Liya Zhu1†
Jie Peng
Jinzhi Lu- 1Department of Infectious Diseases, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China
- 2Department of Obstetrics and Gynecology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China
- 3Department of Radiology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China
- 4Department of Laboratory Medicine, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China
Osimertinib-induced severe lymphocytopenia can create a profound immunodeficiency state, facilitating opportunistic infections and progressive fibrotic lung disease. A 75-year-old female with EGFR-mutant NSCLC developed respiratory failure with diffuse ground-glass opacities and profound lymphocytopenia (ALC 0.48×109/L). Overreliance on BAL-NGS detection of Mycobacterium avium complex delayed diagnosis of cytomegalovirus pneumonia. Guideline-discordant erlotinib rechallenge accelerated lymphocyte depletion, culminating in high-grade CMV viremia with CD4+ lymphocytopenia (0.16×109/L) and irreversible pulmonary fibrosis despite ganciclovir-induced virologic clearance. This case demonstrates an immune-fibrotic axis wherein TKI-induced lymphocytopenia enables CMV pneumonitis and fibrotic remodeling. Lymphocytopenia in this setting mandates urgent viral exclusion before attributing injury to drug toxicity and precludes TKI rechallenge during active infection or severe immunosuppression. BAL-NGS requires rigorous clinicoradiologic correlation.
1 Introduction
Osimertinib, a first-line therapy for EGFR-mutant non-small cell lung cancer (NSCLC), induces severe lymphocytopenia (Grade ≥3: 6.1%) (1, 2). This iatrogenic immunosuppression significantly increases susceptibility to opportunistic infections such as cytomegalovirus (CMV) pneumonitis (3, 4). In clinical practice, differentiating drug-induced interstitial lung disease (ILD) from infection remains a major challenge due to overlapping radiologic features (5, 6). This dilemma is worsened by bronchoalveolar lavage next-generation sequencing (BAL-NGS), where findings require rigorous clinicoradiologic correlation to avoid diagnostic misdirection (7). Although CMV pneumonitis has been reported with other tyrosine kinase inhibitor (TKI) classes (e.g., BCR-ABL inhibitors) (8), it is exceptionally rare with osimertinib. A systematic PubMed search for (“osimertinib”) AND (“cytomegalovirus” OR “CMV”) confirmed the absence of prior cases, and its progression to irreversible pulmonary fibrosis has not been described. We present a pivotal case of fulminant CMV pneumonitis that was misdiagnosed as Mycobacterium avium complex (MAC) infection based on BAL-NGS findings in a lymphocytopenic patient, culminating in irreversible fibrosis. This case underscores critical diagnostic pitfalls during TKI therapy and provides a stark clinical example of a lethal “immune-fibrotic axis,” demonstrating the central role of lymphocyte dynamics in driving this fatal trajectory.
2 Case presentation
2.1 Initial presentation and diagnostic dilemma
A 75-year-old non-smoking female with stage IV EGFR exon 19 deletion NSCLC lung adenocarcinoma (baseline imaging [11 September 2023]: Figure 1A) presented on 28 December 2023 with acute fever, debilitating dyspnea at rest (mMRC grade 4), dry cough, and anorexia 12 days after osimertinib discontinuation (80 mg/day for 1 month). Physical examination revealed tachypnea (28 breaths per minute), tachycardia (110 beats per minute), and coarse crackles on auscultation bilaterally. Thoracic Computed Tomography (CT) revealed new diffuse bilateral ground-glass opacities (GGOs) with smooth interlobular septal thickening (Figure 1B), accompanied by profound lymphocytopenia (absolute lymphocyte count [ALC] 0.48 × 109/L [baseline 1.87 × 109/L]) and elevated C-reactive protein (47.81 mg/L). Despite a clinical triad suggestive of infection, the initial diagnosis favored drug-induced ILD, delaying virologic assessment.
Figure 1. Sequential thoracic CT in EGFR-mutant lung adenocarcinoma with CMV pneumonitis. (All images: lung window [WW 1500, WL -600]). (A) Baseline (11 Sep 2023): Spiculated right hilar mass (47×37 mm) with interlobular septal thickening suggests lymphangitic carcinomatosis. (B) Acute pneumonitis (28 Dec 2023): Diffuse bilateral ground-glass opacities (GGOs) with septal thickening and reticulation. (C) Progressive damage (12 Jan 2024): Increased GGO density with peribronchovascular crazy-paving pattern. (D) Fibrosing phase (18 Feb 2024): Subpleural and peribronchovascular consolidations with reticulation. BAL confirmed CMV viremia (20,000 copies/mL). (E) Post-inflammatory fibrosis (1 May 2024): Irreversible architectural distortion with traction bronchiectasis. BAL, bronchoalveolar lavage; CMV, cytomegalovirus; DAD, diffuse alveolar damage; EGFR, epidermal growth factor receptor; GGO, ground-glass opacity; TKI, tyrosine kinase inhibitor; WL, window level; WW, window width.
2.2 Diagnostic misdirection and management missteps
Although BAL-NGS identified MAC DNA (12,853 copies/mL; 5 January 2024), the BAL cellular profile (neutrophilia 32%) and the absence of cavitation on imaging were inconsistent with typical MAC infection. Subsequent management preceded viral exclusion: viral PCR was not urgently performed despite severe lymphocytopenia (ALC <0.5×109/L), and erlotinib was rechallenged (7 January 2024) before infection exclusion, inducing rapid lymphocyte depletion (ALC decline 2.13→1.28×109/L; 39.9% reduction; see Figure 2). Follow-up CT (12 January 2024) showed progressive crazy-paving patterns and increased GGO density, indicating advancing alveolar damage (Figure 1C). This was interpreted as stabilization, reinforcing the MAC diagnosis and leading to discharge (16 January 2024) on antimycobacterials.
Figure 2. Dynamics of white blood cell, absolute lymphocyte count, and CMV viremia. Serial trends in peripheral WBC and ALC (×109/L). Asterisk (*) indicates BAL-confirmed high-grade CMV viremia (20,000 copies/mL) during a period of profound CD4+ lymphocytopenia. Annotated with key clinical events. ALC, absolute lymphocyte count; BAL, bronchoalveolar lavage; CMV, cytomegalovirus; DLCO, diffusing capacity of the lung for carbon monoxide; FVC, forced vital capacity; WBC, white blood cell count.
2.3 Clinical deterioration and definitive diagnosis
Acute re-admission occurred on 18 February 2024 (10 days post-erlotinib cessation) with fever, dry cough, hypotension (96/52 mmHg), and hypoxemia (SpO2 88% on room air) requiring urgent oxygen therapy due to incapacitating dyspnea. CT showed peri-bronchovascular consolidations with early reticulation and cord-like shadows (Figure 1D). BAL-PCR confirmed high-level CMV viremia (20,000 copies/mL) and profound CD4+ lymphocytopenia (0.16×109/L), following a non-diagnostic lung biopsy that had revealed only non-specific interstitial inflammation. This severe immunosuppression likely resulted from the synergistic interplay of erlotinib-induced lymphotoxicity, uncontrolled CMV dissemination, and prolonged corticosteroid exposure (Figure 2). Serologic tests for viral hepatitis, EBV, HIV, Leishmania, Cryptococcus, and bunyaviruses were negative. Full-dose ganciclovir (5 mg/kg IV q12h) initiated on 21 February 2024 achieved virologic clearance (<500 copies/mL) by day 7 and complete symptom resolution by day 21.
2.4 Treatment response and irreversible sequelae
Despite discharge on 8 March 2024, follow-up CT (1 May 2024) confirmed irreversible fibrotic remodeling with traction bronchiectasis and reticulation (Figure 1E), resulting in permanent respiratory impairment (FVC 48%, DLCO 42%) and functional disability, requiring long-term supplemental oxygen (2–4 L/min) for minimal activities of daily living. The stability of these fibrotic changes on a subsequent CT (12 March 2025) confirmed their irreversible nature. A comprehensive chronology is summarized in Table 1.
Table 1. Clinical timeline of EGFR-mutant NSCLC with treatment complications.
3 Discussion
3.1 Diagnostic pitfalls: overreliance on BAL-NGS and delayed viral testing
This case elucidates a critical immune-fibrotic axis wherein TKI-induced lymphocytopenia drives fulminant viral pneumonitis and irreversible pulmonary fibrosis. The interplay between targeted therapy, immunosuppression, and fibrotic remodeling highlights the role of immune homeostasis in lung pathogenesis (9). Retrospectively, the entire clinical course represented a unified trajectory of progressive CMV pneumonitis—initially attributed to drug toxicity then interpreted as MAC infection—rather than discrete events (5, 6). This delay permitted unimpeded viral propagation in an immunocompromised host, which ultimately led to fibrosis.
3.2 The keystone mechanism: CD4+ T-cell depletion as the central mediator of the immune-fibrotic axis
Osimertinib is clinically associated with a high incidence of severe lymphocytopenia (1, 10), which has been significantly correlated with poorer survival outcomes in patients with EGFR-mutant NSCLC (10, 11). A similar trend of hematologic toxicity is also observed with erlotinib (12). These agents directly induce lymphocyte apoptosis by inhibiting EGFR-dependent survival signals (13–15), which in our patient resulted in profound CD4+ T-cell depletion (nadir 0.16×109/L). This created an immunodeficiency state severe enough to be compared to advanced HIV (CD4+ <0.2×109/L) (3, 16), crippling antiviral surveillance and permitting uncontrolled CMV replication (3, 4). Beyond infection risk, this lymphocytopenia fundamentally disrupted immune-mediated fibrotic regulation (17). The critical loss of CD4+ T cells, particularly regulatory T cells and IFN-γ-producing effectors, removed essential anti-fibrotic brakes. IFN-γ is a potent inhibitor of fibroblast proliferation and collagen synthesis (18, 19); its deficiency created a permissive environment for unchecked fibrogenesis.
3.3 Convergent profibrotic pathways: a hypothetical framework
While the present case lacks direct measurements of TGF-β or other profibrotic mediators, the postulated pathways discussed below represent a plausible and literature-supported hypothesis for the observed irreversible fibrotic outcome. Fibrosis progression resulted from the convergence of viral, immunological, and hypoxic pathways within the immunosuppressed microenvironment. CMV infection directly amplified fibrotic signaling by upregulating TGF-β, a master regulator of fibroblast-to-myofibroblast differentiation and ECM deposition (20–23). Concurrently, viral immunopathology and tissue injury promoted M2 macrophage polarization (24) and potentially neutrophil extracellular trap (NET) release (25, 26), generating a cascade of pro-fibrotic mediators including PDGF and CTGF. Persistent alveolar injury led to chronic hypoxia, stabilizing HIF-1α, which synergizes with TGF-β to enhance myofibroblast activity and suppress apoptosis (27, 28). This multifactorial process, unleashed in the context of failed immune regulation, ultimately drove irreversible fibrotic remodeling (29). A schematic summarizing this proposed ‘immune-fibrotic axis’ is provided in Supplementary Figure S1.
3.4 Clinical implications and proposed management strategies
This case compels a re-evaluation of management strategies for TKI-related pulmonary complications toward an immune-aware approach, particularly since existing guidelines offer no specific directives for this clinical scenario (5, 30). Profound lymphocytopenia (ALC <0.5×109/L) should be recognized not as an incidental laboratory abnormality but as a state of significant immunodeficiency (2, 3, 31, 32). We propose an integrated strategy (Table 2) including: (1) urgent CMV and PJP PCR testing in symptomatic, lymphopenic patients before attributing lung injury to drug toxicity (2, 31, 33, 34); (2) avoiding TKI rechallenge during active infection or persistent severe lymphocytopenia (ALC <0.5×109/L)—a critical measure whose omission led to life-threatening CMV pneumonitis here, aligning with NCCN guidelines (5, 30); (3) rigorous clinicoradiologic correlation for interpreting BAL-NGS findings to avoid diagnostic errors (5, 7, 30, 35); and (4) serial immune monitoring (ALC and CD4+ counts) for risk stratification and early intervention (1, 2, 4, 10). Future studies should investigate whether prophylactic or pre-emptive antiviral strategies can mitigate lung injury in this high-risk population. The patient’s perspective is reflected in her functional decline (mMRC dyspnea scale) and the profound impact on her quality of life, evidenced by permanent supplemental oxygen requirement for minimal daily activities and subsequent transition to palliative care.
Table 2. Summary of clinical scenario, pitfall, and recommended action.
In conclusion, despite the limitations of a single-case retrospective design and non-diagnostic histopathology, this case illustrates how targeted therapy disrupts lymphocyte dynamics, permitting opportunistic infections and initiating a self-perpetuating cycle of inflammatory fibrosis. Understanding this immune-fibrotic axis is key to developing improved preventive and therapeutic strategies.
Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.
Ethics statement
The studies involving humans were approved by This retrospective case analysis received ethical approval from the Institutional Review Board of The First Affiliated Hospital of Yangtze University (Approval No. KY2025-042-01). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent has been obtained from the patient for the publication of this case report.
Author contributions
LZ: Data curation, Investigation, Writing – original draft. DL: Investigation, Data curation, Writing – original draft. JP: Resources, Visualization, Writing – original draft. JL: Conceptualization, Supervision, Writing – original draft, Writing – review & editing.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This research was funded by the Hubei Clinical Medicine Research Center for individualized cancer diagnosis and therapy.
Conflict of interest
The authors declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2025.1702074/full#supplementary-material
Supplementary Figure 1 | Proposed “Immune-Fibrotic Axis”. The hypothesized cascade from TKI-induced CD4+ T-cell depletion leads to uncontrolled cytomegalovirus (CMV) pneumonitis, driving profibrotic signaling and irreversible pulmonary fibrosis. ECM, Extracellular Matrix; NET, Neutrophil Extracellular Trap.
Abbreviations
ALC, Absolute Lymphocyte Count; BAL, Bronchoalveolar Lavage; BAL-NGS, Bronchoalveolar Lavage Next-Generation Sequencing; CD4, Cluster of Differentiation 4; CMV, Cytomegalovirus; CRP, C-Reactive Protein; CT, Computed Tomography; DAD, diffuse alveolar damage; DLCO, Diffusing Capacity of the Lung for Carbon Monoxide; EGFR, Epidermal Growth Factor Receptor; ESMO, European Society for Medical Oncology; FVC, Forced Vital Capacity; ILD, Interstitial Lung Disease; IV, Intravenous; MAC, Mycobacterium avium Complex; mMRC, modified Medical Research Council Dyspnea Scale; NGS, Next-Generation Sequencing; NSCLC, Non-Small Cell Lung Cancer; O2, Oxygen; SpO2, Peripheral Capillary Oxygen Saturation; PCR, Polymerase Chain Reaction; PJP, Pneumocystis jirovecii Pneumonia; TGF-β, Transforming Growth Factor-beta; TKI, Tyrosine Kinase Inhibitor. IASLC, International Association for the Study of Lung Cancer; WL, window level; WBC, White Blood Cell Count; WW, window width.
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Keywords: CD4+ T-cell, CMV pneumonia, diagnostic error, drug-induced lung injury, lymphocytopenia, osimertinib, pulmonary fibrosis
Citation: Zhu L, Liu D, Peng J and Lu J (2025) Lymphocyte dynamics as the central mediator in osimertinib-induced CD4+ T-cell depletion, fulminant cytomegalovirus pneumonitis, and progressive pulmonary fibrosis: a case report. Front. Immunol. 16:1702074. doi: 10.3389/fimmu.2025.1702074
Received: 09 September 2025; Accepted: 02 December 2025; Revised: 26 November 2025;
Published: 17 December 2025.
Edited by:
Alexandre Todorovic Fabro, University of São Paulo, BrazilReviewed by:
Mohammad Asad, Albert Einstein College of Medicine, United StatesSabrina Batah, University of São Paulo, Brazil
Andrea Jazel Rodriguez Herrera, University of Sao Paulo, Brazil
Copyright © 2025 Zhu, Liu, Peng and Lu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jinzhi Lu, amluemhpbHUyMDE1QDE2My5jb20=
†These authors have contributed equally to this work