The advent of immune checkpoint inhibitors (ICIs) has ushered in a new era of treatment options for patients with cancers of all types. While their success is undeniable, these therapies may come with treatment-altering complications. Due to their stimulation of the immune system, ICIs may cause the immune system to go into overdrive, leading to a variety of adverse effects commonly referred to as immune-related adverse events (irAE). While pulmonologists typically encounter inflammatory pneumonitis as a common complication, recent literature has highlighted a rarer yet significant issue: ICI-mediated pleural effusions, the etiologies of which remain unclear. Lack of prompt recognition and appropriate management may also have serious consequences for patients.

ICI-mediated pleural effusions often cause both a diagnostic and therapeutic conundrum for the treating pulmonologist and the oncology teams. New pleural effusions in the context of malignancy often raise concern for the development of a malignant or paramalignant effusion and may be mislabeled as such. However, clinicians should be cognizant of other potential causes of pleural effusions in this context to avoid the pitfall of anchoring bias. Thus, ICI-mediated effusions often require a thorough workup and evaluation to exclude malignancy. Thoracentesis is often necessary early in the evaluation, but other invasive procedures may be necessary, including pleural biopsy. The time course for these effusions can be quite variable as well, occurring at various points of the patient’s disease and treatment processes and raising concern for progression of disease or treatment failure. Additionally, ICI-mediated pleural effusions may present in a variety of ways, from lymphocytic exudative effusions to chylothorax or even eosinophilic effusions.^1–4 Given that cytology will be negative in these situations, pleural biopsy may be necessary before the final diagnosis is made.

Once the diagnosis is made, the treating clinician is then posed with a new challenge: appropriate management of ICI-mediated effusions. These effusions have a high likelihood of recurrence for a protracted time, necessitating management strategies that alleviate and prevent patient dyspnea and preserve quality of life. Clinicians should be comfortable with early referral for evaluation and management of these entities, including medical therapies (eg, steroids, diuretics) and potential procedural interventions such as insertion of a tunneled pleural catheter, medical thoracoscopy, and/or pleurodesis. Serial imaging with CT scans or ultrasound may be necessary to evaluate treatment response. One must also consider if there needs to be a change in therapy once a patient has developed an irAE in collaboration with the patient’s treating oncologist.

Pulmonologists and the medical oncology community must start to consider pleural complications as a potential risk of ICI therapy and work in collaboration to provide patients with appropriate management options.

Key points

1) ICI-mediated pleural effusions can be challenging to diagnose and can present in a variety of pleural manifestations.

2) Thorough workups, including thoracenteses, possible pleural biopsies, and/or serial imaging, may often be necessary to exclude progression of malignancy.

3) A multimodal approach is needed for the management of ICI-mediated effusions, which may include a combination of medical and procedural interventions.

1. Shen CI, Yeh YC, Chiu CH. Progressive pleural effusion as an immune-related adverse event in NSCLC: a case report. JTO Clin Res Rep. 2021;2(5):100156. doi: 10.1016/j.jtocrr.2021.100156

2. Neuville C, Aubin F, Puzenat E, Popescu D, Crepin T, Nardin C. Nivolumab-induced capillary leak syndrome associated with chylothorax in a melanoma patient: a case report and review of the literature. Front Oncol. 2022;12:1032844. PMID: 36578943; PMCID: PMC9791943. doi: 10.3389/fonc.2022.1032844

3. Veerabattini N, Katragadda R, Rosas M. More than just pneumonitis: immune checkpoint inhibitor (ICI)-related chylothorax. Chest. 2023;164(4):A3619-A3620. doi: 10.1016/j.chest.2023.07.2355

4. Lin J, Sabath BF. Chronic pleuritis and recurrent pleural effusion after atezolizumab for small cell lung cancer. Am J Case Rep. 2021;22:e933396. PMID: 34606491; PMCID: PMC8503793. doi: 10.12659/AJCR.933396