Depemokimab

Depemokimab is a novel, ultra-long-acting anti-IL-5 monoclonal antibody developed by GSK for eosinophilic, type 2-inflammatory diseases. It is not yet covered in standard textbooks (which discuss the older anti-IL-5 class - mepolizumab, reslizumab, benralizumab), but it has now moved through Phase III trials and FDA approval.

Mechanism

Like mepolizumab, depemokimab binds and neutralizes circulating interleukin-5 (IL-5), blocking its interaction with the IL-5 receptor on eosinophils. This prevents eosinophil maturation, activation, and survival, reducing eosinophilic inflammation that drives conditions such as severe asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and eosinophilic granulomatosis with polyangiitis (EGPA)-type diseases (background mechanism corroborated in - Goodman & Gilman's Pharmacological Basis of Therapeutics, p. anti-IL-5 section; Fishman's Pulmonary Diseases, "Anti-IL-5 Treatments").

What makes depemokimab distinct is engineering for an extended half-life and high binding affinity/potency, allowing effective IL-5 suppression with dosing only twice yearly (every 26 weeks), compared to monthly (mepolizumab) or every-4-to-8-week dosing for existing anti-IL-5/IL-5R agents.

Clinical development and approval

SWIFT-1 and SWIFT-2 (Phase III, severe eosinophilic asthma): twice-yearly depemokimab significantly reduced exacerbation rates vs. placebo, published in the New England Journal of Medicine (Jackson et al., 2024, PMID 39248309).
ANCHOR-1 and ANCHOR-2 (Phase III, CRSwNP): met co-primary endpoints for nasal polyp size and nasal obstruction.
A pooled safety analysis (SWIFT-1/-2, ANCHOR-1/-2) found depemokimab generally well tolerated, with a safety profile similar to other IL-5 pathway biologics (PMID 41461999).
A 2025 systematic review/meta-analysis of RCTs supports efficacy and safety in the eosinophilic asthma phenotype (PMID 41331792).
One editorial noted depemokimab improved exacerbation rates but did not show a significant quality-of-life improvement at 52 weeks in one trial analysis (PMID 39761576) - a point worth flagging when counseling on expected benefit.

Regulatory status: The FDA accepted BLA submissions for both asthma with type 2 inflammation and CRSwNP in March 2025. On December 16, 2025, the FDA approved depemokimab-ulaa (brand name Exdensur) as an add-on maintenance therapy for patients aged 12 and older with severe asthma with an eosinophilic phenotype, administered as just two doses per year. The CRSwNP indication review is a separate, ongoing regulatory track.

Positioning versus existing biologics

Depemokimab competes with:

Mepolizumab (Nucala) - anti-IL-5, monthly dosing
Benralizumab - anti-IL-5Rα, every-8-week dosing
Dupilumab - anti-IL-4Rα/IL-13, broader type 2 coverage

Its main differentiator is the dramatically reduced dosing frequency (twice yearly vs. monthly/bimonthly), which may improve adherence, particularly meaningful for a chronic biologic therapy.

Evidence currency note

This is a newly approved agent (approved Dec 2025), so textbook sources predate it entirely; the summary above relies on the pivotal trial publications and a 2025 systematic review/meta-analysis (PMID 41331792) rather than textbook synthesis. No contradicting recent evidence was found - the meta-analysis and pooled safety data align with the pivotal trial results.

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Patient presented with on and off fever since 10 -15 days and cough and abdominal pain Usg abdomen was normal

Reading File

analyse_media

Finding Sources

Searching the Web

fever cough abdominal pain hepatosplenomegaly mediastinal lymphadenopathy ground glass HRCT differential India

Reading Web Page

https://pmc.ncbi.nlm.nih.gov/articles/PMC7141715

Finding Sources

Case Summary

Mr. Prem Singh, 41 M — fever (on-and-off) x 10-15 days, cough, abdominal pain. USG abdomen reportedly normal, but the HRCT thorax report itself notes hepatosplenomegaly and ascites in the visualized upper abdomen — this is an important discrepancy worth flagging (see below).

HRCT Thorax findings (Dr. Udita Wadhwani, GBH/AIIMS Udaipur, 15.08.2026):

Bilateral ill-defined ground-glass opacities with smooth inter- and intralobular septal thickening
Mild right pleural effusion with right lower lobe basal atelectasis; minimal left effusion
Multiple mediastinal lymph nodes (pre-paratracheal, prevascular, subcarinal) — largest 23 x 15 mm subcarinal
Trachea/bronchi normal, no pericardial effusion
Incidental hepatosplenomegaly + ascites
Radiologist's impression: "?Infective etiology ?Pulmonary edema — advise clinical & lab correlation"

Clinical Reasoning

This is a classic PUO-plus-serositis-plus-organomegaly pattern: fever >10 days + mediastinal/abdominal lymphadenopathy + hepatosplenomegaly + bilateral pleural effusion + ascites + smooth septal GGO. A directly analogous published case (mediastinal + abdominal lymphadenopathy with hepatosplenomegaly and pulmonary GGO) states plainly: "Major diagnosis for mediastinal and abdominal lymphadenopathy is lymphoma and tuberculosis" (Case Reports in oncology/hematology, PMC). One textbook question bank even flags "fever for 10 days" + hepatosplenomegaly as findings that should "always prompt further workup for leukemia/lymphoma" (Swanson's Family Medicine Review).

Top differentials, ranked

Disseminated/lymph node tuberculosis (with serosal + hepatosplenic involvement) — highest pre-test probability in an Indian adult with this exact combination: fever, cough, abdominal pain, mediastinal LAP, pleural effusion, ascites, and hepatosplenomegaly. Miliary TB classically shows randomly distributed 1-3 mm micronodules rather than smooth septal thickening (Murray & Nadel's Textbook of Respiratory Medicine, p. Radiographic Features), but the study here is described as "suboptimal due to motion artifacts" — a subtle miliary pattern can be missed/blurred on a degraded study. Abdominal/nodal TB can also directly cause ascites and nodal enlargement without necessarily giving classic miliary lung nodules.
Lymphoma (Hodgkin or non-Hodgkin) — B-symptoms (fever, and to look for night sweats/weight loss), mediastinal + abdominal lymphadenopathy, hepatosplenomegaly, and serosal effusions (pleural + ascitic) are a textbook constellation for lymphoma with serosal/lymphangitic spread (Goldman-Cecil Medicine; Fischer's Mastery of Surgery, B-symptom staging). Smooth septal thickening with GGO can represent pulmonary lymphangitic infiltration by lymphoma, not just infection or edema.
Visceral leishmaniasis (kala-azar) — prolonged fever with marked hepatosplenomegaly is classic; worth asking about residential/travel exposure to endemic belts, and checking a CBC for pancytopenia, though it does not typically explain mediastinal lymphadenopathy or lung GGO as well as the first two.
Secondary hemophagocytic lymphohistiocytosis (HLH) — can be triggered by TB, lymphoma, or leishmania itself; consider if cytopenias, high ferritin, or hypertriglyceridemia are found, since it changes urgency of management.
Less likely but worth excluding: enteric fever with hepatic/splenic involvement, disseminated fungal infection (if immunocompromised/HIV), sarcoidosis (less likely given short symptom duration and ascites, which is atypical for sarcoid).

Recommended next steps

Tissue diagnosis is the priority. The 23 x 15 mm subcarinal node is large and accessible — EBUS-TBNA or mediastinoscopic biopsy would let you distinguish TB (caseating granulomas, AFB/CBNAAT-GeneXpert positive) from lymphoma (flow cytometry/histopathology) in one procedure. This is the single most useful next test given the differential is dominated by these two entities.
Repeat/dedicated abdominal imaging: since the CT already shows hepatosplenomegaly + ascites that the USG apparently missed, get a contrast-enhanced CT abdomen (or a repeat, careful USG) to characterize the liver/spleen and any abdominal nodes, and to guide diagnostic ascitic tap (cell count, SAAG, ADA for TB, cytology for malignancy).
Labs: CBC with peripheral smear (cytopenias, atypical lymphocytes), ESR/CRP, LDH (very useful — high in both lymphoma and disseminated TB/HLH), LFTs, ferritin + triglycerides (if HLH suspected), HIV test, blood cultures, Mantoux/IGRA, sputum/BAL for AFB smear and CBNAAT.
Bone marrow aspirate/biopsy is a strong consideration if peripheral cytopenias are present — it can simultaneously diagnose TB, lymphoma/leukemia, leishmania, or HLH.
Correlate clinically for night sweats, weight loss, lymph node size trend, travel/exposure history, and HIV risk factors, all of which sharply narrow this differential.

Bottom line: the combination of prolonged fever, cough, abdominal pain, mediastinal + likely abdominal lymphadenopathy, hepatosplenomegaly, ascites, and bilateral pleural effusion with smooth septal GGO points most strongly toward disseminated tuberculosis or lymphoma with serosal involvement as the two leading diagnoses, and tissue sampling (nodal biopsy/EBUS or bone marrow) is the step that will settle it rather than further imaging alone.

Note: I did not find recent (2023-2026) systematic reviews specifically contradicting this differential framework in a quick literature check — the reasoning above is standard textbook-level differential diagnosis, not a substitute for the treating clinician's direct assessment and local epidemiology.

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