outside facility, laboratory tests showed WBC 3.4 \u0026times; 10⁹/L, hemoglobin (HGB) 72 g/L, and high-sensitivity C-reactive protein (hs-CRP) 76.12 mg/L. Chest CT demonstrated bronchitic changes, a small patchy opacity in the right upper lobe, and small bilateral pleural effusions. Empiric oral levofloxacin/cephalosporin, ambroxol, and antipyretics yielded no improvement.\u003c/p\u003e \u003cp\u003eOn evaluation at our clinic, repeat testing showed WBC 2.9 \u0026times; 10⁹/L, platelets (PLT) 39 \u0026times; 10⁹/L, HGB 64 g/L, and CRP 126.8 mg/L. She was admitted with the working diagnoses of suspected pneumonia, infectious fever, and trilineage cytopenia. Admission vitals were: temperature 37.0\u0026deg;C, heart rate 107/min, respiratory rate 20/min, blood pressure 107/56 mmHg, and SpO₂ 97% on room air. Omadacycline 0.1 g once daily was initiated (first dose doubled as a loading dose).\u003c/p\u003e \u003cp\u003eLater on the day of admission, SpO₂ declined to 94% and expiratory wheeze was noted. CT pulmonary angiography revealed no pulmonary embolism but showed predominant interstitial changes, small bilateral pleural effusions, and subcarinal lymphadenopathy. Transthoracic echocardiography and B-type natriuretic peptide were not suggestive of heart failure.\u003c/p\u003e \u003cp\u003eOn hospital Day 2, fever recrudesced and hypoxemia worsened (SpO₂ 80% on room air, 92% on 2 L/min via nasal cannula). Bone-marrow examination demonstrated active erythroid hyperplasia with iron deficiency, increased megakaryocytes with poor platelet production, and hemophagocytosis. Intravenous methylprednisolone 40 mg was added, and ferritin, fasting triglycerides, NK-cell cytotoxicity, and soluble interleukin-2 receptor (sCD25) were ordered.\u003c/p\u003e \u003cp\u003eShe experienced two seizure-like episodes accompanied by delirium/catatonia and was transferred to the respiratory intensive care unit (RICU). Representative laboratory data included IL-6 618.7 pg/mL, procalcitonin 0.57 ng/mL, ferritin 168.7 ng/mL, D-dimer 2.93 mg/L, albumin 36.4 g/L, γ-glutamyltransferase 214 U/L, triglycerides 2.33 mmol/L, ALT 71 U/L, and AST 29 U/L. Urinalysis showed ketones (++) and trace protein; EBV DNA was 6.01 \u0026times; 10\u0026sup2; copies/mL. Bedside EEG was mildly to moderately abnormal. Lumbar puncture revealed an opening pressure\u0026thinsp;\u0026gt;\u0026thinsp;250 mmH₂O, with otherwise unremarkable CSF studies (glucose 4.50 mmol/L). Bronchoscopy showed white, viscous secretions and mucosal edema. On this basis, ceftriaxone 2.0 g twice daily, ganciclovir 250 mg every 12 h, methylprednisolone 40 mg daily, and mannitol 125 mL every 8 h were administered; she also received midazolam for sedation, high-flow nasal oxygen, and symptomatic olanzapine/tandospirone. Forty-antigen flow cytometry showed no abnormal clonal population.\u003c/p\u003e \u003cp\u003eMicrobiology: CSF mNGS (DNA\u0026thinsp;+\u0026thinsp;RNA) and cryptococcal antigen were negative. BALF mNGS (DNA\u0026thinsp;+\u0026thinsp;RNA) detected \u003cb\u003ehuman metapneumovirus (HMPV)\u003c/b\u003e at high abundance (38,433 reads, dominant), along with lower reads for \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e (2,900), \u003cem\u003eHaemophilus influenzae\u003c/em\u003e (1,360), \u003cem\u003eStaphylococcus aureus\u003c/em\u003e (837), \u003cem\u003eCandida albicans\u003c/em\u003e (1,022), \u003cem\u003eAspergillus flavus\u003c/em\u003e (46), and \u003cem\u003eAspergillus nidulans\u003c/em\u003e (7). GeneXpert MTB/RIF was negative. BALF cytology showed neutrophils 7.0%, macrophages 20.0%, and lymphocytes 73.0%. HMPV was judged the principal pathogen/trigger, with consideration of possible bacterial coinfection and steroid-related fungal risk. Omadacycline and ceftriaxone were discontinued; therapy was changed to cefoperazone\u0026ndash;sulbactam 3 g every 8 h (Day 4\u0026ndash;Day 12), with voriconazole 200 mg every 12 h added empirically (Day 6\u0026ndash;Day 12). Ganciclovir was continued to Day 10. Methylprednisolone was tapered (Day 1\u0026ndash;Day 4: 40 mg daily; Day 5\u0026ndash;Day 8: 20 mg daily). Mannitol was given from Day 4 to Day 8.\u003c/p\u003e \u003cp\u003eDays 5\u0026ndash;8: the patient defervesced; after sedation weaning, consciousness cleared without further seizures. Peripheral counts rose and inflammatory markers declined. Anxiety/insomnia were managed with tandospirone 1 tablet three times daily and lorazepam 0.5 mg nightly; valproate was continued for seizure prophylaxis, with iron and potassium supplementation as needed. Oxygen support was de-escalated to nasal cannula, the urinary catheter was removed, and she was transferred out of the RICU. Bone-marrow biopsy with immunohistochemistry showed active trilineage hematopoiesis without dysplasia; NK-cell cytotoxicity was 8.6% (reference\u0026thinsp;\u0026gt;\u0026thinsp;15%). Hematology favored infection-associated cytokine storm/HLH without evidence of hematologic malignancy.\u003c/p\u003e \u003cp\u003eDays 10\u0026ndash;11: brain MRI was normal; repeat lumbar puncture showed an opening pressure of 165 mmH₂O, and CSF routine/biochemistry and cultures remained unremarkable. The patient ambulated independently, maintained SpO₂ 98% off oxygen, and was discharged on Day 11 in stable condition.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eFollow-up\u003c/strong\u003e \u003cp\u003ePost-discharge chest CT demonstrated complete radiographic resolution (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis case highlights that (HMPV can serve as a potential trigger of sHLH even in immunocompetent adults. The patient presented with persistent high fever, pancytopenia, bone-marrow hemophagocytosis, and markedly reduced NK-cell activity.mNGS of BALF identified HMPV as the predominant pathogen, whereas CSF testing was negative, indicating that the infection was confined mainly to the lower respiratory tract. The clinical progression followed a characteristic pattern in which viral pneumonia precipitated systemic immune dysregulation culminating in HLH.\u003c/p\u003e \u003cp\u003eFrom a mechanistic standpoint, sHLH represents a hyperinflammatory syndrome driven by impaired cytotoxic lymphocyte function, principally NK cells and CD8⁺ T cells, resulting in uncontrolled macrophage activation and cytokine storm. Previous studies have demonstrated that several HMPV-encoded proteins, including G, SH, and M2-2, can suppress the RIG-I/MAVS and NF-κB/IRF-3 signaling pathways, thereby attenuating type I interferon responses and prolonging viral replication and antigen exposure \u003csup\u003e6\u0026ndash;8\u003c/sup\u003e. Such sustained antigenic stimulation, under conditions of compromised immune clearance, can lead to interferon-γ\u0026ndash;driven monocyte\u0026ndash;macrophage activation accompanied by elevated IL-6 and IL-1), forming the classical hyperinflammatory milieu observed in sHLH \u003csup\u003e9,10\u003c/sup\u003e. The patient\u0026rsquo;s reduced NK-cell cytotoxicity, increased serum IL-6, and bone-marrow hemophagocytosis were consistent with this pathogenic framework.\u003c/p\u003e \u003cp\u003eFrom a diagnostic perspective, this case underscores the importance of simultaneously screening for HLH and performing pathogen identification in adults presenting with severe viral pneumonia and unexplained cytopenias. mNGS of BALF offers a significant diagnostic advantage, particularly when viral replication is localized to the lower respiratory tract, as upper-airway swabs or blood samples may yield false-negative results. Parallel implementation of the HLH-2004 diagnostic criteria or the HScore together with mNGS facilitates early identification of infectious triggers and timely initiation of immunomodulatory therapy, which is critical for improving outcomes \u003csup\u003e11 3\u003c/sup\u003e. In adult HLH management, prompt recognition of the hyperinflammatory phenotype and dynamic monitoring of organ dysfunction remain key determinants of survival \u003csup\u003e9\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTherapeutically, there are currently no antiviral agents specifically approved for the treatment of HMPV infection. Although ribavirin has been used in select cases involving transplant or hematologic patients, evidence in immunocompetent adults remains limited \u003csup\u003e6\u003c/sup\u003e. In the present case, ganciclovir was administered prophylactically to prevent potential herpesvirus reactivation during corticosteroid therapy rather than to target HMPV directly. Moderate-dose, short-course methylpre dnisolone was employed to mitigate the cytokine storm, consistent with established adult HLH management protocols \u003csup\u003e12\u003c/sup\u003e. Considering the central role of IFN-γ in HLH pathogenesis, cytokine-targeted interventions such as the anti\u0026ndash;IFN-γ monoclonal antibody emapalumab and JAK inhibitors (e.g., ruxolitinib) have shown promise in refractory or relapsing cases \u003csup\u003e13\u003c/sup\u003e; however, prospective data in adults remain scarce. The favorable clinical response in this patient suggests that an integrated strategy combining pathogen control with immunomodulation may be both feasible and effective in cases without advanced multiorgan failure.\u003c/p\u003e \u003cp\u003eThis study has inherent limitations. As a single-case report, it cannot establish a definitive causal relationship between HMPV infection and HLH onset. The potential contribution of individual genetic susceptibility cannot be excluded. Future multicenter cohort studies focusing on HMPV-triggered sHLH in adults, incorporating immunophenotyping and molecular profiling, will be essential to delineate the pathogenic threshold and optimal timing for intervention in virus-associated HLH.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eHMPV Human Metapneumovirus\u003c/p\u003e\u003cp\u003eHLH Hemophagocytic Lymphohistiocytosis\u003c/p\u003e\u003cp\u003emNGS Metagenomic next-generation Sequencing\u003c/p\u003e\u003cp\u003eBALF Bronchoalveolar-lavage Fluid\u003c/p\u003e\u003cp\u003eCSF Cerebrospinal Fluid\u003c/p\u003e\u003cp\u003eHGB Hemoglobin\u003c/p\u003e\u003cp\u003ehs-CRP High Sensitive C-reactive Protein\u003c/p\u003e\u003cp\u003ePLT Platelets\u003c/p\u003e\u003cp\u003eRICU Respiratory Intensive Care Unit\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003c/p\u003e\u003cp\u003e Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Institutional approval was not required to publish the case details. Ethics Committee: Ethics Committee of The Second Affiliated Hospital of Zhejiang Chinese Medical University.\u003c/p\u003e \u003cp\u003e\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003c/p\u003e\u003cp\u003eWritten informed consent was obtained from the patient.\u003c/p\u003e \u003cp\u003e\u003c/p\u003e\u003cp\u003e \u003c/p\u003e\u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e \u003cp\u003e\u003c/p\u003e\u003ch2\u003eFunding Statement\u003c/h2\u003e \u003cp\u003eThis work was supported by fundings from Zhejiang Traditional Chinese Medicine Science and Technology Project (2024ZL513) and National Natural Science Foundation of China (82505433).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eLiting Zhang and Guannan Ma contributed to data collection and drafted the manuscript. Mingzhu Ling, Wenbin Cheng and Cuiting Shan were involved in data acquisition, analysis, interpretation and contributed to manuscript drafting. Ye Chen supervised the writing and guided the discussion of medical records.\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e \u003cp\u003eNone.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eData available on request from the Corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003e Henter, J. I. \u003cem\u003eet al.\u003c/em\u003e HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. \u003cem\u003ePediatric blood \u0026amp; cancer\u003c/em\u003e \u003cb\u003e48\u003c/b\u003e, 124\u0026ndash;131, doi:10.1002/pbc.21039 (2007).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Jordan, M. B., Allen, C. E., Weitzman, S., Filipovich, A. H. \u0026amp; McClain, K. L. How I treat hemophagocytic lymphohistiocytosis. \u003cem\u003eBlood\u003c/em\u003e \u003cb\u003e118\u003c/b\u003e, 4041\u0026ndash;4052, doi:10.1182/blood-2011-03-278127 (2011).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e La Rosee, P. \u003cem\u003eet al.\u003c/em\u003e Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. \u003cem\u003eBlood\u003c/em\u003e \u003cb\u003e133\u003c/b\u003e, 2465\u0026ndash;2477, doi:10.1182/blood.2018894618 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Barrera-Badillo, G. \u003cem\u003eet al.\u003c/em\u003e Human Metapneumovirus: Etiological Agent of Severe Acute Respiratory Infections in Hospitalized and Deceased Patients with a Negative Diagnosis of Influenza. \u003cem\u003ePathogens\u003c/em\u003e \u003cb\u003e9\u003c/b\u003e, doi:10.3390/pathogens9020085 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Tamura, D., Inoue, S., Kawahara, Y., Mori, M. \u0026amp; Yamagata, T. Hypercytokinemia with hemophagocytic syndrome due to human metapneumovirus. \u003cem\u003ePediatrics international : official journal of the Japan Pediatric Society\u003c/em\u003e \u003cb\u003e60\u003c/b\u003e, 974\u0026ndash;976, doi:10.1111/ped.13665 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Soto, J. A. \u003cem\u003eet al.\u003c/em\u003e Human Metapneumovirus: Mechanisms and Molecular Targets Used by the Virus to Avoid the Immune System. \u003cem\u003eFrontiers in immunology\u003c/em\u003e \u003cb\u003e9\u003c/b\u003e, 2466, doi:10.3389/fimmu.2018.02466 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Tanaka, Y., Morita, N., Kitagawa, Y., Gotoh, B. \u0026amp; Komatsu, T. Human metapneumovirus M2-2 protein inhibits RIG-I signaling by preventing TRIM25-mediated RIG-I ubiquitination. \u003cem\u003eFrontiers in immunology\u003c/em\u003e \u003cb\u003e13\u003c/b\u003e, 970750, doi:10.3389/fimmu.2022.970750 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Bao, X. \u003cem\u003eet al.\u003c/em\u003e Human metapneumovirus glycoprotein G inhibits innate immune responses. \u003cem\u003ePLaoS pathogens\u003c/em\u003e \u003cb\u003e4\u003c/b\u003e, e1000077, doi:10.1371/journal.ppat.1000077 (2008).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Montrucchio, G. \u003cem\u003eet al.\u003c/em\u003e Hemophagocytic Lymphohistiocytosis in the adult critically ill: a narrative review of case reports and case series. \u003cem\u003eFrontiers in medicine\u003c/em\u003e \u003cb\u003e12\u003c/b\u003e, 1622770, doi:10.3389/fmed.2025.1622770 (2025).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Toumeh, N., Abu-Zeinah, K. F. \u0026amp; Godby, R. C. Hemophagocytic lymphohistiocytosis (HLH): a narrative review of the pathogenesis, clinical presentation, diagnosis, treatment, and prognosis. \u003cem\u003eAnnals of Blood\u003c/em\u003e \u003cb\u003e10\u003c/b\u003e (2025).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Notghi, A. A., Delahunty, J., Tattersall, R. S. \u0026amp; Stone, B. Haemophagocytic lymphohistiocytosis (HLH) secondary to measles in an adult with a loss of post-vaccination humoral immunity following rituximab. \u003cem\u003eThe Lancet. Infectious diseases\u003c/em\u003e \u003cb\u003e25\u003c/b\u003e, e667-e675, doi:10.1016/S1473-3099(25)00223-3 (2025).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Allen, C. E., Yu, X., Kozinetz, C. A. \u0026amp; McClain, K. L. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. \u003cem\u003ePediatric blood \u0026amp; cancer\u003c/em\u003e \u003cb\u003e50\u003c/b\u003e, 1227\u0026ndash;1235, doi:10.1002/pbc.21423 (2008).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e Orti, G. \u003cem\u003eet al.\u003c/em\u003e Less frequent complications following CAR T-cell therapies: hemophagocytic lymphohistiocytosis, graft-versus-host disease, thrombotic microangiopathy, coagulation disorders and secondary malignancies: best practice recommendations from the EBMT Practice Harmonization and Guidelines Committee. \u003cem\u003eBone marrow transplantation\u003c/em\u003e \u003cb\u003e60\u003c/b\u003e, 751\u0026ndash;758, doi:10.1038/s41409-025-02567-5 (2025).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"human metapneumovirus, hemophagocytic lymphohistiocytosis, metagenomic next-generation sequencing, severe viral pneumonia, case report","lastPublishedDoi":"10.21203/rs.3.rs-8610490/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8610490/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eHuman metapneumovirus (HMPV) commonly causes severe lower respiratory tract infection in adults, but HMPV-triggered secondary hemophagocytic lymphohistiocytosis (HLH) is exceedingly rare.\u003c/p\u003e\u003ch2\u003eCase presentation:\u003c/h2\u003e \u003cp\u003eA previously healthy 44-year-old woman presented with 4 days of fever and cough. On admission she had pancytopenia (white blood cells 2.9\u0026times;10⁹/L, hemoglobin 64 g/L, platelets 39\u0026times;10⁹/L). Bone-marrow smears showed hemophagocytosis and NK-cell cytotoxicity was reduced (8.6%). Metagenomic next-generation sequencing (mNGS) of bronchoalveolar-lavage fluid (BALF) identified HMPV (38,433 reads) as the predominant pathogen; cerebrospinal fluid (CSF) mNGS was negative. She met 7/8 HLH-2004 criteria (persistent fever, \u0026ge;\u0026thinsp;2-line cytopenias, hemophagocytosis, low NK activity, hypofibrinogenemia, elevated ferritin, and elevated sCD25) and was diagnosed with HMPV-associated secondary HLH. Management included ganciclovir for antiviral coverage, a short taper of methylprednisolone for cytokine control, empiric voriconazole under steroid exposure (Day 6\u0026ndash;12), high-flow oxygen, and osmotherapy for intracranial hypertension. Defervescence occurred by Day 5 with rapid hematologic and neurologic recovery; she was discharged on Day 11 and remained well at follow-up.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eHMPV can precipitate HLH in immunocompetent adults. In severe viral pneumonia with otherwise unexplained cytopenias, early bone-marrow evaluation and HLH assessment are essential. Pathogen-directed therapy guided by respiratory-sample mNGS, combined with measured immunomodulation, may improve outcomes.\u003c/p\u003e","manuscriptTitle":"Human Metapneumovirus-Associated Secondary Hemophagocytic Syndrome in an Immunocompetent Adult: A Rapid-Response Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-13 09:24:50","doi":"10.21203/rs.3.rs-8610490/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-03-25T17:17:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"59793683488037008443669503579948791863","date":"2026-03-16T16:24:52+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-09T07:21:48+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-04T12:01:54+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-09T10:01:54+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-07T07:18:50+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pulmonary Medicine","date":"2026-02-07T07:10:44+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"97c9427c-2a85-42d9-b503-a02362eca71a","owner":[],"postedDate":"March 13th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-13T09:24:50+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-13 09:24:50","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8610490","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8610490","identity":"rs-8610490","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}