Checkpoint Inhibitor Pneumonitis With Pneumomediastinum Following Nivolumab-AVD in Classical Hodgkin Lymphoma: A Case Report

Checkpoint Inhibitor Pneumonitis With Pneumomediastinum Following Nivolumab-AVD in Classical Hodgkin Lymphoma: A Case Report | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 13 November 2025 V1 Latest version Share on Checkpoint Inhibitor Pneumonitis With Pneumomediastinum Following Nivolumab-AVD in Classical Hodgkin Lymphoma: A Case Report Authors : Siddarth R. Ganesh , Aaron Hodes , and Burton Appel [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.176304435.59932745/v1 342 views 124 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Immune checkpoint inhibitors have transformed cancer treatment but may cause immune-related toxicities even after therapy completion. A young patient with classical Hodgkin lymphoma developed checkpoint inhibitor pneumonitis with pneumomediastinum following nivolumab-AVD. She presented with progressive dyspnea and imaging that revealed right lower lobe consolidation with mediastinal air extending into the neck. Esophagram ruled out perforation, and symptoms improved rapidly with intravenous corticosteroids followed by an oral taper. This case describes a rare presentation of immunotherapy-related toxicity in a younger patient and reflects the need for vigilance as immunotherapy use expands across age groups and malignancies. Title: Checkpoint Inhibitor Pneumonitis With Pneumomediastinum Following Nivolumab-AVD in Classical Hodgkin Lymphoma: A Case Report Siddarth R. Ganesh 1 , Aaron Hodes 2 , Burton Appel 3 1 Department of Medical Sciences, Hackensack Meridian School of Medicine, Nutley, New Jersey, USA 2 Department of Radiology, Hackensack University Medical Center, Hackensack, NJ 3 Division of Pediatric Hematology/Oncology, Joseph M. Sanzari Children’s Hospital, Hackensack, NJ Text Word Count: 1,038 Figure Count: 2 Reference Count: 30 Running Title: Immunotherapy-Related Pneumomediastinum Keywords: immune checkpoint inhibitor, pneumonitis, pneumomediastinum, classical Hodgkin lymphoma, nivolumab Abbrevation Full Term ICI Immune checkpoint inhibitor irAEs Immune-related adverse events CIP Checkpoint inhibitor pneumonitis cHL Classical Hodgkin lymphoma N-AVD Nivolumab plus doxorubicin/vinblastine/dacarbazine RLL Right lower lobe NSCLC Non-small cell lung cancer Abstract Immune checkpoint inhibitors have transformed cancer treatment but may cause immune-related toxicities even after therapy completion. A young patient with classical Hodgkin lymphoma developed checkpoint inhibitor pneumonitis with pneumomediastinum following nivolumab-AVD. She presented with progressive dyspnea and imaging that revealed right lower lobe consolidation with mediastinal air extending into the neck. Esophagram ruled out perforation, and symptoms improved rapidly with intravenous corticosteroids followed by an oral taper. This case describes a rare presentation of immunotherapy-related toxicity in a younger patient and reflects the need for vigilance as immunotherapy use expands across age groups and malignancies. Introduction Immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1, and CTLA-4 have transformed cancer care by enabling durable antitumor responses across multiple malignancies 1–7 . This immune activation carries a distinct profile of immune-related adverse events (irAEs) that may affect any organ system 1,3,7–10 . Among pulmonary irAEs, checkpoint inhibitor pneumonitis (CIP) is the most clinically consequential. Reported CIP rates vary by tumor type, regimen, and patient factors, with the incidence ranging from 5% to 19% 6,11,12 . Risk is increased by baseline lung disease, prior thoracic radiation, and smoking 4,8 . Onset typically occurs within 2.7-4.6 months of ICI initiation, though later presentations occur 13 . Radiographic patterns include organizing pneumonia, ground-glass opacities, hypersensitivity pneumonitis, and interstitial lung disease, making infection and tumor progression key diagnostic exclusions 1 . Corticosteroids are the first-line treatment, while refractory cases may require additional immunosuppression and often require ICI discontinuation 1,2,5 . Pneumomediastinum has been reported rarely in the setting of CIP and can be a significant factor in morbidity/mortality 1,3,8,10 . In classical Hodgkin lymphoma (cHL), 9p24.1 alterations drive PD-L1/PD-L2 overexpression and sensitivity to PD-1 blockade 14 . A recent study demonstrated that nivolumab plus doxorubicin/vinblastine/dacarbazine (N-AVD) significantly improved progression-free survival with infrequent (<3%) pulmonary irAEs 14 . As real-world experience using ICIs as first-line treatment for cHL increases, the true incidence of CIP may be higher. Here we report the first case of CIP with pneumomediastinum in a young adult following successful treatment for high-stage cHL. Case Presentation A 16-year-old female was diagnosed with stage IIIA nodular-sclerosing cHL after presenting with dyspnea. Imaging revealed an anterior mediastinal mass occupying one-third of the thorax; biopsy of a supraclavicular node confirmed cHL. She was treated with N-AVD; one nivolumab dose was held for laboratory evidence of hypothyroidism. End-of-therapy PET/CT demonstrated complete metabolic response; no radiation was given. Three months after therapy completion she presented with worsening dyspnea. CT showed pneumomediastinum extending into the neck and retropharyngeal space with right-lower-lobe (RLL) consolidation [Fig. 1, Fig. 2]. Esophagram excluded perforation. Radiographic findings were consistent with grade 3 pneumonitis. She received IV methylprednisolone 4 mg/kg/day per guideline-based recommendations, with rapid clinical improvement and complete resolution of the pneumomediastinum on CXR within three days. She was discharged on a two-month oral prednisone taper. Follow-up imaging confirmed full resolution of the RLL consolidation. She remains in complete remission more than two years after diagnosis, with no recurrent respiratory symptoms. She continues follow-up for mild, exercise-induced asthma managed with inhaled bronchodilator therapy. Discussion CIP likely reflects unchecked T-cell activation, autoantibody augmentation, and cytokine-drive lung injury after checkpoint blockade. Bronchoalveolar lavage and biopsy studies show increased CD8+ T-cell infiltration, CD4+ T-cell imbalance, and reduced regulatory T-cells, all of which are features of lost pulmonary tolerance 3–6 . Shared T-cell receptor clonotypes between tumor and lung suggest cross-antigen activity 6 . Elevated IL-6, IL-17A, and IFN-γ have been linked to inflammation and fibrotic remodeling, while PD-1 expression on resident immune and epithelial cells may locally perturb checkpoint signaling 5–7 . Histopathology may show diffuse alveolar damage, organizing pneumonia, and nonspecific-interstitial-pneumonia-like (NSIP-like) changes correlating with imaging 5,7 . Spontaneous mediastinum, as in this case, likely reflects structural consequences of severe alveolar injury with a subsequent migration of air through the mediastinum, consistent with the Macklin effect 15 . Widespread mucosal or alveolar failure can result in systemic air-leak syndromes, including concurrent pneumoperitoneum and pneumatosis intestinalis 16,17 . Less commonly, extrapulmonary irAEs can introduce mediastinal air secondarily, highlighting both pulmonary and gastrointestinal routes in checkpoint inhibitors toxicity 18 . Although rare, pneumomediastinum has been increasingly recognized with ICI treatment across cancer types with a range of outcomes. Previous reports have all occurred in patients 50 years of age and older, and most of these cases have been fatal. In one of the earliest autopsy-correlated cases, a 67-year-old man with metastatic non-small cell lung cancer (NSCLC) on pembrolizumab developed tension pneumothorax and pneumomediastinum, with histologic evidence of diffuse alveolar damage despite corticosteroid therapy 19 . A 73-year-old male with NSCLC developed diffuse alveolar damage with bilateral pneumothoraces and died despite high-dose steroids and mycophenolate 20 . An 87-year-old male with metastatic colorectal cancer on pembrolizumab developed pneumomediastinum secondary to ICI-associated pneumonitis shortly after bronchoscopy, but he remained clinically stable and improved with conservative management and corticosteroid taper 21 . A 72-year-old male with renal cell carcinoma on pembrolizumab developed recurrent steroid-refractory pneumonitis progressing to pneumomediastinum and succumbed to respiratory failure 22 . In autoimmune-predisposed settings, a 55-year-old female positive for anti-MDA5 antibodies developed rapidly progressive interstitial pneumonitis complicated by pneumomediastinum despite pulse steroids, tacrolimus, and cyclophosphamide, resulting in death 23 . Extrapulmonary irAEs may also cause secondary air-leak syndromes. For example, a 58-year-old male with ICI-induced ulcerative gastritis and perforation developed pneumomediastinum 18 . A 50-year-old female with triple-negative breast cancer on pembrolizumab developed extensive air-leak syndrome, including pneumomediastinum, pneumoperitoneum, and pneumatosis intestinalis, which resolved with conservative management 24 . High-resolution CT is used as the primary diagnostic test for CIP, revealing organizing-pneumonia-like or ground-glass patterns most commonly, followed by NSIP-like and ARDS-like changes that correlate with disease severity 10,25,26 . When pneumomediastinum is detected, esophageal perforation should be ruled out with contrast esophagram or CT with oral contrast. When pneumomediastinum accompanies CIP, management focuses on aggressive treatment of the underlying pneumonitis plus supportive measures: oxygen therapy, cough suppression, analgesia, and avoidance of unnecessary positive-pressure ventilation that could worsen air dissection. Therapy may include ICI discontinuation with high-dose corticosteroid (1-4 mg/kg/day prednisone equivalent) administration for more extensive CIP, with consideration of second-line immunosuppressants for refractory cases 1,13,26,27 . Surgical consultation is prudent for tension physiology or large/complicated pneumothoraces, though most cases are managed more conservatively 1,21,24 . Risk-stratification and early detection efforts with biomarkers (IL-6, anti-CD74) as well as AI-assisted CT are promising avenues to identify high-risk patients and guide earlier escalation 5,6 . Immunotherapy has transformed frontline therapy for classical Hodgkin lymphoma with improved efficacy and a favorable short-term safety profile 14,28–30 . However, serious pulmonary irAEs can occur even in younger patients without underlying lung disease. This case illustrates the first report of pneumomediastinum complicating CPI-induced pneumonitis in a young patient with cHL. Clinicians should maintain a high index of suspicion for CIP and pneumomediastinum in symptomatic patients on or recently completing ICI therapy and promptly exclude alternative diagnoses. 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Toxicity of Immune-Checkpoint Inhibitors in Hematological Malignancies. Front Pharmacol . 2021;12:733890. doi:10.3389/fphar.2021.733890 Figure Legends Figure 1: Coronal CT image showing RLL consolidation pneumonitis (depicted inside blue polygon) and pneumomediastinum (indicated by orange). Orange arrows show pneumomediastinum extending into the neck and the orange polygon depicts pneumomediastinum extending inferiorly. Figure 2: Transverse CT image showing pneumomediastinum (depicted by orange polygon) posterior to the trachea, tracking superiorly from the chest. Information & Authors Information Version history V1 Version 1 13 November 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords hodgkin's disease immunotherapy oncology pediatric oncology Authors Affiliations Siddarth R. Ganesh Hackensack Meridian School of Medicine View all articles by this author Aaron Hodes Hackensack Meridian Hackensack University Medical Center View all articles by this author Burton Appel [email protected] Hackensack Meridian Joseph M Sanzari Children's Hospital View all articles by this author Metrics & Citations Metrics Article Usage 342 views 124 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Siddarth R. Ganesh, Aaron Hodes, Burton Appel. Checkpoint Inhibitor Pneumonitis With Pneumomediastinum Following Nivolumab-AVD in Classical Hodgkin Lymphoma: A Case Report. Authorea . 13 November 2025. DOI: https://doi.org/10.22541/au.176304435.59932745/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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