Pembrolizumab-associated eosinophilic polyserositis with pericardial involvement during adjuvant therapy for clear cell renal cell carcinoma: a case report and narrative review

Pembrolizumab-associated eosinophilic polyserositis with pericardial involvement during adjuvant therapy for clear cell renal cell carcinoma: a case report and narrative review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Pembrolizumab-associated eosinophilic polyserositis with pericardial involvement during adjuvant therapy for clear cell renal cell carcinoma: a case report and narrative review Mikel Portu, Judit Sanz-Beltran, Maria Alejandra Duarte, Julieta Navarro, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8910623/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background : Pembrolizumab is a standard adjuvant option for patients with high-risk clear cell renal cell carcinoma after nephrectomy. Serositis is an uncommon immune-related adverse event under programmed cell death 1/programmed death ligand 1 blockade. Pericardial involvement is the best-characterized serosal compartment, and cohort data suggest a several-fold increased risk of pericardial events compared with non-immune checkpoint inhibitor-treated controls. However, eosinophil percentages in serosal fluid are rarely reported, leaving the incidence and clinical significance of eosinophilic serositis poorly characterized. Case presentation: A 55-year-old man with clear cell renal cell carcinoma (metastatic disease with no evidence of disease after nephrectomy and bone metastasectomy) received adjuvant pembrolizumab (200 mg every 3 weeks) per the KEYNOTE-564 regimen. After six cycles he developed anasarca with large bilateral pleural effusions, mild ascites, and a small pericardial effusion. Pleural fluid was exudative and eosinophil-rich (20%), consistent with eosinophilic pleural effusion, with negative cytology and microbiology. Adenosine deaminase was mildly elevated (42.8 U/L) but tuberculosis evaluation was negative. Transthoracic echocardiography showed preserved biventricular function and no tamponade. Pembrolizumab discontinuation, thoracentesis, and systemic corticosteroids (methylprednisolone 1 mg/kg with taper) resulted in rapid clinical and laboratory improvement. Conclusions : This case supports pembrolizumab-associated eosinophilic polyserositis with pericardial involvement as a rare phenotype within the cardio-oncology spectrum. In a targeted review of published immune checkpoint inhibitor-associated serositis/pleuritis reports, effusion eosinophil percentage was explicitly reported in only a small minority of cases, a gap that may obscure a mechanistically and therapeutically distinct inflammatory subgroup. We provide a diagnostic and management framework and highlight emerging options, including interleukin-5 axis blockade, for eosinophil-driven disease. Immune checkpoint inhibitor immune-related adverse events serositis polyserositis eosinophilic pleural effusion pericardial effusion interleukin-5 cardio-oncology case report KEYNOTE-564 Figures Figure 1 Background The programmed cell death 1 inhibitor pembrolizumab improves disease-free and overall survival as adjuvant therapy for patients with high-risk clear cell renal cell carcinoma after nephrectomy [1–2]. Immune checkpoint inhibitors can trigger immune-related adverse events across organ systems, with management guidance from major societies [3–5]. Serosal inflammation (serositis) is increasingly recognized within the cardiovascular immune-related adverse event spectrum. Pericardial disease is the best characterized serosal compartment, supported by cohort and systematic review data [6–10]. In contrast, pleural and peritoneal involvement are supported largely by case reports and small series of polyserositis or immune-related generalized edema [11–13]. Eosinophilia is also a recognized class effect of programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade [14–16]. However, eosinophil percentages in serosal fluid are rarely reported in immune checkpoint inhibitor-associated serositis, leaving eosinophilic serositis poorly characterized, which may contribute to delayed diagnosis. We report a case of eosinophilic pleural effusion with concurrent polyserositis during adjuvant pembrolizumab and provide a narrative synthesis focused on phenotyping, differential diagnosis, and management in cardio-oncology practice. Case presentation A 55-year-old man with Wolff-Parkinson-White syndrome (treated with ablation) and active tobacco use underwent right nephrectomy for clear cell renal cell carcinoma (pT1b, grade 2). He later developed a solitary metastasis to the left proximal humerus that was completely resected with limb-sparing surgery and megaprosthesis reconstruction, achieving metastatic disease with no evidence of disease (M1-NED). Adjuvant pembrolizumab (200 mg every 3 weeks) was initiated following the KEYNOTE-564 dosing schedule (timeline in Table 1). After six cycles (approximately 18 weeks), he developed progressive scrotal and lower abdominal edema with exertional dyspnea. Computed tomography showed large bilateral pleural effusions and mild ascites without evidence of tumor progression (Figure 1). Pembrolizumab was held, and he was admitted shortly thereafter for worsening anasarca. On admission he was afebrile and hemodynamically stable, with decreased breath sounds bilaterally and prominent genital edema. Laboratory testing showed eosinophilia (absolute eosinophil count approximately 1.5 × 10^9/L), hypoalbuminemia (28 g/L [2.8 g/dL]), preserved renal function, and low inflammatory markers. Therapeutic thoracentesis removed 1.5 L of serous fluid. The pleural fluid met exudative criteria and contained 20% eosinophils, consistent with eosinophilic pleural effusion (≥10%). Cytology was negative for malignancy. Bacterial, mycobacterial, and fungal cultures were negative. Adenosine deaminase was mildly elevated at 42.8 U/L (upper limit of normal, 40 U/L), prompting careful tuberculosis exclusion, which was negative. Transthoracic echocardiography showed a nondilated left ventricle with preserved systolic function (left ventricular ejection fraction 71%), normal right ventricular size and function, no significant valvular disease, and a small anterior pericardial effusion (0.53 cm) without hemodynamic compromise. The differential diagnosis included malignant serosal involvement, infection (including tuberculosis), heart failure, nephrotic syndrome, venous thromboembolism, hepatic disease, and immune-mediated serositis. The temporal relationship to pembrolizumab, multi-compartment serosal involvement, concurrent peripheral eosinophilia, negative cytology and microbiology, absence of heart failure or renal disease, normal liver function tests with no radiologic evidence of cirrhosis, and rapid response to corticosteroids supported pembrolizumab-associated immune-mediated eosinophilic polyserositis. Pembrolizumab was permanently discontinued. The patient received therapeutic thoracentesis, diuretics, and methylprednisolone 1 mg/kg/day followed by an oral taper, consistent with guideline-based management of moderate-to-severe immune-related adverse events. Within days, dyspnea and edema improved markedly. Eosinophil counts normalized and albumin improved. At 2-week follow-up he remained stable without recurrent effusions, and prednisone taper continued. At last oncologic assessment, he remains M1-NED without evidence of disease recurrence. Discussion and Conclusions Literature review strategy To contextualize this presentation and inform the diagnostic and management recommendations below, we performed a narrative review. We searched PubMed (inception through January 2026) using combinations of “immune checkpoint inhibitor,” “serositis,” “polyserositis,” “pleural effusion,” “pericarditis,” “pericardial effusion,” “eosinophilia,” and “generalized edema.” We prioritized systematic reviews, cohort studies, and consensus guideline documents, and supplemented these with representative case reports identified from reference lists and related-article searches. We additionally included foundational sources for pleural effusion classification (Light’s criteria), eosinophilic pleural effusion definitions, and evidence on pleural adenosine deaminase and the etiologic spectrum of eosinophilic effusions [17–21]. For representative serositis case reports and small series, we assessed reporting of serosal fluid inflammatory phenotyping (whether a cell count with differential was provided) and whether an eosinophil percentage in the effusion was explicitly stated. This targeted extraction was intended to evaluate reporting practices rather than to estimate incidence. Representative reports included chronic pleuritis/pleural effusion described after atezolizumab and pembrolizumab and a nivolumab-associated pericardial effusion case report [22–24]. Serositis as an emerging cardiovascular immune-related adverse event Serosal inflammation under immune checkpoint inhibitor therapy has been recognized since the mid-2010s, initially through case reports of pericardial tamponade [25–26]. Controlled cohort data later quantified this signal: in a study comparing 2,842 immune checkpoint inhibitor-treated patients with 2,699 matched metastatic controls, immune checkpoint inhibitor exposure was associated with 1.57 pericardial events per 100 person-years and an approximately fourfold increased risk (adjusted hazard ratio 4.37, 95% confidence interval 2.09–9.14) [6]. Reported frequency varies substantially across study designs (typically <1% in clinical trials and pharmacovigilance datasets, but higher in retrospective imaging-based series when any new effusion is counted), so the true incidence likely remains underestimated [6–7]. Morbidity can be substantial: in systematic reviews of published cases, tamponade has been reported in approximately 41% and pericardiocentesis in approximately 68% [7]. Meta-analyses of cardiovascular immune-related adverse events from randomized trials and pharmacovigilance databases corroborate a clinically meaningful signal for pericardial toxicity [9–10]. Cancer-type patterns are broadly consistent across published datasets. Lung cancer predominates in pericardial immune-related adverse event series, comprising up to 81% of cases in one systematic review [7]. Melanoma is also frequently represented [7–9]. In contrast, pleural and peritoneal immune serositis lack reliable incidence estimates. These compartments are captured mainly in polyserositis case series and reports of immune-related generalized edema [11–13]. Data specific to renal cell carcinoma remain sparse, limited to isolated pericarditis case reports [27]. Clinical spectrum and timing Immune checkpoint inhibitor-related serositis spans a broad spectrum, ranging from incidentally detected small effusions to life-threatening tamponade requiring emergent drainage [7–8]. Polyserositis (simultaneous involvement of two or more serous cavities) typically presents with dyspnea, weight gain, and peripheral or genital edema and may co-occur with other immune-related adverse events [11–12]. Timing is highly variable. Many pericardial events occur early, with median onset around four treatment cycles (approximately 12 weeks) in systematic reviews [7]. However, late presentations are well documented, including cases arising after prolonged exposure or after immune checkpoint inhibitor discontinuation [12, 28]. Our patient developed symptoms after six cycles (approximately 18 weeks), consistent with this broad window. The eosinophilic dimension Eosinophilia is a recognized class effect of programmed cell death 1/programmed death ligand 1 blockade. In a national reference center series of 37 patients with moderate-to-severe immune checkpoint inhibitor-induced eosinophilia, the median absolute eosinophil count reached 2.7 × 10^9/L and peak values occurred at a median of 15 weeks after initiation. Fifty-seven percent developed eosinophil-related organ manifestations [14]. A pharmacovigilance analysis identified hundreds of eosinophil-associated adverse events across programmed cell death 1/programmed death ligand 1 inhibitors, supporting this as a class phenomenon [15]. Early reports described immune-related eosinophilia across PD-1/PD-L1 agents [16], and subsequent referral-center experience recommended routine monitoring of the absolute eosinophil count during immune checkpoint inhibitor (ICI) therapy [14]. Critically, the eosinophilic immune-related adverse event literature and the immune checkpoint inhibitor-serositis literature have evolved largely in parallel. In many published serositis cases, effusion characterization focuses on cytology and microbiology, while differential cell counts (and particularly eosinophil percentages) are absent. Conversely, eosinophil-focused series rarely report compartment-specific fluid phenotyping. This disconnect makes it difficult to estimate how often an eosinophilic serositis phenotype occurs under immune checkpoint inhibitor therapy and whether it carries distinct prognostic or therapeutic implications. Our case, with pleural fluid eosinophilia (20%) and concurrent peripheral eosinophilia, sits at this intersection and suggests that a subset of immune checkpoint inhibitor-associated polyserositis may represent a type 2-skewed, eosinophil-predominant inflammatory signature with potential mechanistic and therapeutic relevance. Pathophysiology Direct mechanistic data for serosal immune-related adverse events are limited. For pericardial disease, available biopsy and cytology data suggest a T-cell-predominant lymphocytic inflammation without malignant cells [7, 29–30]. Proposed mechanisms include loss of peripheral tolerance enabling autoreactive T-cell activation against serosal antigens, molecular mimicry between tumor neoantigens and mesothelial or stromal proteins, and amplification of local inflammatory cascades at serosal surfaces [7–8, 31]. The frequent co-occurrence of pericardial disease with myocarditis and other systemic immune-related adverse events suggests broader immune dysregulation [8–9, 31]. Eosinophilic phenotypes likely reflect activation of a type 2 immune axis, particularly interleukin-5, the principal cytokine driving eosinophil differentiation, survival, and tissue recruitment. Programmed cell death 1 blockade can augment both type 1 and type 2 immune responses. In susceptible individuals, type 2 skewing may predominate, with interleukin-4, interleukin-5, interleukin-13, and eotaxins orchestrating eosinophilic inflammation. Case-level evidence from small case series suggests that targeted interleukin-5 axis blockade (mepolizumab, benralizumab) can control severe or steroid-refractory eosinophilic immune-related adverse events and support steroid tapering [32]. Future translational work should prioritize cytokine and immune-cell profiling of serosal fluid to determine whether eosinophilic serositis represents a biologically distinct subtype with steroid-sparing therapeutic opportunities. Diagnostic approach Immune-mediated serositis remains a diagnosis of exclusion. The differential diagnosis for new effusions in patients receiving immune checkpoint inhibitors includes malignant serosal involvement, infection, heart failure, nephrotic syndrome, hepatic failure, and thromboembolism. When an eosinophilic pleural effusion is identified, the differential further expands to include drug reactions, parasitic infection, air or blood in the pleural space, pulmonary embolism, and connective tissue disease [19, 21]. We propose a systematic approach (Table 2) with four components. First, reassess cancer status and assess imaging features suggestive of malignant serosal involvement. Second, perform comprehensive serosal fluid analysis with a mandatory cell count and differential, including explicit eosinophil percentage. Third, complete microbiologic evaluation before immunosuppression. Fourth, complete compartment-specific evaluation. When the pericardium is involved, this includes electrocardiography, cardiac biomarkers, and echocardiography, with selective use of cardiac magnetic resonance imaging (CMR) and pericardiocentesis based on hemodynamic status and diagnostic uncertainty [8, 33]. For pleural fluid, adenosine deaminase can be useful to support or exclude tuberculous pleuritis, but commonly cited thresholds (e.g., 40 U/L) are not absolute and may yield false positives in malignancy and other inflammatory conditions [20]. In our case, a mildly elevated adenosine deaminase (42.8 U/L) prompted careful tuberculosis exclusion before attributing the effusion to an immune-related adverse event. The absence of malignant cells on cytology does not exclude malignant effusion and repeat sampling or tissue biopsy may be required in selected cases. Conversely, eosinophilia does not exclude malignancy, as eosinophilic effusions can occur with lung cancer and lymphoma [21]. Integration of clinical context, imaging trajectory, fluid characteristics, and response to therapy is essential. Management and emerging therapies Management depends on severity, compartment, and suspected mechanism (Table 3). Symptomatic large effusions require prompt drainage (thoracentesis, paracentesis, or pericardiocentesis/pericardial window, as indicated). For moderate-to-severe suspected immune-mediated serositis, interruption of the immune checkpoint inhibitor and systemic corticosteroids (prednisone 1-2 mg/kg/day or equivalent) are standard, followed by a prolonged taper to reduce relapse risk [3–5, 7–8]. Steroid-refractory or steroid-dependent cases require multidisciplinary input. In pericardial phenotypes, adjuncts used in idiopathic pericarditis (colchicine and/or nonsteroidal anti-inflammatory drugs) are commonly applied, acknowledging limited immune checkpoint inhibitor-specific evidence. Interleukin-1 blockade (e.g., anakinra or rilonacept) has strong evidence in idiopathic recurrent pericarditis and is highlighted in contemporary guidance. However, supporting data in immune checkpoint inhibitor-associated pericardial disease are limited, particularly for eosinophil-predominant presentations. Use remains extrapolative, and decisions should be individualized [7, 34]. Other immunosuppressants and biologics have been reported anecdotally [35–36]. When an eosinophil-driven phenotype is documented (marked peripheral eosinophilia and/or eosinophil-rich effusions), targeted interleukin-5 axis blockade (mepolizumab, benralizumab) represents a rational and increasingly evidence-supported option [32]. These agents may allow steroid sparing and, in selected situations, may facilitate continuation of oncologic therapy. We suggest considering interleukin-5 axis blockade for eosinophilic serositis that is steroid-refractory, steroid-dependent, or associated with severe hypereosinophilia. Immune checkpoint inhibitor rechallenge and the adjuvant context Most reports of severe pericardial disease (tamponade or hemodynamic compromise) or multi-compartment polyserositis describe permanent immune checkpoint inhibitor discontinuation [7, 12]. Rechallenge after resolution has been successful in selected pericardial cases, though recurrence risk remains uncertain and likely depends on severity and compartment involvement [37]. Within eosinophilic immune-related adverse events, improvement may occur despite continued immune checkpoint inhibitor exposure in some patients, whereas others relapse even after discontinuation [11, 14]. The adjuvant setting warrants particular consideration. Unlike metastatic disease, where immune checkpoint inhibition may represent a key life-prolonging option, adjuvant therapy targets recurrence risk in patients who are currently disease-free. Accordingly, the threshold for permanent discontinuation is typically lower after grade 3 or higher toxicity, particularly after severe multi-compartment involvement. In our patient, permanent discontinuation reflected this calculus after six cycles in the M1-NED setting. Implications for reporting and practice This case illustrates that immune checkpoint inhibitor-related serositis can present as a capillary leak-like phenotype with anasarca and multi-compartment fluid accumulation, similar to published reports of polyserositis and immune-related generalized edema [11–13]. The presence of eosinophilic pleural effusion with concurrent peripheral eosinophilia suggests a type 2-skewed inflammatory signature that is rarely documented in the serositis literature and may represent an underrecognized subgroup amenable to eosinophil-targeted therapy. Our targeted extraction (Table 4) highlights a practical reporting gap: eosinophil percentage in serosal fluid is often omitted. We recommend routine documentation of serosal fluid differential cell counts, including eosinophil percentage, in suspected immune checkpoint inhibitor-related effusions to facilitate phenotype recognition and future aggregation of data. Strengths of this report include the comprehensive diagnostic workup with serosal fluid phenotyping, the systematic literature review contextualizing reporting gaps, and a structured management algorithm. Limitations inherent to a single case report include the inability to establish causality definitively, the absence of serosal tissue biopsy, and the lack of cytokine profiling of the effusion fluid, which would have strengthened the mechanistic interpretation. In conclusion, pembrolizumab-associated eosinophilic polyserositis represents a rare but clinically significant immune-related adverse event that can mimic disease progression or infection. Early recognition, exclusion of malignant and infectious etiologies, and timely immunosuppression enable symptom control while informing decisions about therapy discontinuation or rechallenge. For eosinophil-driven disease, interleukin-5 axis blockade is a promising steroid-sparing option in selected cases. Patient’s perspective The patient was invited to provide a written account of his experience but declined to contribute a personal narrative. He provided written informed consent for publication of this case report. Abbreviations ADA: adenosine deaminase AFB: acid-fast bacilli ANA: antinuclear antibodies ANCA: anti-neutrophil cytoplasmic antibodies CMR: cardiac magnetic resonance CT: computed tomography CTPA: computed tomography pulmonary angiography ECG: electrocardiography FAERS: Food and Drug Administration Adverse Event Reporting System ICI: immune checkpoint inhibitor IGRA: interferon-gamma release assay irAE: immune-related adverse event LVEF: left ventricular ejection fraction M1-NED: metastatic disease with no evidence of disease NAAT: nucleic acid amplification test PD-1: programmed cell death 1 PD-L1: programmed death ligand 1 PET-CT: positron emission tomography-computed tomography TB: tuberculosis TTE: transthoracic echocardiography Declarations Ethics approval and consent to participate: Not applicable. Ethics approval was not required for this case report in accordance with local institutional policy (Comité Ético de Investigación con Medicamentos (CEIm) del Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; reference number: not applicable). Consent for publication: Written informed consent was obtained from the patient for publication of this case report and any accompanying de-identified data. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Availability of data and materials: All data generated or analyzed during this study are included in this published article and its additional file(s). Additional de-identified details are available from the corresponding author upon reasonable request. Competing interests: The authors declare that they have no competing interests. Funding: No specific funding was received for this work. Authors' contributions : MP conceptualized the report, collected clinical data, performed the literature review, and drafted the manuscript. JSB, MADB, JN, AA, PA, AFR, CR, and GA contributed to clinical data acquisition and interpretation and critically revised the manuscript for important intellectual content. PM supervised the work and critically revised the manuscript. All authors read and approved the final manuscript. Acknowledgements: Not applicable. References Choueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;385(8):683-694. Choueiri TK, Tomczak P, Park SH, et al. Overall survival with adjuvant pembrolizumab in renal-cell carcinoma. N Engl J Med. 2024;390(15):1359-1371. Schneider BJ, Naidoo J, Santomasso BD, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol. 2021;39(36):4073-4126. Haanen J, Obeid M, Spain L, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline. Ann Oncol. 2022;33(12):1217-1238. Brahmer JR, Abu-Sbeih H, Ascierto PA, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer. 2021;9(6):e002435. Gong J, Drobni ZD, Zafar A, et al. Pericardial disease in patients treated with immune checkpoint inhibitors. J Immunother Cancer. 2021;9(6):e002771. Mudra SE, Rayes DL, Agrawal A, et al. Immune checkpoint inhibitors and pericardial disease: a systematic review. Cardio-Oncology. 2024;10(1):29. Inno A, Maurea N, Metro G, et al. Immune checkpoint inhibitors-associated pericardial disease: a systematic review of case reports. Cancer Immunol Immunother. 2021;70(10):3041-3053. Dolladille C, Akroun J, Morice PM, et al. Cardiovascular immunotoxicities associated with immune checkpoint inhibitors: a safety meta-analysis. Eur Heart J. 2021;42(48):4964-4977. Salem JE, Manouchehri A, Moey M, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. 2018;19(12):1579-1589. Zierold S, Akcetin LS, Gresser E, et al. Checkpoint inhibitor-induced polyserositis with edema. Cancer Immunol Immunother. 2022;71(12):3087-3092. Sawada R, Matsui Y, Uchino J, et al. Late-onset Pleural and Pericardial Effusion as Immune-related Adverse Events after 94 Cycles of Nivolumab. Intern Med. 2021;60(22):3585-3588. Velev M, Baroudjian B, Pruvost R, et al. Immune-related generalised oedema: a new category of adverse events with immune checkpoint inhibitors. Eur J Cancer. 2023;179:28-47. Scanvion Q, Béné J, Gautier S, et al. Moderate-to-severe eosinophilia induced by treatment with immune checkpoint inhibitors: 37 cases from a national reference center for hypereosinophilic syndromes. Oncoimmunology. 2020;9(1):1722022. Lyu L, Bian S, Guan K, Zhao B. Eosinophil-induced adverse events induced by treatment with programmed cell death 1/ligand 1 inhibitors: a comprehensive disproportionality analysis of the FDA adverse event reporting system. Int J Cancer. 2025;157(2):317-324. Bernard-Tessier A, Jeanville P, Champiat S, et al. Immune-related eosinophilia induced by anti-programmed death 1 or death-ligand 1 antibodies. Eur J Cancer. 2017;81:135-137. Light RW, Macgregor MI, Luchsinger PC, Ball WC Jr. Pleural effusions: the diagnostic separation of transudates and exudates. Ann Intern Med. 1972;77(4):507-513. Adelman M, Albelda SM, Gottlieb J, Haponik EF. Diagnostic utility of pleural fluid eosinophilia. Am J Med. 1984;77(5):915-920. Kalomenidis I, Light RW. Eosinophilic pleural effusions. Curr Opin Pulm Med. 2003;9(4):254-260. Aggarwal AN, Agarwal R, Sehgal IS, et al. Diagnostic accuracy of adenosine deaminase for tuberculous pleural effusion: a systematic review and meta-analysis. PLoS One. 2019;14(3):e0213728. Li M, Zeng Y, Li Y, et al. Incidence, aetiology and clinical features of eosinophilic pleural effusion: a retrospective study. BMC Pulm Med. 2021;21(1):402. Lin J, Sabath BF. Chronic pleuritis and recurrent pleural effusion after atezolizumab for small cell lung cancer. Am J Case Rep. 2021;22:e933396. 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. Shaheen S, Mirshahidi H, Nagaraj G, Hsueh CT. Conservative management of nivolumab-induced pericardial effusion: a case report and review of literature. Exp Hematol Oncol. 2018;7:11. Kushnir I, Wolf I. Nivolumab-induced pericardial tamponade: a case report and discussion. Cardiology. 2017;136(1):49-51. Nesfeder J, Elsensohn AN, Thind M, et al. Pericardial effusion with tamponade physiology induced by nivolumab. Int J Cardiol. 2016;222:613-614. Ali MR, Darwish OJ, Alhuneafat L, Abdallah BN, Saleh Y. Rechallenging nivolumab following immune checkpoint inhibitor-induced pericarditis. Proc (Bayl Univ Med Cent). 2022;36(1):83-84. Castelli M, Betelli M, Valenti A, et al. A case of polyserositis, chylous ascites and hepatitis induced by immune checkpoint inhibitors. Eur J Case Rep Intern Med. 2024;11(7):004237. Saade A, Mansuet-Lupo A, Arrondeau J, et al. Pericardial effusion under nivolumab: case-reports and review of the literature. J Immunother Cancer. 2019;7:266. de Almeida DVP, Gomes JR, Haddad FJ, Buzaid AC. Immune-mediated pericarditis with pericardial tamponade during nivolumab therapy. J Immunother. 2018;41(7):329-331. Heinzerling L, Ott PA, Hodi FS, et al. Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy. J Immunother Cancer. 2016;4:50. Rubin L, Talmon A, Ribak Y, et al. Targeted inhibition of the IL5 axis for immune checkpoint inhibitors eosinophilic-induced adverse events. J Immunother Cancer. 2024;12(10):e009658. Lyon AR, López-Fernández T, Couch LS, et al. 2022 ESC Guidelines on cardio-oncology. Eur Heart J. 2022;43(41):4229-4361. Wang TKM, Klein AL, Cremer PC, et al. 2025 Concise Clinical Guidance: An ACC Expert Consensus Statement on the Diagnosis and Management of Pericarditis: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2025;86(25):2691-2719. Verhaert M, Mebis J, Aspeslagh S, von Kemp B. Steroid-dependent pericarditis following anti-PD1 immunotherapy in a metastatic melanoma patient: a case report. Eur Heart J Case Rep. 2023;7(3):ytad112. Moriyama S, Fukata M, Tatsumoto R, Kono M. Refractory constrictive pericarditis caused by an immune checkpoint inhibitor properly managed with infliximab: a case report. Eur Heart J Case Rep. 2021;5(1):ytab002. Chye AM, Nordman IIC, Sverdlov AL. Successful immune checkpoint inhibitor rechallenge after immune-related pericarditis: clinical case series. Front Cardiovasc Med. 2022;9:964324. Tables Table 1. Clinical timeline relative to pembrolizumab initiation Timepoint Event Prior history Right nephrectomy for clear cell renal cell carcinoma (pT1b, grade 2) Pre-adjuvant baseline Complete resection of solitary humerus metastasis; M1-NED status achieved T0 Pembrolizumab initiated (200 mg q3 weeks; KEYNOTE-564 dosing schedule) T+~18 weeks (after cycle 6) After cycle 6: progressive anasarca and dyspnea; pembrolizumab held T+~18 weeks CT: large bilateral pleural effusions, mild ascites, no tumor progression T+~19-20 weeks Hospital admission; thoracentesis (1.5 L): exudative, 20% eosinophils, ADA 42.8 U/L, cytology/cultures negative T+~19-20 weeks TTE: LVEF 71%, small pericardial effusion (0.53 cm), no tamponade T+~19-20 weeks Methylprednisolone 1 mg/kg initiated; rapid clinical improvement Follow-up (2 weeks) Symptom resolution, normalized eosinophils, steroid taper ongoing, M1-NED maintained T0 indicates pembrolizumab initiation. Table 2. Diagnostic approach to suspected immune checkpoint inhibitor-related serositis Domain Key elements Rationale Oncologic assessment CT/PET-CT for tumor response; exclude new serosal nodularity; repeat sampling or tissue biopsy if uncertainty persists; tumor markers if relevant Differentiate irAE from malignant serosal involvement or progression Serosal fluid analysis Cell count with differential (mandatory eosinophil %); protein/LDH (Light's criteria); glucose; cytology; flow cytometry if lymphoma possible Characterize inflammatory phenotype; detect malignancy; identify eosinophilic effusion Microbiology Gram stain/culture; fungal culture; AFB smear/culture; TB NAAT/ADA/IGRA as appropriate Exclude infection before immunosuppression Cardiac evaluation ECG; troponin; natriuretic peptides; echocardiography; consider CMR; pericardiocentesis if tamponade or diagnostic uncertainty Assess pericardial involvement; rule out myocarditis Systemic causes Renal function; urinalysis/proteinuria; liver tests; albumin; thyroid function; venous duplex/CTPA if thromboembolism suspected Exclude heart/renal/hepatic failure and thromboembolism Eosinophil context Serial absolute eosinophil counts; review for rash, asthma, atopy; basic autoimmunity (ANA/ANCA) if indicated Characterize eosinophilic phenotype; consider alternative inflammatory etiologies Table 3. Management of immune checkpoint inhibitor-related serositis by scenario Scenario Management considerations Asymptomatic small effusion Repeat imaging; evaluate for progression/infection; consider holding ICI if rapid accumulation; cardio-oncology/pulmonology consultation Symptomatic moderate-large effusion Diagnostic/therapeutic drainage with fluid differential and cytology; hold ICI; systemic corticosteroids (1-2 mg/kg) once infection excluded; slow taper Pericardial effusion with hemodynamic compromise Urgent pericardiocentesis or surgical window; intensive care unit monitoring; high-dose steroids once infection excluded; evaluate for myocarditis (troponin, CMR) Steroid-refractory/dependent disease Multidisciplinary input; steroid-sparing agents (azathioprine, infliximab) for pericardial disease; IL-5 axis blockade (mepolizumab, benralizumab) for eosinophil-driven disease; IL-1 blockade (anakinra, rilonacept) may be considered for recurrent pericarditis phenotypes (evidence largely extrapolated to ICI-associated cases). ICI rechallenge Individualize based on severity, compartment, and oncologic context; consider only after complete resolution with close monitoring; avoid after life-threatening events unless no alternatives Table 4. Reporting of effusion eosinophils in selected immune checkpoint inhibitor-associated serositis reports Publication (ref.) ICI (agent) Serosal manifestation(s) Effusion sampled Cell differential reported Eosinophil % in effusion 35 Pembro Pericarditis (steroid-dependent) Not specified Not reported Not reported 36 ICI (NR) Constrictive pericarditis Not specified Not reported Not reported 27 Nivo Recurrent pericarditis No N/A Not reported 29 Nivo Pericardial effusion/tamponade (3 cases) + review Yes Partially (cytology/leukocytes) Not reported 24 Nivo Pericardial effusion (case report) No N/A Not reported 37 ICI (various) Immune-related pericarditis (case series; rechallenge) Not specified Not reported Not reported 28 Nivo Polyserositis (chylous ascites ± effusions) Yes Partially (lymphocyte-predominant described) Not reported 12 Nivo Pleural + pericardial effusions (late-onset) Yes Not reported Not reported 23 Pembro Chronic pleuritis/pleural effusion Yes Yes (lymphocytes 90%, neutrophils 10%) Not reported 22 Atezo Chronic pleuritis/pleural effusion Yes Yes Yes (13%) Abbreviations: Atezo, atezolizumab; ICI, immune checkpoint inhibitor; N/A, not applicable; NR, not reported; Nivo, nivolumab; Pembro, pembrolizumab. “Not reported” includes cases where effusion was not sampled and/or the differential was not specified. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8910623","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":600853581,"identity":"898b5fd3-d00d-4e53-bd86-5acf5cde3819","order_by":0,"name":"Mikel Portu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvUlEQVRIiWNgGAWjYPACG1I1HGBIA5LMUB4bcVoOk6BFd3bzsc8f287b88/uP/bgZxuDPP/8BvxazO4cS55xsO124ow7h9kNe9sYDGccI2CL2Y0cYwaglgSGG8lsErxtDAkMRGo5Zy8P1CL5F6hFnkgtBxg3ALVIg2wxIKgF6BeGM+eSEzfeSDY3ljknYbjxWAIBLbebDzNUlNnZy91IfPbwTZmNvNzhAwSskUAw2VC5xGoZBaNgFIyCUYAJAPoGREv7DJZLAAAAAElFTkSuQmCC","orcid":"","institution":"Hospital de la Santa Creu i Sant Pau","correspondingAuthor":true,"prefix":"","firstName":"Mikel","middleName":"","lastName":"Portu","suffix":""},{"id":600853582,"identity":"6f0f60cf-1949-41b8-86c3-0af88b37c84d","order_by":1,"name":"Judit Sanz-Beltran","email":"","orcid":"","institution":"Hospital de la Santa Creu i Sant Pau","correspondingAuthor":false,"prefix":"","firstName":"Judit","middleName":"","lastName":"Sanz-Beltran","suffix":""},{"id":600853583,"identity":"f4ad4125-059b-4e01-b454-4ad546a8c3f0","order_by":2,"name":"Maria Alejandra Duarte","email":"","orcid":"","institution":"Hospital de la Santa Creu i Sant Pau","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Alejandra","lastName":"Duarte","suffix":""},{"id":600853584,"identity":"5f4ee67d-ac9f-4b5a-ac5c-008d5caafedc","order_by":3,"name":"Julieta Navarro","email":"","orcid":"","institution":"Hospital de la Santa Creu i Sant Pau","correspondingAuthor":false,"prefix":"","firstName":"Julieta","middleName":"","lastName":"Navarro","suffix":""},{"id":600853585,"identity":"bfa560a8-9b5b-4390-ab45-1fe74ee1401c","order_by":4,"name":"Alexandra Arias","email":"","orcid":"","institution":"Hospital de la Santa Creu i Sant Pau","correspondingAuthor":false,"prefix":"","firstName":"Alexandra","middleName":"","lastName":"Arias","suffix":""},{"id":600853586,"identity":"193b8d69-e49b-4fb7-99f6-4298458008c6","order_by":5,"name":"Paula Alvarez","email":"","orcid":"","institution":"Hospital de la Santa Creu i Sant Pau","correspondingAuthor":false,"prefix":"","firstName":"Paula","middleName":"","lastName":"Alvarez","suffix":""},{"id":600853587,"identity":"303dbf3e-5b9d-4f50-ad8e-a4741c12e9b4","order_by":6,"name":"Angel Fernández-Rebollo","email":"","orcid":"","institution":"Hospital de la Santa Creu i Sant Pau","correspondingAuthor":false,"prefix":"","firstName":"Angel","middleName":"","lastName":"Fernández-Rebollo","suffix":""},{"id":600853588,"identity":"07355db6-7273-4de3-8dac-b95182c797c2","order_by":7,"name":"Carlos Reyes","email":"","orcid":"","institution":"Hospital de la Santa Creu i Sant Pau","correspondingAuthor":false,"prefix":"","firstName":"Carlos","middleName":"","lastName":"Reyes","suffix":""},{"id":600853589,"identity":"0f36e9a6-044b-4eba-b877-3a94fc38021d","order_by":8,"name":"Juan Flores","email":"","orcid":"","institution":"Hospital de la Santa Creu i Sant Pau","correspondingAuthor":false,"prefix":"","firstName":"Juan","middleName":"","lastName":"Flores","suffix":""},{"id":600853590,"identity":"79c815ad-acf8-42b0-a0f2-07cd0748e7d9","order_by":9,"name":"Georgia Anguera","email":"","orcid":"","institution":"Hospital de la Santa Creu i Sant Pau","correspondingAuthor":false,"prefix":"","firstName":"Georgia","middleName":"","lastName":"Anguera","suffix":""},{"id":600853591,"identity":"259bbbe0-2af7-4be2-ae17-10d9d9c2a3df","order_by":10,"name":"Pablo Maroto","email":"","orcid":"","institution":"Hospital de la Santa Creu i Sant Pau","correspondingAuthor":false,"prefix":"","firstName":"Pablo","middleName":"","lastName":"Maroto","suffix":""}],"badges":[],"createdAt":"2026-02-18 15:23:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8910623/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8910623/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104180416,"identity":"c0f68977-a334-4047-a163-0e7ea826b45d","added_by":"auto","created_at":"2026-03-08 17:14:28","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":738177,"visible":true,"origin":"","legend":"\u003cp\u003eContrast-enhanced computed tomography (CT) images demonstrating findings consistent with generalized edema. (A) Axial thoracic CT showing large bilateral pleural effusions associated with mild pericardial effusion. (B) Axial pelvic CT demonstrating mild right hydrocele, consistent with scrotal edema. (C) Axial abdominal CT showing mild ascites, predominantly perihepatic.\u003c/p\u003e","description":"","filename":"Figure1combined300dpi.png","url":"https://assets-eu.researchsquare.com/files/rs-8910623/v1/c788f86514dd1456bff1649d.png"},{"id":104782010,"identity":"ce99473a-a1bc-461a-8b0a-fcc828b14c8e","added_by":"auto","created_at":"2026-03-17 07:56:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1768298,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8910623/v1/6dbf8e6d-a67c-4aba-af91-14f04685dc5c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pembrolizumab-associated eosinophilic polyserositis with pericardial involvement during adjuvant therapy for clear cell renal cell carcinoma: a case report and narrative review","fulltext":[{"header":"Background","content":"\u003cp\u003eThe programmed cell death 1 inhibitor pembrolizumab improves disease-free and overall survival as adjuvant therapy for patients with high-risk clear cell renal cell carcinoma after nephrectomy [1\u0026ndash;2]. Immune checkpoint inhibitors can trigger immune-related adverse events across organ systems, with management guidance from major societies [3\u0026ndash;5].\u003c/p\u003e\n\u003cp\u003eSerosal inflammation (serositis) is increasingly recognized within the cardiovascular immune-related adverse event spectrum. Pericardial disease is the best characterized serosal compartment, supported by cohort and systematic review data [6\u0026ndash;10]. In contrast, pleural and peritoneal involvement are supported largely by case reports and small series of polyserositis or immune-related generalized edema [11\u0026ndash;13].\u003c/p\u003e\n\u003cp\u003eEosinophilia is also a recognized class effect of programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade [14\u0026ndash;16]. However, eosinophil percentages in serosal fluid are rarely reported in immune checkpoint inhibitor-associated serositis, leaving eosinophilic serositis poorly characterized, which may contribute to delayed diagnosis. We report a case of eosinophilic pleural effusion with concurrent polyserositis during adjuvant pembrolizumab and provide a narrative synthesis focused on phenotyping, differential diagnosis, and management in cardio-oncology practice.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 55-year-old man with Wolff-Parkinson-White syndrome (treated with ablation) and active tobacco use underwent right nephrectomy for clear cell renal cell carcinoma (pT1b, grade 2). He later developed a solitary metastasis to the left proximal humerus that was completely resected with limb-sparing surgery and megaprosthesis reconstruction, achieving metastatic disease with no evidence of disease (M1-NED). Adjuvant pembrolizumab (200 mg every 3 weeks) was initiated following the KEYNOTE-564 dosing schedule (timeline in Table 1).\u003c/p\u003e\n\u003cp\u003eAfter six cycles (approximately 18 weeks), he developed progressive scrotal and lower abdominal edema with exertional dyspnea. Computed tomography showed large bilateral pleural effusions and mild ascites without evidence of tumor progression (Figure 1). Pembrolizumab was held, and he was admitted shortly thereafter for worsening anasarca.\u003c/p\u003e\n\u003cp\u003eOn admission he was afebrile and hemodynamically stable, with decreased breath sounds bilaterally and prominent genital edema. Laboratory testing showed eosinophilia (absolute eosinophil count approximately 1.5 \u0026times; 10^9/L), hypoalbuminemia (28 g/L [2.8 g/dL]), preserved renal function, and low inflammatory markers.\u003c/p\u003e\n\u003cp\u003eTherapeutic thoracentesis removed 1.5 L of serous fluid. The pleural fluid met exudative criteria and contained 20% eosinophils, consistent with eosinophilic pleural effusion (\u0026ge;10%). Cytology was negative for malignancy. Bacterial, mycobacterial, and fungal cultures were negative. Adenosine deaminase was mildly elevated at 42.8 U/L (upper limit of normal, 40 U/L), prompting careful tuberculosis exclusion, which was negative.\u003c/p\u003e\n\u003cp\u003eTransthoracic echocardiography showed a nondilated left ventricle with preserved systolic function (left ventricular ejection fraction 71%), normal right ventricular size and function, no significant valvular disease, and a small anterior pericardial effusion (0.53 cm) without hemodynamic compromise.\u003c/p\u003e\n\u003cp\u003eThe differential diagnosis included malignant serosal involvement, infection (including tuberculosis), heart failure, nephrotic syndrome, venous thromboembolism, hepatic disease, and immune-mediated serositis. The temporal relationship to pembrolizumab, multi-compartment serosal involvement, concurrent peripheral eosinophilia, negative cytology and microbiology, absence of heart failure or renal disease, normal liver function tests with no radiologic evidence of cirrhosis, and rapid response to corticosteroids supported pembrolizumab-associated immune-mediated eosinophilic polyserositis.\u003c/p\u003e\n\u003cp\u003ePembrolizumab was permanently discontinued. The patient received therapeutic thoracentesis, diuretics, and methylprednisolone 1 mg/kg/day followed by an oral taper, consistent with guideline-based management of moderate-to-severe immune-related adverse events. Within days, dyspnea and edema improved markedly. Eosinophil counts normalized and albumin improved. At 2-week follow-up he remained stable without recurrent effusions, and prednisone taper continued. At last oncologic assessment, he remains M1-NED without evidence of disease recurrence.\u003c/p\u003e"},{"header":"Discussion and Conclusions","content":"\u003ch2\u003eLiterature review strategy\u003c/h2\u003e\n\u003cp\u003eTo contextualize this presentation and inform the diagnostic and management recommendations below, we performed a narrative review. We searched PubMed (inception through January 2026) using combinations of \u0026ldquo;immune checkpoint inhibitor,\u0026rdquo; \u0026ldquo;serositis,\u0026rdquo; \u0026ldquo;polyserositis,\u0026rdquo; \u0026ldquo;pleural effusion,\u0026rdquo; \u0026ldquo;pericarditis,\u0026rdquo; \u0026ldquo;pericardial effusion,\u0026rdquo; \u0026ldquo;eosinophilia,\u0026rdquo; and \u0026ldquo;generalized edema.\u0026rdquo; We prioritized systematic reviews, cohort studies, and consensus guideline documents, and supplemented these with representative case reports identified from reference lists and related-article searches. We additionally included foundational sources for pleural effusion classification (Light\u0026rsquo;s criteria), eosinophilic pleural effusion definitions, and evidence on pleural adenosine deaminase and the etiologic spectrum of eosinophilic effusions [17\u0026ndash;21].\u003c/p\u003e\n\u003cp\u003eFor representative serositis case reports and small series, we assessed reporting of serosal fluid inflammatory phenotyping (whether a cell count with differential was provided) and whether an eosinophil percentage in the effusion was explicitly stated. This targeted extraction was intended to evaluate reporting practices rather than to estimate incidence. Representative reports included chronic pleuritis/pleural effusion described after atezolizumab and pembrolizumab and a nivolumab-associated pericardial effusion case report [22\u0026ndash;24].\u003c/p\u003e\n\u003ch2\u003eSerositis as an emerging cardiovascular immune-related adverse event\u003c/h2\u003e\n\u003cp\u003eSerosal inflammation under immune checkpoint inhibitor therapy has been recognized since the mid-2010s, initially through case reports of pericardial tamponade [25\u0026ndash;26]. Controlled cohort data later quantified this signal: in a study comparing 2,842 immune checkpoint inhibitor-treated patients with 2,699 matched metastatic controls, immune checkpoint inhibitor exposure was associated with 1.57 pericardial events per 100 person-years and an approximately fourfold increased risk (adjusted hazard ratio 4.37, 95% confidence interval 2.09\u0026ndash;9.14) [6]. Reported frequency varies substantially across study designs (typically \u0026lt;1% in clinical trials and pharmacovigilance datasets, but higher in retrospective imaging-based series when any new effusion is counted), so the true incidence likely remains underestimated [6\u0026ndash;7].\u003c/p\u003e\n\u003cp\u003eMorbidity can be substantial: in systematic reviews of published cases, tamponade has been reported in approximately 41% and pericardiocentesis in approximately 68% [7]. Meta-analyses of cardiovascular immune-related adverse events from randomized trials and pharmacovigilance databases corroborate a clinically meaningful signal for pericardial toxicity [9\u0026ndash;10].\u003c/p\u003e\n\u003cp\u003eCancer-type patterns are broadly consistent across published datasets. Lung cancer predominates in pericardial immune-related adverse event series, comprising up to 81% of cases in one systematic review [7]. Melanoma is also frequently represented [7\u0026ndash;9]. In contrast, pleural and peritoneal immune serositis lack reliable incidence estimates. These compartments are captured mainly in polyserositis case series and reports of immune-related generalized edema [11\u0026ndash;13]. Data specific to renal cell carcinoma remain sparse, limited to isolated pericarditis case reports [27].\u003c/p\u003e\n\u003ch2\u003eClinical spectrum and timing\u003c/h2\u003e\n\u003cp\u003eImmune checkpoint inhibitor-related serositis spans a broad spectrum, ranging from incidentally detected small effusions to life-threatening tamponade requiring emergent drainage [7\u0026ndash;8]. Polyserositis (simultaneous involvement of two or more serous cavities) typically presents with dyspnea, weight gain, and peripheral or genital edema and may co-occur with other immune-related adverse events [11\u0026ndash;12].\u003c/p\u003e\n\u003cp\u003eTiming is highly variable. Many pericardial events occur early, with median onset around four treatment cycles (approximately 12 weeks) in systematic reviews [7]. However, late presentations are well documented, including cases arising after prolonged exposure or after immune checkpoint inhibitor discontinuation [12, 28]. Our patient developed symptoms after six cycles (approximately 18 weeks), consistent with this broad window.\u003c/p\u003e\n\u003ch2\u003eThe eosinophilic dimension\u003c/h2\u003e\n\u003cp\u003eEosinophilia is a recognized class effect of programmed cell death 1/programmed death ligand 1 blockade. In a national reference center series of 37 patients with moderate-to-severe immune checkpoint inhibitor-induced eosinophilia, the median absolute eosinophil count reached 2.7 \u0026times; 10^9/L and peak values occurred at a median of 15 weeks after initiation. Fifty-seven percent developed eosinophil-related organ manifestations [14]. A pharmacovigilance analysis identified hundreds of eosinophil-associated adverse events across programmed cell death 1/programmed death ligand 1 inhibitors, supporting this as a class phenomenon [15]. Early reports described immune-related eosinophilia across PD-1/PD-L1 agents [16], and subsequent referral-center experience recommended routine monitoring of the absolute eosinophil count during immune checkpoint inhibitor (ICI) therapy [14].\u003c/p\u003e\n\u003cp\u003eCritically, the eosinophilic immune-related adverse event literature and the immune checkpoint inhibitor-serositis literature have evolved largely in parallel. In many published serositis cases, effusion characterization focuses on cytology and microbiology, while differential cell counts (and particularly eosinophil percentages) are absent. Conversely, eosinophil-focused series rarely report compartment-specific fluid phenotyping. This disconnect makes it difficult to estimate how often an eosinophilic serositis phenotype occurs under immune checkpoint inhibitor therapy and whether it carries distinct prognostic or therapeutic implications.\u003c/p\u003e\n\u003cp\u003eOur case, with pleural fluid eosinophilia (20%) and concurrent peripheral eosinophilia, sits at this intersection and suggests that a subset of immune checkpoint inhibitor-associated polyserositis may represent a type 2-skewed, eosinophil-predominant inflammatory signature with potential mechanistic and therapeutic relevance.\u003c/p\u003e\n\u003ch2\u003ePathophysiology\u003c/h2\u003e\n\u003cp\u003eDirect mechanistic data for serosal immune-related adverse events are limited. For pericardial disease, available biopsy and cytology data suggest a T-cell-predominant lymphocytic inflammation without malignant cells [7, 29\u0026ndash;30]. Proposed mechanisms include loss of peripheral tolerance enabling autoreactive T-cell activation against serosal antigens, molecular mimicry between tumor neoantigens and mesothelial or stromal proteins, and amplification of local inflammatory cascades at serosal surfaces [7\u0026ndash;8, 31]. The frequent co-occurrence of pericardial disease with myocarditis and other systemic immune-related adverse events suggests broader immune dysregulation [8\u0026ndash;9, 31].\u003c/p\u003e\n\u003cp\u003eEosinophilic phenotypes likely reflect activation of a type 2 immune axis, particularly interleukin-5, the principal cytokine driving eosinophil differentiation, survival, and tissue recruitment. Programmed cell death 1 blockade can augment both type 1 and type 2 immune responses. In susceptible individuals, type 2 skewing may predominate, with interleukin-4, interleukin-5, interleukin-13, and eotaxins orchestrating eosinophilic inflammation. Case-level evidence from small case series suggests that targeted interleukin-5 axis blockade (mepolizumab, benralizumab) can control severe or steroid-refractory eosinophilic immune-related adverse events and support steroid tapering [32].\u003c/p\u003e\n\u003cp\u003eFuture translational work should prioritize cytokine and immune-cell profiling of serosal fluid to determine whether eosinophilic serositis represents a biologically distinct subtype with steroid-sparing therapeutic opportunities.\u003c/p\u003e\n\u003ch2\u003eDiagnostic approach\u003c/h2\u003e\n\u003cp\u003eImmune-mediated serositis remains a diagnosis of exclusion. The differential diagnosis for new effusions in patients receiving immune checkpoint inhibitors includes malignant serosal involvement, infection, heart failure, nephrotic syndrome, hepatic failure, and thromboembolism. When an eosinophilic pleural effusion is identified, the differential further expands to include drug reactions, parasitic infection, air or blood in the pleural space, pulmonary embolism, and connective tissue disease [19, 21].\u003c/p\u003e\n\u003cp\u003eWe propose a systematic approach (Table 2) with four components. First, reassess cancer status and assess imaging features suggestive of malignant serosal involvement. Second, perform comprehensive serosal fluid analysis with a mandatory cell count and differential, including explicit eosinophil percentage. Third, complete microbiologic evaluation before immunosuppression. Fourth, complete compartment-specific evaluation. When the pericardium is involved, this includes electrocardiography, cardiac biomarkers, and echocardiography, with selective use of cardiac magnetic resonance imaging (CMR) and pericardiocentesis based on hemodynamic status and diagnostic uncertainty [8, 33].\u003c/p\u003e\n\u003cp\u003eFor pleural fluid, adenosine deaminase can be useful to support or exclude tuberculous pleuritis, but commonly cited thresholds (e.g., 40 U/L) are not absolute and may yield false positives in malignancy and other inflammatory conditions [20]. In our case, a mildly elevated adenosine deaminase (42.8 U/L) prompted careful tuberculosis exclusion before attributing the effusion to an immune-related adverse event.\u003c/p\u003e\n\u003cp\u003eThe absence of malignant cells on cytology does not exclude malignant effusion and repeat sampling or tissue biopsy may be required in selected cases. Conversely, eosinophilia does not exclude malignancy, as eosinophilic effusions can occur with lung cancer and lymphoma [21]. Integration of clinical context, imaging trajectory, fluid characteristics, and response to therapy is essential.\u003c/p\u003e\n\u003ch2\u003eManagement and emerging therapies\u003c/h2\u003e\n\u003cp\u003eManagement depends on severity, compartment, and suspected mechanism (Table 3). Symptomatic large effusions require prompt drainage (thoracentesis, paracentesis, or pericardiocentesis/pericardial window, as indicated). For moderate-to-severe suspected immune-mediated serositis, interruption of the immune checkpoint inhibitor and systemic corticosteroids (prednisone 1-2 mg/kg/day or equivalent) are standard, followed by a prolonged taper to reduce relapse risk [3\u0026ndash;5, 7\u0026ndash;8].\u003c/p\u003e\n\u003cp\u003eSteroid-refractory or steroid-dependent cases require multidisciplinary input. In pericardial phenotypes, adjuncts used in idiopathic pericarditis (colchicine and/or nonsteroidal anti-inflammatory drugs) are commonly applied, acknowledging limited immune checkpoint inhibitor-specific evidence. Interleukin-1 blockade (e.g., anakinra or rilonacept) has strong evidence in idiopathic recurrent pericarditis and is highlighted in contemporary guidance. However, supporting data in immune checkpoint inhibitor-associated pericardial disease are limited, particularly for eosinophil-predominant presentations. Use remains extrapolative, and decisions should be individualized [7, 34]. Other immunosuppressants and biologics have been reported anecdotally [35\u0026ndash;36].\u003c/p\u003e\n\u003cp\u003eWhen an eosinophil-driven phenotype is documented (marked peripheral eosinophilia and/or eosinophil-rich effusions), targeted interleukin-5 axis blockade (mepolizumab, benralizumab) represents a rational and increasingly evidence-supported option [32]. These agents may allow steroid sparing and, in selected situations, may facilitate continuation of oncologic therapy. We suggest considering interleukin-5 axis blockade for eosinophilic serositis that is steroid-refractory, steroid-dependent, or associated with severe hypereosinophilia.\u003c/p\u003e\n\u003ch2\u003eImmune checkpoint inhibitor rechallenge and the adjuvant context\u003c/h2\u003e\n\u003cp\u003eMost reports of severe pericardial disease (tamponade or hemodynamic compromise) or multi-compartment polyserositis describe permanent immune checkpoint inhibitor discontinuation [7, 12]. Rechallenge after resolution has been successful in selected pericardial cases, though recurrence risk remains uncertain and likely depends on severity and compartment involvement [37]. Within eosinophilic immune-related adverse events, improvement may occur despite continued immune checkpoint inhibitor exposure in some patients, whereas others relapse even after discontinuation [11, 14].\u003c/p\u003e\n\u003cp\u003eThe adjuvant setting warrants particular consideration. Unlike metastatic disease, where immune checkpoint inhibition may represent a key life-prolonging option, adjuvant therapy targets recurrence risk in patients who are currently disease-free. Accordingly, the threshold for permanent discontinuation is typically lower after grade 3 or higher toxicity, particularly after severe multi-compartment involvement. In our patient, permanent discontinuation reflected this calculus after six cycles in the M1-NED setting.\u003c/p\u003e\n\u003ch2\u003eImplications for reporting and practice\u003c/h2\u003e\n\u003cp\u003eThis case illustrates that immune checkpoint inhibitor-related serositis can present as a capillary leak-like phenotype with anasarca and multi-compartment fluid accumulation, similar to published reports of polyserositis and immune-related generalized edema [11\u0026ndash;13]. The presence of eosinophilic pleural effusion with concurrent peripheral eosinophilia suggests a type 2-skewed inflammatory signature that is rarely documented in the serositis literature and may represent an underrecognized subgroup amenable to eosinophil-targeted therapy.\u003c/p\u003e\n\u003cp\u003eOur targeted extraction (Table 4) highlights a practical reporting gap: eosinophil percentage in serosal fluid is often omitted. We recommend routine documentation of serosal fluid differential cell counts, including eosinophil percentage, in suspected immune checkpoint inhibitor-related effusions to facilitate phenotype recognition and future aggregation of data.\u003c/p\u003e\n\u003cp\u003eStrengths of this report include the comprehensive diagnostic workup with serosal fluid phenotyping, the systematic literature review contextualizing reporting gaps, and a structured management algorithm. Limitations inherent to a single case report include the inability to establish causality definitively, the absence of serosal tissue biopsy, and the lack of cytokine profiling of the effusion fluid, which would have strengthened the mechanistic interpretation.\u003c/p\u003e\n\u003cp\u003eIn conclusion, pembrolizumab-associated eosinophilic polyserositis represents a rare but clinically significant immune-related adverse event that can mimic disease progression or infection. Early recognition, exclusion of malignant and infectious etiologies, and timely immunosuppression enable symptom control while informing decisions about therapy discontinuation or rechallenge. For eosinophil-driven disease, interleukin-5 axis blockade is a promising steroid-sparing option in selected cases.\u003c/p\u003e\n\u003ch2\u003ePatient\u0026rsquo;s perspective\u003c/h2\u003e\n\u003cp\u003eThe patient was invited to provide a written account of his experience but declined to contribute a personal narrative. He provided written informed consent for publication of this case report.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eADA:\u0026nbsp;\u003c/strong\u003eadenosine deaminase\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAFB:\u0026nbsp;\u003c/strong\u003eacid-fast bacilli\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eANA:\u0026nbsp;\u003c/strong\u003eantinuclear antibodies\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eANCA:\u0026nbsp;\u003c/strong\u003eanti-neutrophil cytoplasmic antibodies\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCMR:\u0026nbsp;\u003c/strong\u003ecardiac magnetic resonance\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCT:\u0026nbsp;\u003c/strong\u003ecomputed tomography\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCTPA:\u0026nbsp;\u003c/strong\u003ecomputed tomography pulmonary angiography\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eECG:\u0026nbsp;\u003c/strong\u003eelectrocardiography\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFAERS:\u0026nbsp;\u003c/strong\u003eFood and Drug Administration Adverse Event Reporting System\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eICI:\u0026nbsp;\u003c/strong\u003eimmune checkpoint inhibitor\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIGRA:\u0026nbsp;\u003c/strong\u003einterferon-gamma release assay\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eirAE:\u0026nbsp;\u003c/strong\u003eimmune-related adverse event\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLVEF:\u0026nbsp;\u003c/strong\u003eleft ventricular ejection fraction\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eM1-NED:\u0026nbsp;\u003c/strong\u003emetastatic disease with no evidence of disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNAAT:\u0026nbsp;\u003c/strong\u003enucleic acid amplification test\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePD-1:\u0026nbsp;\u003c/strong\u003eprogrammed cell death 1\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePD-L1:\u0026nbsp;\u003c/strong\u003eprogrammed death ligand 1\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePET-CT:\u0026nbsp;\u003c/strong\u003epositron emission tomography-computed tomography\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTB:\u0026nbsp;\u003c/strong\u003etuberculosis\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTTE:\u0026nbsp;\u003c/strong\u003etransthoracic echocardiography\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e Not applicable. Ethics approval was not required for this case report in accordance with local institutional policy (Comit\u0026eacute; \u0026Eacute;tico de Investigaci\u0026oacute;n con Medicamentos (CEIm) del Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; reference number: not applicable).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication: \u003c/strong\u003eWritten informed consent was obtained from the patient for publication of this case report and any accompanying de-identified data. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eAll data generated or analyzed during this study are included in this published article and its additional file(s). Additional de-identified details are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eNo specific funding was received for this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e: MP conceptualized the report, collected clinical data, performed the literature review, and drafted the manuscript. JSB, MADB, JN, AA, PA, AFR, CR, and GA contributed to clinical data acquisition and interpretation and critically revised the manuscript for important intellectual content. PM supervised the work and critically revised the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eChoueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;385(8):683-694.\u003c/li\u003e\n\u003cli\u003eChoueiri TK, Tomczak P, Park SH, et al. Overall survival with adjuvant pembrolizumab in renal-cell carcinoma. N Engl J Med. 2024;390(15):1359-1371.\u003c/li\u003e\n\u003cli\u003eSchneider BJ, Naidoo J, Santomasso BD, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol. 2021;39(36):4073-4126.\u003c/li\u003e\n\u003cli\u003eHaanen J, Obeid M, Spain L, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline. Ann Oncol. 2022;33(12):1217-1238.\u003c/li\u003e\n\u003cli\u003eBrahmer JR, Abu-Sbeih H, Ascierto PA, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer. 2021;9(6):e002435.\u003c/li\u003e\n\u003cli\u003eGong J, Drobni ZD, Zafar A, et al. Pericardial disease in patients treated with immune checkpoint inhibitors. J Immunother Cancer. 2021;9(6):e002771.\u003c/li\u003e\n\u003cli\u003eMudra SE, Rayes DL, Agrawal A, et al. Immune checkpoint inhibitors and pericardial disease: a systematic review. Cardio-Oncology. 2024;10(1):29.\u003c/li\u003e\n\u003cli\u003eInno A, Maurea N, Metro G, et al. Immune checkpoint inhibitors-associated pericardial disease: a systematic review of case reports. Cancer Immunol Immunother. 2021;70(10):3041-3053.\u003c/li\u003e\n\u003cli\u003eDolladille C, Akroun J, Morice PM, et al. Cardiovascular immunotoxicities associated with immune checkpoint inhibitors: a safety meta-analysis. Eur Heart J. 2021;42(48):4964-4977.\u003c/li\u003e\n\u003cli\u003eSalem JE, Manouchehri A, Moey M, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. 2018;19(12):1579-1589.\u003c/li\u003e\n\u003cli\u003eZierold S, Akcetin LS, Gresser E, et al. Checkpoint inhibitor-induced polyserositis with edema. Cancer Immunol Immunother. 2022;71(12):3087-3092.\u003c/li\u003e\n\u003cli\u003eSawada R, Matsui Y, Uchino J, et al. Late-onset Pleural and Pericardial Effusion as Immune-related Adverse Events after 94 Cycles of Nivolumab. Intern Med. 2021;60(22):3585-3588.\u003c/li\u003e\n\u003cli\u003eVelev M, Baroudjian B, Pruvost R, et al. Immune-related generalised oedema: a new category of adverse events with immune checkpoint inhibitors. Eur J Cancer. 2023;179:28-47.\u003c/li\u003e\n\u003cli\u003eScanvion Q, B\u0026eacute;n\u0026eacute; J, Gautier S, et al. Moderate-to-severe eosinophilia induced by treatment with immune checkpoint inhibitors: 37 cases from a national reference center for hypereosinophilic syndromes. Oncoimmunology. 2020;9(1):1722022.\u003c/li\u003e\n\u003cli\u003eLyu L, Bian S, Guan K, Zhao B. Eosinophil-induced adverse events induced by treatment with programmed cell death 1/ligand 1 inhibitors: a comprehensive disproportionality analysis of the FDA adverse event reporting system. Int J Cancer. 2025;157(2):317-324.\u003c/li\u003e\n\u003cli\u003eBernard-Tessier A, Jeanville P, Champiat S, et al. Immune-related eosinophilia induced by anti-programmed death 1 or death-ligand 1 antibodies. Eur J Cancer. 2017;81:135-137.\u003c/li\u003e\n\u003cli\u003eLight RW, Macgregor MI, Luchsinger PC, Ball WC Jr. Pleural effusions: the diagnostic separation of transudates and exudates. Ann Intern Med. 1972;77(4):507-513.\u003c/li\u003e\n\u003cli\u003eAdelman M, Albelda SM, Gottlieb J, Haponik EF. Diagnostic utility of pleural fluid eosinophilia. Am J Med. 1984;77(5):915-920.\u003c/li\u003e\n\u003cli\u003eKalomenidis I, Light RW. Eosinophilic pleural effusions. Curr Opin Pulm Med. 2003;9(4):254-260.\u003c/li\u003e\n\u003cli\u003eAggarwal AN, Agarwal R, Sehgal IS, et al. Diagnostic accuracy of adenosine deaminase for tuberculous pleural effusion: a systematic review and meta-analysis. PLoS One. 2019;14(3):e0213728.\u003c/li\u003e\n\u003cli\u003eLi M, Zeng Y, Li Y, et al. Incidence, aetiology and clinical features of eosinophilic pleural effusion: a retrospective study. BMC Pulm Med. 2021;21(1):402.\u003c/li\u003e\n\u003cli\u003eLin J, Sabath BF. Chronic pleuritis and recurrent pleural effusion after atezolizumab for small cell lung cancer. Am J Case Rep. 2021;22:e933396.\u003c/li\u003e\n\u003cli\u003eShen 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.\u003c/li\u003e\n\u003cli\u003eShaheen S, Mirshahidi H, Nagaraj G, Hsueh CT. Conservative management of nivolumab-induced pericardial effusion: a case report and review of literature. Exp Hematol Oncol. 2018;7:11.\u003c/li\u003e\n\u003cli\u003eKushnir I, Wolf I. Nivolumab-induced pericardial tamponade: a case report and discussion. Cardiology. 2017;136(1):49-51.\u003c/li\u003e\n\u003cli\u003eNesfeder J, Elsensohn AN, Thind M, et al. Pericardial effusion with tamponade physiology induced by nivolumab. Int J Cardiol. 2016;222:613-614.\u003c/li\u003e\n\u003cli\u003eAli MR, Darwish OJ, Alhuneafat L, Abdallah BN, Saleh Y. Rechallenging nivolumab following immune checkpoint inhibitor-induced pericarditis. Proc (Bayl Univ Med Cent). 2022;36(1):83-84.\u003c/li\u003e\n\u003cli\u003eCastelli M, Betelli M, Valenti A, et al. A case of polyserositis, chylous ascites and hepatitis induced by immune checkpoint inhibitors. Eur J Case Rep Intern Med. 2024;11(7):004237.\u003c/li\u003e\n\u003cli\u003eSaade A, Mansuet-Lupo A, Arrondeau J, et al. Pericardial effusion under nivolumab: case-reports and review of the literature. J Immunother Cancer. 2019;7:266.\u003c/li\u003e\n\u003cli\u003ede Almeida DVP, Gomes JR, Haddad FJ, Buzaid AC. Immune-mediated pericarditis with pericardial tamponade during nivolumab therapy. J Immunother. 2018;41(7):329-331.\u003c/li\u003e\n\u003cli\u003eHeinzerling L, Ott PA, Hodi FS, et al. Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy. J Immunother Cancer. 2016;4:50.\u003c/li\u003e\n\u003cli\u003eRubin L, Talmon A, Ribak Y, et al. Targeted inhibition of the IL5 axis for immune checkpoint inhibitors eosinophilic-induced adverse events. J Immunother Cancer. 2024;12(10):e009658.\u003c/li\u003e\n\u003cli\u003eLyon AR, L\u0026oacute;pez-Fern\u0026aacute;ndez T, Couch LS, et al. 2022 ESC Guidelines on cardio-oncology. Eur Heart J. 2022;43(41):4229-4361.\u003c/li\u003e\n\u003cli\u003eWang TKM, Klein AL, Cremer PC, et al. 2025 Concise Clinical Guidance: An ACC Expert Consensus Statement on the Diagnosis and Management of Pericarditis: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2025;86(25):2691-2719.\u003c/li\u003e\n\u003cli\u003eVerhaert M, Mebis J, Aspeslagh S, von Kemp B. Steroid-dependent pericarditis following anti-PD1 immunotherapy in a metastatic melanoma patient: a case report. Eur Heart J Case Rep. 2023;7(3):ytad112.\u003c/li\u003e\n\u003cli\u003eMoriyama S, Fukata M, Tatsumoto R, Kono M. Refractory constrictive pericarditis caused by an immune checkpoint inhibitor properly managed with infliximab: a case report. Eur Heart J Case Rep. 2021;5(1):ytab002.\u003c/li\u003e\n\u003cli\u003eChye AM, Nordman IIC, Sverdlov AL. Successful immune checkpoint inhibitor rechallenge after immune-related pericarditis: clinical case series. Front Cardiovasc Med. 2022;9:964324.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Clinical timeline relative to pembrolizumab initiation\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eTimepoint\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eEvent\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003ePrior history\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eRight nephrectomy for clear cell renal cell carcinoma (pT1b, grade 2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003ePre-adjuvant baseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eComplete resection of solitary humerus metastasis; M1-NED status achieved\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eT0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003ePembrolizumab initiated (200 mg q3 weeks; KEYNOTE-564 dosing schedule)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eT+~18 weeks (after cycle 6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eAfter cycle 6: progressive anasarca and dyspnea; pembrolizumab held\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eT+~18 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eCT: large bilateral pleural effusions, mild ascites, no tumor progression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eT+~19-20 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eHospital admission; thoracentesis (1.5 L): exudative, 20% eosinophils, ADA 42.8 U/L, cytology/cultures negative\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eT+~19-20 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eTTE: LVEF 71%, small pericardial effusion (0.53 cm), no tamponade\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eT+~19-20 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eMethylprednisolone 1 mg/kg initiated; rapid clinical improvement\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eFollow-up (2 weeks)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eSymptom resolution, normalized eosinophils, steroid taper ongoing, M1-NED maintained\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eT0 indicates pembrolizumab initiation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Diagnostic approach to suspected immune checkpoint inhibitor-related serositis\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eDomain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eKey elements\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eRationale\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eOncologic assessment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eCT/PET-CT for tumor response; exclude new serosal nodularity; repeat sampling or tissue biopsy if uncertainty persists; tumor markers if relevant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eDifferentiate irAE from malignant serosal involvement or progression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eSerosal fluid analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eCell count with differential (mandatory eosinophil %); protein/LDH (Light\u0026apos;s criteria); glucose; cytology; flow cytometry if lymphoma possible\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eCharacterize inflammatory phenotype; detect malignancy; identify eosinophilic effusion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eMicrobiology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eGram stain/culture; fungal culture; AFB smear/culture; TB NAAT/ADA/IGRA as appropriate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eExclude infection before immunosuppression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eCardiac evaluation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eECG; troponin; natriuretic peptides; echocardiography; consider CMR; pericardiocentesis if tamponade or diagnostic uncertainty\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eAssess pericardial involvement; rule out myocarditis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eSystemic causes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eRenal function; urinalysis/proteinuria; liver tests; albumin; thyroid function; venous duplex/CTPA if thromboembolism suspected\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eExclude heart/renal/hepatic failure and thromboembolism\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eEosinophil context\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eSerial absolute eosinophil counts; review for rash, asthma, atopy; basic autoimmunity (ANA/ANCA) if indicated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eCharacterize eosinophilic phenotype; consider alternative inflammatory etiologies\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Management of immune checkpoint inhibitor-related serositis by scenario\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eScenario\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eManagement considerations\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eAsymptomatic small effusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eRepeat imaging; evaluate for progression/infection; consider holding ICI if rapid accumulation; cardio-oncology/pulmonology consultation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eSymptomatic moderate-large effusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eDiagnostic/therapeutic drainage with fluid differential and cytology; hold ICI; systemic corticosteroids (1-2 mg/kg) once infection excluded; slow taper\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003ePericardial effusion with hemodynamic compromise\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eUrgent pericardiocentesis or surgical window; intensive care unit monitoring; high-dose steroids once infection excluded; evaluate for myocarditis (troponin, CMR)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eSteroid-refractory/dependent disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eMultidisciplinary input; steroid-sparing agents (azathioprine, infliximab) for pericardial disease; IL-5 axis blockade (mepolizumab, benralizumab) for eosinophil-driven disease; IL-1 blockade (anakinra, rilonacept) may be considered for recurrent pericarditis phenotypes (evidence largely extrapolated to ICI-associated cases).\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eICI rechallenge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eIndividualize based on severity, compartment, and oncologic context; consider only after complete resolution with close monitoring; avoid after life-threatening events unless no alternatives\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4. Reporting of effusion eosinophils in selected immune checkpoint inhibitor-associated serositis reports\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003ePublication (ref.)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eICI (agent)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eSerosal manifestation(s)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eEffusion sampled\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eCell differential reported\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eEosinophil % in effusion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003ePembro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003ePericarditis (steroid-dependent)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eNot specified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eICI (NR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eConstrictive pericarditis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eNot specified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eNivo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eRecurrent pericarditis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eNivo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003ePericardial effusion/tamponade (3 cases) + review\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003ePartially (cytology/leukocytes)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eNivo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003ePericardial effusion (case report)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eICI (various)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eImmune-related pericarditis (case series; rechallenge)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eNot specified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eNivo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003ePolyserositis (chylous ascites \u0026plusmn; effusions)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003ePartially (lymphocyte-predominant described)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eNivo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003ePleural + pericardial effusions (late-onset)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003ePembro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eChronic pleuritis/pleural effusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eYes (lymphocytes 90%, neutrophils 10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eAtezo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eChronic pleuritis/pleural effusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003eYes (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: Atezo, atezolizumab; ICI, immune checkpoint inhibitor; N/A, not applicable; NR, not reported; Nivo, nivolumab; Pembro, pembrolizumab. \u0026ldquo;Not reported\u0026rdquo; includes cases where effusion was not sampled and/or the differential was not specified.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Immune checkpoint inhibitor, immune-related adverse events, serositis, polyserositis, eosinophilic pleural effusion, pericardial effusion, interleukin-5, cardio-oncology, case report, KEYNOTE-564","lastPublishedDoi":"10.21203/rs.3.rs-8910623/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8910623/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Pembrolizumab is a standard adjuvant option for patients with high-risk clear cell renal cell carcinoma after nephrectomy. Serositis is an uncommon immune-related adverse event under programmed cell death 1/programmed death ligand 1 blockade. Pericardial involvement is the best-characterized serosal compartment, and cohort data suggest a several-fold increased risk of pericardial events compared with non-immune checkpoint inhibitor-treated controls. However, eosinophil percentages in serosal fluid are rarely reported, leaving the incidence and clinical significance of eosinophilic serositis poorly characterized.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation: \u003c/strong\u003eA 55-year-old man with clear cell renal cell carcinoma (metastatic disease with no evidence of disease after nephrectomy and bone metastasectomy) received adjuvant pembrolizumab (200 mg every 3 weeks) per the KEYNOTE-564 regimen. After six cycles he developed anasarca with large bilateral pleural effusions, mild ascites, and a small pericardial effusion. Pleural fluid was exudative and eosinophil-rich (20%), consistent with eosinophilic pleural effusion, with negative cytology and microbiology. Adenosine deaminase was mildly elevated (42.8 U/L) but tuberculosis evaluation was negative. Transthoracic echocardiography showed preserved biventricular function and no tamponade. Pembrolizumab discontinuation, thoracentesis, and systemic corticosteroids (methylprednisolone 1 mg/kg with taper) resulted in rapid clinical and laboratory improvement.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: This case supports pembrolizumab-associated eosinophilic polyserositis with pericardial involvement as a rare phenotype within the cardio-oncology spectrum. In a targeted review of published immune checkpoint inhibitor-associated serositis/pleuritis reports, effusion eosinophil percentage was explicitly reported in only a small minority of cases, a gap that may obscure a mechanistically and therapeutically distinct inflammatory subgroup. We provide a diagnostic and management framework and highlight emerging options, including interleukin-5 axis blockade, for eosinophil-driven disease.\u003c/p\u003e","manuscriptTitle":"Pembrolizumab-associated eosinophilic polyserositis with pericardial involvement during adjuvant therapy for clear cell renal cell carcinoma: a case report and narrative review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-08 17:14:24","doi":"10.21203/rs.3.rs-8910623/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5a6709c0-ae0d-41cb-ba5e-5ac4b1e3d104","owner":[],"postedDate":"March 8th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-12T20:39:33+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-08 17:14:24","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8910623","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8910623","identity":"rs-8910623","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}