Emapalumab for Maladaptive Interferon‐γ‐Mediated Inflammation in Drug Reaction With Eosinophilia and Systemic Symptoms Complicating First‐Line Antituberculosis Therapy

To the Editor: We describe the first reported case of pulmonary tuberculosis (TB) complicated by fulminant drug reaction with eosinophilia and systemic symptoms (DRESS) in the context of markedly elevated C-X-C motif chemokine ligand 9 (CXCL9) levels. Management required multidisciplinary, intensive, and time-sensitive care, including targeted interferon (IFN)-γ neutralization with emapalumab. A 19-year-old female presented to an outside hospital emergency department complaining of 3 weeks of progressive right-sided chest pain. Social history was notable for recent homelessness, incarceration for 6 months, and multiple tattoos. On admission, computed tomography (CT) of the chest revealed a 2.5 cm thick-walled cavitary lesion in the right lower lobe (Figure 1). Further testing confirmed the diagnosis of TB. Rapid resistance testing for rifampin was negative. Radiographic and cutaneous manifestations (Days 53–55 from initial presentation). (A) Axial chest CT image demonstrating a 2.5 cm thick-walled cavitary lesion in the right lower lobe with surrounding patchy and tree-in-bud opacities. (B) Petechial-to-purpuric papules scattered over the dorsum of the right foot with associated oedema. (C) Diffuse, blanching, erythematous macules and papules on the lower abdomen. (D) Confluent, serpiginous erythema involving the volar forearm. Black rectangles obscure potentially identifying features. Composite assembled in Microsoft Paint (v 11.2503.381.0). On Day 9 from initial presentation, she was transferred to our center with persistent fevers, pleural pain, and elevated inflammatory markers. Additional work-up was unrevealing for other pathogens. Four-drug rifapentine-moxifloxacin (RPT-MOX)-based therapy was started on Day 12 of presentation, which included rifapentine 1200 mg daily, isoniazid 300 mg daily with pyridoxine 25 mg daily, pyrazinamide 1500 mg daily, and moxifloxacin 400 mg daily. She was discharged on Day 15 with explicit instructions to avoid acetaminophen. Compliance with RPT-MOX was monitored via video recordings of administration. On Day 36, she re-presented to our center with fevers, diarrhea, and pleuritic pain. CT imaging revealed a large right hydropneumothorax, small pericardial effusion, and decompression of the cavitary lesion. Pleural fluid and sputum acid-fast bacilli stains were negative. Over the next week, she had daily fevers, developed a fleeting morbilliform truncal rash (Day 39), and had a negative evaluation for drug-induced lupus and viral infections. On Day 48, she developed acute decompensated shock (lactate 13.3 mmol/L), acute liver failure (aspartate aminotransferase 1210 units/L, alanine aminotransferase 763 units/L, total bilirubin 7.2 mg/dL, international normalized ratio 3.1, ammonia 96 µmol/L), acute kidney injury (creatinine 2.0 mg/dL), and neutropenic leukopenia. She was intubated and treated with vasopressors, stress-dose hydrocortisone, and broad-spectrum antibiotics. First-line TB drugs were suspended. Continuous renal-replacement therapy (CRRT) and molecular adsorbent recirculating system (MARS) were initiated on Day 49. Laboratory studies showed CXCL9 level above the assay's upper reportable limit of 608,000 pg/mL, and elevated soluble interleukin-2 receptor alpha (sIL2RA) at 22,655 units/mL, IL-18 at 2868 pg/mL, and ferritin at 3829 ng/mL. A single 10 mg/kg dose of emapalumab was given on Day 50. Repeat CXCL9 drawn prior to emapalumab administration on Day 50 was 48,676 pg/mL. Figure 2 depicts notable lab results over time. Laboratory trends and clinical milestones (Days 36–75 since first presentation). (A) Normalized trajectories of five markers. Each marker is rescaled 0–1 by its own minimum-to-maximum span. Line/point codes: Absolute eosinophil count (AEC; red circles), CXCL9 (olive triangles), erythrocyte-sedimentation rate (ESR; green squares), ferritin (blue crosses), and soluble IL-2 receptor-α (sIL-2R; magenta diamonds). Black dashed vertical lines mark major clinical events. (B) Raw values for four panels: C-reactive protein (CRP), absolute neutrophil count (ANC), alanine/aspartate aminotransferases (ALT/AST), and serum creatinine. Blue lines trace individual results; salmon-tinted ribbons indicate our institutional reference ranges. Figure produced in R 4.3.2 with ggplot2 v3.5.0 in RStudio (V 2024.4.0.735). Within the next 24 h, the patient was extubated and came off vasopressors. Both CRRT and MARS were discontinued on Day 52; CXCL9 fell to 24,059 pg/mL on Day 51. Treatment for TB was changed to ethambutol and levofloxacin on Day 50, followed by the addition of linezolid on Day 54 with normalization of absolute neutrophil count. Rapid whole-exome sequencing was unrevealing. Blood, urine, and pleural fluid cultures showed no microbial growth. On Day 53, a generalized purpuric rash appeared (Figure 2) after stress-dose hydrocortisone was discontinued on Day 52, accompanied by eosinophilia (0.8 × 103 cells/µL) and the appearance of atypical lymphocytes (16.1% on Day 49). Using Registry on Severe Cutaneous Adverse Drug Reactions (RegiSCAR) criteria [1], her score of 7 (i.e., 2 points for internal organs involvement; 3 points for fever, eosinophilia, and atypical lymphocytes; and 2 points for skin rash) indicated definite DRESS, attributed to her first-line anti-TB drugs. Methylprednisolone 1 mg/kg/day was started on Day 54, with ensuing improvement in transaminases, renal function, and rash. By Day 57, she was discharged from intensive care. Liver enzymes and creatinine normalized over the next week; CXCL9 fell to 282 pg/mL and sIL2RA to 586 units/mL by Day 71, paralleling her clinical improvement. A slow 10 mg/week prednisone taper over 10 weeks was arranged. Therapy for TB was transitioned to BPaL (bedaquiline, pretomanid, linezolid) that started prior to discharge, on Day 76. DRESS is a life-threatening idiosyncratic hypersensitivity marked by fever, rash, hematologic shifts, lymphadenopathy, and visceral involvement, features quantified by the RegiSCAR score [1]. IFN-γ drives control of Mycobacterium TB, and serum CXCL9 mirrors its bioactivity, falling with adequate therapy and spiking during unchecked inflammation [2, 3]. While the patient fulfilled definite RegiSCAR criteria for DRESS, a paradoxical reaction following initiation of TB treatment, another IFN-γ–mediated process, may have contributed and potentially coexisted with DRESS in this case, reinforcing the centrality of dysregulated IFN-γ signaling [4]. This case shows how real-time cytokine profiling can guide immunomodulation when first-line antitubercular drugs trigger fulminant DRESS [5]. The syndrome typically appears 3–6 weeks after therapy starts, matching the 24-day latency observed [6]. Pathogenesis often combines drug-specific T-cell activation, viral reactivation, and host factors, producing T-helper cell type 2- (Th2-) mediated inflammatory response alongside Th1/IFN-γ signaling [7]; the latter may explain why, in its severest form, DRESS mimics hemophagocytic lymphohistiocytosis, an approved indication for emapalumab [8, 9]. Emaplumab use has not previously been reported in active TB or DRESS [10-12]. Of note, in this patient, Th2-associated mediators were not profiled, and activated T-cell phenotyping, which could have further supported systemic IFN-γ-driven T-cell activation, was not performed [13]. In our patient, CXCL9 rose beyond assay limits immediately before clinical decompensation. A 10 mg/kg dose of emapalumab, alongside supportive care, produced rapid hemodynamic and laboratory recovery, suggesting that short-term IFN-γ blockade can quell pathologic inflammation without undermining mycobacterial control. Given concurrent severe kidney and liver injury, transient accumulation and/or amplified production may have contributed to the extreme CXCL9 value; pediatric hematopoietic transplantation cohorts link acute kidney injury to elevations in CXCL9/CXCL10, though absolute levels reported there are far lower than in our case [14]. Nonetheless, organ support (CRRT/MARS) likely contributed to the early decline in CXCL9 that preceded emapalumab. Clinicians should monitor for DRESS during TB therapy and, when inflammation escalates, obtain timely cytokine panels. Carefully selected patients may benefit from brief IFN-γ neutralization decided with multidisciplinary expert guidance. The authors have nothing to report. This single-case report was reviewed by the Cincinnati Children's Hospital Medical Center Institutional Review Board and deemed exempt (IRB 2025-0440). In accordance with the exemption, written patient consent for publication was not obtained. The authors declare no conflicts of interest. De-identified clinical data underlying this report are available from the corresponding author upon reasonable request, subject to institutional and patient privacy regulations.