Severe edema as an immune-related adverse event following nivolumab therapy: a case report

Introduction

Immune checkpoint inhibitors (ICIs) have been reported to be effective in treating many types of cancer, including lung cancer. However, ICI therapy is associated with various immune-related adverse events (irAEs) that can affect all organs and be life-threatening (1). Serous membranes can also be affected by ICI-related immunological reactions, leading to fluid retention. However, few reports have described peripheral edema as a manifestation of irAEs. We present the case of a patient who developed generalized edema and weight gain as irAEs, posing diagnostic and therapeutic challenges. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-298/rc).

Case presentation

A 78-year-old man was admitted to our hospital because of a hilar lymph node mass detected on computed tomography at his annual follow-up (Figure 1A). He had undergone left upper partial resection for lung cancer 12 years ago (Figure 1B). However, he developed recurrence and underwent right lower partial resection 2 years later (Figure 1C) followed by five courses of chemotherapy with carboplatin plus paclitaxel. No new lesions were observed after chemotherapy, and the patient was followed up at another hospital. Endobronchial ultrasound-guided transbronchial needle aspiration of the hilar lymph node confirmed carcinoma recurrence. Because the patient had been treated with carboplatin and paclitaxel, nivolumab therapy was initiated. On day 36 after the initial treatment, the patient was admitted to our hospital because of worsening edema in both legs and a weight gain of 7.5 kg. Cardiac or renal dysfunction induced by nivolumab was initially considered a possible cause of edema; however, no abnormalities were found in these organs. Serum electrolyte levels, creatinine, and blood urea nitrogen were measured shortly after admission and were all within normal limits. Transthoracic echocardiography also revealed no abnormal findings. Computed tomography revealed subcutaneous edema (Figure S1). We initiated treatment with furosemide and tolvaptan for the edema; nevertheless, adequate improvement was not observed. Hypoalbuminemia and pleural effusion developed after hospitalization and required frequent albumin administration and thoracentesis. Because there was a report of protein-losing enteropathy due to ICIs (2), abdominal scintigraphy with Technetium (99mTc) Human Serum Albumin was performed; however, no abnormalities were noted. The causes of edema and weight gain were examined in many aspects and concluded to be ICI-induced edema. We initiated prednisolone (PSL) administration 70 days after the initial treatment. Edema and weight gain alleviated rapidly after PSL initiation, eliminating the need for further intervention for the pleural effusion. The patient was discharged to his home on day 99 after the initial treatment. PSL was gradually tapered in the outpatient setting, and there was no recurrence of edema or weight gain during follow-up (Figure 2). The patient was followed up without treatment; however, five months after discharge from the hospital, a new lesion was detected and treatment with nab-paclitaxel was initiated.

Figure 1 Radiological findings of the patient. (A) Chest computed tomography showing a lymph nodal mass in the pulmonary hilum (arrowhead). (B) The patient underwent left upper partial resection for lung cancer (arrowhead) 12 years ago (pT1aN0M0 Stage IA). (C) He underwent right lower partial resection for recurrence (arrowhead) 10 years ago.

Figure 2 Clinical course of the case after admission. The blue line indicates body weight, and the burgundy line indicates serum albumin levels. PSL, prednisolone.

All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Edema results from an imbalance in the filtration system between the capillary and interstitial spaces, causing peripheral edema, ascites, pleural effusion, pericardial effusion, and capillary leak syndrome. The fluid balance between the interstitial space and plasma is influenced by factors such as hydrostatic pressure, differences in oncotic pressures, and hydraulic and oncotic permeabilities of the blood vessel wall. The fluid in extravasation is typically balanced through reabsorption mediated by oncotic pressure and drainage via lymphatic vessels. Disturbances in this balance that increase net filtration from the vascular space or hinder the return of fluid by lymphatics from the extravascular space result in edema. The common causes of edema include heart failure, kidney disease, cirrhosis, and the use of medications that can induce peripheral edema.

Drug-induced edema can be classified according to four mechanisms: pre-capillary vasodilation (vasodilatory edema), sodium and/or water retention (renal edema), lymphatic insufficiency (lymphedema), and increased capillary permeability (permeability edema) (3). Drug-induced edema can vary in terms of mechanism, severity, and clinical presentation. In patients with cancer, many anticancer drugs can cause permeability edema or lymphedema. ICIs are widely used to treat various types of cancers; as a result, there have been numerous reports of irAEs. A systematic review found that patients treated with anti-programmed cell death (ligand) 1 [PD-(L)1] inhibitors, anti-CTLA-4 inhibitors, and a combination of immunotherapy and chemotherapy developed Grade  ≥3 irAEs at rates of 14% (95% CI: 12–16), 34% (95% CI: 27–42), and 46% (95% CI: 40–53), respectively (1). Recently, the concept of ICI-induced edema has been proposed. Zierold et al. reported three patients with ICI-induced edema (4), and Velev et al. reported that 20 out of 6,633 patients in a French database developed ICI-induced edema (5). The clinical characteristics of these 23 patients and of our patient are summarized in Table 1. The median age of the patients (range) was 62 (26–81) years, and 12 (50%) were female. Weight gain at the time of ICI-induced edema diagnosis ranged from 2 to 30 kg. The onset of ICI-induced edema after the first ICI administration ranged from 4 to 121 weeks, and 19 (79.1%) patients were treated with steroids. The common treatments for edema include identification of the underlying disease, restriction of salt intake, and the use of diuretics to promote dehydration (6,7). In this case, we initially considered the common causes of edema such as congestive heart failure and renal impairment, followed by hypothyroidism and proteinuria syndrome as potential manifestations of irAEs; however, they were ruled out on further examination. Treatment with diuretics and albumin was ineffective, and the patient was diagnosed with ICI-induced edema. The edema was alleviated shortly after the initiation of steroid treatment. In this case, since lymphedema was not observed, we hypothesized that endothelial injury associated with irAE, leading to increased vascular permeability, was the primary mechanism underlying the edema. ICI-induced edema has been sporadically reported in the literature, with most reports focusing on pericardial or pleural effusions. In this case, pleural and pericardial effusions were observed during hospitalization. Pleural effusion can lead to respiratory failure, while pericardial effusion can result in cardiac tamponade. ICI-induced edema may serve as a precursor to these more severe irAEs. If ICI-induced edema is suspected, steroid administration should be actively considered, because it differs from the standard treatment for normal edema.

Conclusions

ICIs are widely used in the management of various types of cancers, and our knowledge of irAEs is increasing. However, few case reports of ICI-induced edema have been published. ICI-induced edema may be a sign of severe irAEs, and therefore, it is necessary to take appropriate action at an early stage.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-298/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-298/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-298/coif). The authors have no conflicts of Interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work and for ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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