The ClinicianThe ClinicianКлиницист1818-83382412-8775Publishing House ABV Press68810.17650/1818-8338-2025-19-4-K759REVIEWОБЗОРReview ArticleCapillary leak syndrome – rare complication of therapy with immune checkpoint inhibitorСиндром капиллярной утечки – редкое осложнение терапии ингибиторами контрольных точек иммунного ответаhttps://orcid.org/0000-0002-7410-9784KlimenkoAlesya A.КлименкоАлеся Александровна
Russian Federation

MD, PhD, Associate Professor, Head of the Department of Acad. A.I. Nesterov of Faculty Therapy

д.м.н., доцент, заведующая кафедрой факультетской терапии им. акад. А.И. Нестерова Института клинической медицины

kaartem@gmail.comhttps://orcid.org/0000-0001-9152-3234KondrashovArtem A.КондрашовАртем Александрович
Russian Federation
kaartem@gmail.comhttps://orcid.org/0000-0001-8266-6022AndriyashkinaDarya Yu.АндрияшкинаДарья Юрьевна
Russian Federation
andryashkina.darya@yandex.ruhttps://orcid.org/0009-0001-8667-8511KrimanE. S. R.КриманЭ. С. Р.
Russian Federation
kaartem@gmail.comhttps://orcid.org/0009-0009-3651-5990KorchmaS. Yu.КорчмаС. Ю.
Russian Federation
kaartem@gmail.comN.I. Pirogov Russian National Research Medical University, Ministry of Health of RussiaФГАОУ ВО «Российский национальный исследовательский медицинский университет им. Н. И. Пирогова» Минздрава РоссииN.I. Pirogov City Clinical Hospital No. 1, Moscow Healthcare DepartmentГБУЗ г. Москвы «Городская клиническая больница № 1 им. Н. И. Пирогова Департамента здравоохранения г. Москвы»1703202619419331603202616032026Copyright ©; 2026, Klimenko A.А., Kondrashov A.A., Andriyashkina D.Y., Kriman E.R., Korchma S.Y.Copyright ©; 2026, Клименко А.А., Кондрашов А.А., Андрияшкина Д.Ю., Криман Э.Р., Корчма С.Ю.2026Klimenko A.А., Kondrashov A.A., Andriyashkina D.Y., Kriman E.R., Korchma S.Y.Клименко А.А., Кондрашов А.А., Андрияшкина Д.Ю., Криман Э.Р., Корчма С.Ю.https://creativecommons.org/licenses/by/4.0https://klinitsist.abvpress.ru/Klin/article/view/688

Immune checkpoint inhibitors are relatively new and effective agents for treatment of malignant tumors, widely used to combat neoplasms of various locations. Nevertheless, these drugs can cause unwanted immune-mediated phenomena, one of which is capillary leak syndrome. Capillary leak syndrome is characterized by leakage of the liquid part of the plasma from the vascular lumen and is complicated by development of generalized edematous syndrome and hypovolemic shock. Although this complication is rare, it is associated with high risk of fatal outcome, and currently there are no established diagnostic and therapeutic approaches. The aim of our review was to present modern data on capillary leak syndrome caused by immune checkpoint inhibitors. We performed a search and comparative analysis of articles describing this complication. In the PubMed / Medline, Scopus, Web of Science, Google Scholar, and eLibrary databases, 30 clinical case descriptions from 2019 to 2025 were found, 25 of which were included in the review. Development of this complication was most often associated with the use of pembrolizumab (44 %). The median time to development was 12.7 weeks. In one patient, the complication developed against the background of tumor progression. Peripheral edema was described in 96 % of patients. Pleural effusion was the 2nd most common clinical manifestation (68 %). For the management of the complication, 1st-line systemic glucocorticoids were used in 80 % of patients, and they were effective in approximately one third of cases. 13 patients received 2nd-line immunosuppressants, mostly intravenous immunoglobulin. The mortality rate during follow-up was 28 %. With accumulating clinical experience of immune checkpoint inhibitor use, the spectrum and frequency of associated adverse events, including capillary leak syndrome, are expected to grow. This underscores the need to develop diagnostic and therapeutic strategies for this adverse reaction.

Ингибиторы контрольных точек иммунного ответа (ИКТИ) – сравнительно новые и эффективные средства лечения злокачественных опухолей. Тем не менее эти препараты способны вызывать нежелательные иммуноопосредованные явления, одним из которых является синдром капиллярной утечки (СКУ). СКУ характеризуется выходом жидкой части плазмы из просвета сосудов и осложняется формированием генерализованного отечного синдрома и гиповолемического шока. Хотя осложнение является редким, оно ассоциировано с высоким риском летального исхода, а диагностические и терапевтические подходы к нему в настоящий момент не разработаны. Цель обзора – представить современные данные о СКУ, вызванном ИКТИ. Проведен поиск и сравнительный анализ статей, описывающих данное осложнение. В базах PubMed / Medline, Scopus, Web of Science, Google Scholar, eLIBRARY найдено 30 описаний клинических случаев с 2019 по 2025 г., 25 из них включены в обзор. Наиболее часто (44 %) развитие СКУ было ассоциировано с приемом пембролизумаба. Медиана срока развития синдрома составила 12,7 нед. У 1 пациента СКУ развился на фоне прогрессирования злокачественного новообразования. Периферические отеки описаны у 96 % пациентов, 2-м по частоте встречаемости среди клинических проявлений был плевральный выпот (68 %). Для купирования осложнения в качестве препаратов 1-й линии у 80 % пациентов использовали системные глюкокортикоиды, их эффективность наблюдалась примерно в 1 / 3 случаев. Иммуносупрессивную терапию 2-й линии получали 13 пациентов. В 12 наблюдениях применяли внутривенный иммуноглобулин, в 58 % случаев наблюдался явный клинический эффект. Летальность в ходе наблюдения составила 28 %. Ожидается, что по мере накопления клинического опыта применения ИКТИ спектр и частота ассоциированных с иммунотерапией нежелательных явлений, включая СКУ, будут пересматриваться в сторону увеличения, что определяет необходимость разработки подходов к диагностике и лечению данной нежелательной реакции.

capillary leak syndromeimmune checkpoint inhibitormalignant neoplasmimmunotherapyimmune-mediated adverse eventimmune-mediated edemaClarkson’s diseaseimmunosuppressionglucocorticoidсиндром капиллярной утечкиингибитор контрольных точек иммунного ответазлокачественное новообразованиеиммунотерапияиммуноопосредованное нежелательное явлениеиммуноопосредованный отексиндром КларксонаиммуносупрессияглюкокортикоидPauken K.E., Dougan M., Rose N.R. et al. Adverse events following cancer immunotherapy: obstacles and opportunities. Trends Immunol 2019;40(6):511–23. DOI: 10.1016/j.it.2019.04.002Tivol E.A., Borriello F., Schweitzer A.N. et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995;3(5):541–7. DOI: 10.1016/1074-7613(95)90125-6Wang Y., Zhang H., Liu C. et al. Immune checkpoint modulators in cancer immunotherapy: recent advances and emerging concepts. J Hematol Oncol 2022;15(1):111. DOI: 10.1186/s13045-022-01325-0Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, Published: November 27, 2017, U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute.De Miguel M., Calvo E. Clinical challenges of immune checkpoint inhibitors. Cancer Cell 2020;38(3):326–33. DOI: 10.1016/j.ccell.2020.07.004Martins F., Sofiya L., Sykiotis G.P. et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol 2019;16(9):563–80. DOI: 10.1038/s41571-019-0218-0Larkin J., Chiarion-Sileni V., Gonzalez R. et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2019;381(16):1535–46. DOI: 10.1056/NEJMoa1910836Eggermont A.M.M., Kicinski M., Blank C.U. et al. Association between immune-related adverse events and recurrence-free survival among patients with stage III melanoma randomized to receive pembrolizumab or placebo: a secondary analysis of a randomized clinical trial. JAMA Oncol 2020;6(4):519–27. DOI: 10.1001/jamaoncol.2019.5570Serna-Higuita L.M., Amaral T., Forschner A. et al. Association between immune-related adverse events and survival in 319 stage IV melanoma patients treated with PD-1-based immunotherapy: an approach based on clinical chemistry. Cancers (Basel) 2021;13(23):6141. DOI: 10.3390/cancers13236141Haanen J.B.A.G., Carbonnel F., Robert C. et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28(suppl_4):iv119–42. DOI: 10.1093/annonc/mdx225Andres M.S., Ramalingam S., Rosen S.D. et al. The spectrum of cardiovascular complications related to immune-checkpoint inhibitor treatment: including myocarditis and the new entity of non inflammatory left ventricular dysfunction. Cardiooncology 2022;8(1):21. DOI: 10.1186/s40959-022-00147-wSalem J.E., Manouchehri A., Moey M. et al. Spectrum of cardiovascular toxicities of immune checkpoint inhibitors: a pharmacovigilance study. Lancet Oncol 2018;19(12):1579–89. DOI: 10.1016/S1470-2045(18)30608-9Javaid A., Bennett C., Rao A. et al. Rare immune-related adverse events (irAEs): approach to diagnosis and management. Pharmaceut Med 2024;38(1):25–38. DOI: 10.1007/s40290-023-00508-5Velev 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. DOI: 10.1016/j.ejca.2022.11.001Phillips G.S., Wu J., Hellmann M.D. et al. Treatment outcomes of immune-related cutaneous adverse events. J Clin Oncol 2019;37(30):2746–58. DOI: 10.1200/JCO.18.02141Belum V.R., Benhuri B., Postow M.A. et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer 2016;60:12–25. DOI: 10.1016/j.ejca.2016.02.010Zhai Y., Ye X., Hu F. et al. Endocrine toxicity of immune checkpoint inhibitors: a real-world study leveraging US Food and Drug Administration adverse events reporting system. J Immunother Cancer 2019;7(1):286. DOI: 10.1186/s40425-019-0754-2Johnson D.B., Nebhan C.A., Moslehi J.J. et al. Immune-checkpoint inhibitors: long-term implications of toxicity. Nat Rev Clin Oncol 2022;19(4):254–67. DOI: 10.1038/s41571-022-00600-wRiveiro-Barciela M., Carballal S., Díaz-González Á. et al. Management of liver and gastrointestinal toxicity induced by immune checkpoint inhibitors: position statement of the AEEH-AEG-SEPD-SEOM-GETECCU. Gastroenterol Hepatol 2024;47(4):401–32. DOI: 10.1016/j.gastrohep.2023.10.009Suresh K., Naidoo J., Lin C.T. et al. Immune checkpoint immunotherapy for non-small cell lung cancer: Benefits and pulmonary toxicities. Chest 2018;154(6):1416–23. DOI: 10.1016/j.chest.2018.08.1048Choi J., Lee S.Y. Clinical characteristics and treatment of immune-related adverse events of immune checkpoint inhibitors. Immune Netw 2020;20(1):e9. DOI: 10.4110/in.2020.20.e9Spain L., Diem S., Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev 2016;44:51–60. DOI: 10.1016/j.ctrv.2016.02.001Abdel-Wahab N., Suarez-Almazor M.E. Frequency and distribution of various rheumatic disorders associated with checkpoint inhibitor therapy. Rheumatology (Oxford) 2019;58(Suppl 7):vii40–8. DOI: 10.1093/rheumatology/kez297Clarkson B., Thompson D., Horwith M. et al. Cyclical edema and shock due to increased capillary permeability. Am J Med 1960;29:193–216. DOI: 10.1016/0002-9343(60)90018-8Kapoor P., Greipp P.T., Schaefer E.W. et al. Idiopathic systemic capillary leak syndrome (Clarkson’s disease): the Mayo clinic experience. Mayo Clin Proc 2010;85(10):905–12. DOI: 10.4065/mcp.2010.0159Anipindi M., Kacarow J., Bitetto D. Systemic capillary leak syndrome (SCLS) presentation in patients receiving anti-cancer treatments. Cureus 2023;15(4):e38335. DOI: 10.7759/cureus.38335Shin J.I., Lee K.H., Lee I.R. et al. Systemic capillary leak syndrome (Clarkson’s syndrome) in cancer patients: a systematic review. J Clin Med 2018;7(11):418. DOI: 10.3390/jcm7110418Mertz P., Lebrun-Vignes B., Salem J.E. et al. Characterizing drug-induced capillary leak syndromes using the World Health Organization VigiBase. J Allergy Clin Immunol 2019;143(1):433–6. DOI: 10.1016/j.jaci.2018.09.001Izzedine H., Mathian A., Amoura Z. et al. Anticancer drug-induced capillary leak syndrome. Kidney Int Rep 2022;7(5): 945–053. DOI: 10.1016/j.ekir.2022.02.014Lescure C., Lescoat A., Sale A. et al. Systemic capillary leak syndrome (Clarkson’s disease) as a complication of anti-programmed death 1 immunotherapy. J Thorac Oncol 2019;14(6):e131–2. DOI: 10.1016/j.jtho.2019.02.003Umeda Y., Hayashi H., Sugiyama S. et al. Systemic capillary leak syndrome triggered by anti-programmed death 1 checkpoint inhibitor in psoriasis. J Dermatol 2020;47:1322–5. DOI: 10.1111/1346-8138.15541Polishchuk I., Yakobson A., Zemel M. et al. Nivolumab-induced systemic capillary leak syndrome as an ultra rare life-threatening phenomenon of late toxicity and intravenous immunoglobulin efficacy. Immunotherapy 2021;13(10):807–11. DOI: 10.2217/imt-2020-0335Qin H., Vlaminck B., Owoyemi I. et al. Successful treatment of pembrolizumab-induced severe capillary leak syndrome and lymphatic capillary dysfunction. Mayo Clin Proc Innov Qual Outcomes 2021;5(3):670–4. DOI: 10.1016/j.mayocpiqo.2021.01.004Neuville C., Aubin F., Puzenat E. et al. Nivolumab-induced capillary leak syndrome associated with chylothorax in a melanoma patient: a case report and review of the literature. Front Oncol 2022;12:1032844. DOI: 10.3389/fonc.2022.1032844Marin A.I., Deitz G.A., Mudie L.I. et al. Bilateral choroidal effusions and angle closure in the setting of systemic capillary leak syndrome from HLA-directed vaccine and pembrolizumab therapy for squamous cell carcinoma. Am J Ophthalmol Case Rep 2022;29:101777. DOI: 10.1016/j.ajoc.2022.101777Petitdemange A., Béguin L., Dimitrov Y. Immune checkpoint inhibitors-induced systemic capillary leak syndrome: a report of two cases. Rev Med Interne 2023;44(1):35–7. DOI: 10.1016/j.revmed.2022.11.001Grzegorczyk A., Marczyńska Z., Matkowski R. et al. Severe complications of nivolumab monotherapy in an adolescent with malignant melanoma. Cent Eur J Immunol 2023;48(3):251–6. DOI: 10.5114/ceji.2023.130864Ni H., Ding X., Wu S. et al. Case report: clinical experience of treating pembrolizumab-induced systemic capillary leak syndrome (SCLS) in one patient with metastatic gastroesophageal junction squamous cell carcinoma. Pathol Oncol Res 2023;29:1611330. DOI: 10.3389/pore.2023.1611330Tachi H., Shibagaki A., Teshima S. et al. Capillary leak syndrome with pulmonary edema preceded by organizing pneumonia caused by combination therapy with nivolumab and ipilimumab: a case report. JTO Clin Res Rep 2023;4(4):100491. DOI: 10.1016/j.jtocrr.2023.100491Raja A., Kumar A., Abdullah M. et al. Checkpoint inhibitor-related capillary leak syndrome (CLS). Cureus 2024;16(3):e55719. DOI: 10.7759/cureus.55719Castelli 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. DOI: 10.12890/2024_004237Imam N., Khan I., Michael G. et al. Capillary leak syndrome following immune checkpoint inhibition: a unique cause of acute kidney injury. AJKD 2024;83(4):26. DOI: 10.1053/j.ajkd.2024.01.090Ertl C., Kroiss M., French L.E. et al. Extracorporeal photopheresis effective in immune-related capillary leak/polyserositis in splenectomized patient. Eur J Cancer 2025;216:115189. DOI: 10.1016/j.ejca.2024.115189Shah R., Saff R. Delayed capillary leak syndrome after pembrolizumab treatment of breast cancer. Ann Allergy Asthma Immunol 2024;1336:114. DOI: 10.1016/j.anai.2024.08.491Peddi V.C., Siddique M.S., Jones C. et al. Pembrolizumab-induced capillary leak syndrome and recurrent pleural effusions: a rare complication. Chest 2024;166(4):a4162–3. DOI: 10.1016/j.chest.2024.06.2527Roberge-Maltais E., Lévesque E., Castonguay V. et al. Pembrolizumab-induced simultaneous and refractory systemic capillary leak and cytokine release syndromes: a case report. Curr Oncol 2025;32(8):469. DOI: 10.3390/curroncol32080469Branford R.K., Hernandez Lopez L., Gonzalez Frontera A.P. et al. Pembrolizumab-induced capillary leak syndrome: a rare but life-threatening immune-related adverse event. Cureus 2024;17(10):e95038. DOI: 10.7759/cureus.95038Muddasani A., Waymire M.P., Bhatti S.A. Combination immunotherapy (relatlimab/nivolumab)-associated capillary leak syndrome: a case report. AIM Clinical Cases 2025;4:e250753. DOI:10.7326/aimcc.2025.0753Lambert K., Kistenfeger Q., Chalif J. et al. Immunotherapy-associated capillary leak syndrome in endometrial cancer: a case report and review of the literature. Gynecol Oncol Rep 2025;61:101955. DOI: 10.1016/j.gore.2025.101955Pineton de Chambrun M., Constantin J.M., Mathian A. et al. Clarkson’s disease episode or secondary systemic capillary leak-syndrome: that is the question! Chest 2021;159(1):441. DOI: 10.1016/j.chest.2020.07.084Duron L., Delestre F., Amoura Z. et al. Idiopathic and secondary capillary leak syndromes: a systematic review of the literature. Rev Med Interne 2015;36(6):386–94. [In French]. DOI: 10.1016/j.revmed.2014.11.005Wong So J., Bouibede F., Jonville-Béra A.P. et al. Immune checkpoint inhibitor-associated capillary leak syndrome: a systematic review and a worldwide pharmacovigilance study. J Intern Med 2023;294(1):58–68. DOI: 10.1111/joim.13641Siddall E., Khatri M., Radhakrishnan J. Capillary leak syndrome: etiologies, pathophysiology, and management. Kidney Int 2017;92(1):37–46. DOI: 10.1016/j.kint.2016.11.029Largeau B., Cracowski J.L., Lengellé C. et al. Drug-induced peripheral oedema: an aetiology-based review. Br J Clin Pharmacol 2021;87(8):3043–55. DOI: 10.1111/bcp.14752Xie Z., Chan E., Yin Y. et al. Inflammatory markers of the systemic capillary leak syndrome (Clarkson disease). J Clin Cell Immunol 2014;5:1000213. DOI: 10.4172/2155-9899.1000213Benzaquen M., Christ L., Sutter N., Özdemir B.C. Nivolumab-induced eosinophilic fasciitis: an unusual immune-related adverse event that needs to be recognized by practitioners. Ann Dermatol Venerol 2023;140(4):304–7. DOI: 10.1016/j.annder.2023.07.001Bichon A., Bourenne J., Gainnier M. et al. Capillary leak syndrome: state of the art in 2021. Rev Med Interne 2021;42(11):789–96. DOI: 10.1016/j.revmed.2021.05.012Zierold S., Akcetin L.S., Gresser E. et al. Checkpoint-inhibitor induced oolyserositis with edema. Cancer Immunol Immunother 2022;71(12):3087–92. DOI: 10.1007/s00262-022-03211-7Druey K.M., Greipp P.R. Narrative review: Clarkson disease-systemic capillary leak syndrome. Ann Intern Med 2010;153(2): 90–8. DOI: 10.1059/0003-4819-153-2-201007200-00005Amoura Z., Papo T., Ninet J. et al. Systemic capillary leak syndrome: report on 13 patients with special focus on course and treatment. Am J Med 1997;103(6):514–9. DOI: 10.1016/s0002-9343(97)00272-6Yabe H., Yabe M., Koike T. et al. Rapid improvement of life-threatening capillary leak syndrome after stem cell transplantation by bevacizumab. Blood 2010;115(13):2723–4. DOI: 10.1182/blood-2009-11-247056Brahmer J.R., Lacchetti C., Schneider B.J. et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018;36(17):1714–68. DOI: 10.1200/JCO.2017.77.6385Dolladille C., Ederhy S., Sassier M. et al. Immune checkpoint inhibitor rechallenge after immune-related adverse events in patients with cancer. JAMA Oncol 2020;6(6):865–71. DOI: 10.1001/jamaoncol.2020.0726L’Orphelin J.M., Da Silva A., Cabon J. et al. Immune checkpoint inhibitor rechallenge after immune-related adverse events: a retrospective study from VigiBase update in 2024 looking for emergent safety signals. BMJ Open 2024;14(12):e091708. DOI: 10.1136/bmjopen-2024-091708Ruf T., Kramer R., Forschner A. et al. Second-line therapies for steroid-refractory immune-related adverse events in patients treated with immune checkpoint inhibitors. Eur J Cancer 2024;203:114028. DOI: 10.1016/j.ejca.2024.114028Ogusu S., Harutani Y., Tozuka T. et al. Second-line immunosuppressant administration for steroid-refractory immune-related adverse events in patients with lung cancer. Cancer Immunol Immunother 2023;72(11):3765–72. DOI: 10.1007/s00262-023-03528-xVerheijden R.J., van Eijs M.J.M., May A.M. et al. Immunosuppression for immune-related adverse events during checkpoint inhibition: an intricate balance. NPJ Precis Oncol 2023;7(1):41. DOI: 10.1038/s41698-023-00380-1Verheijden R.J., Burgers F.H., Janssen J.C. et al. Corticosteroids and other immunosuppressants for immune-related adverse events and checkpoint inhibitor effectiveness in melanoma. Eur J Cancer 2024;207:114172. DOI: 10.1016/j.ejca.2024.114172Bai X., Hu J., Betof Warner A. et al. Early use of high-dose glucocorticoid for the management of irAE is associated with poorer survival in patients with advanced melanoma treated with anti-PD-1 monotherapy. Clin Cancer Res 2021;27(21):5993–6000. DOI: 10.1158/1078-0432.CCR-21-1283