Capillary leak syndrome: etiologies, pathophysiology, and management

In various human diseases, an increase in capillary permeability to proteins leads to the loss of protein-rich fluid from the intravascular to the interstitial space. Although sepsis is the disease most commonly associated with this phenomenon, many other diseases can lead to a “sepsis-like” syndrome with manifestations of diffuse pitting edema, exudative serous cavity effusions, noncardiogenic pulmonary edema, hypotension, and, in some cases, hypovolemic shock with multiple-organ failure. The term capillary leak syndrome has been used to describe this constellation of disease manifestations associated with an increased capillary permeability to proteins. Diseases other than sepsis that can result in capillary leak syndrome include the idiopathic systemic capillary leak syndrome or Clarkson’s disease, engraftment syndrome, differentiation syndrome, the ovarian hyperstimulation syndrome, hemophagocytic lymphohistiocytosis, viral hemorrhagic fevers, autoimmune diseases, snakebite envenomation, and ricin poisoning. Drugs including some interleukins, some monoclonal antibodies, and gemcitabine can also cause capillary leak syndrome. Acute kidney injury is commonly seen in all of these diseases. In addition to hypotension, cytokines are likely to be important in the pathophysiology of acute kidney injury in capillary leak syndrome. Fluid management is a critical part of the treatment of capillary leak syndrome; hypovolemia and hypotension can cause organ injury, whereas capillary leakage of administered fluid can worsen organ edema leading to progressive organ injury. The purpose of this article is to discuss the diseases other than sepsis that produce capillary leak and review their collective pathophysiology and treatment. In various human diseases, an increase in capillary permeability to proteins leads to the loss of protein-rich fluid from the intravascular to the interstitial space. Although sepsis is the disease most commonly associated with this phenomenon, many other diseases can lead to a “sepsis-like” syndrome with manifestations of diffuse pitting edema, exudative serous cavity effusions, noncardiogenic pulmonary edema, hypotension, and, in some cases, hypovolemic shock with multiple-organ failure. The term capillary leak syndrome has been used to describe this constellation of disease manifestations associated with an increased capillary permeability to proteins. Diseases other than sepsis that can result in capillary leak syndrome include the idiopathic systemic capillary leak syndrome or Clarkson’s disease, engraftment syndrome, differentiation syndrome, the ovarian hyperstimulation syndrome, hemophagocytic lymphohistiocytosis, viral hemorrhagic fevers, autoimmune diseases, snakebite envenomation, and ricin poisoning. Drugs including some interleukins, some monoclonal antibodies, and gemcitabine can also cause capillary leak syndrome. Acute kidney injury is commonly seen in all of these diseases. In addition to hypotension, cytokines are likely to be important in the pathophysiology of acute kidney injury in capillary leak syndrome. Fluid management is a critical part of the treatment of capillary leak syndrome; hypovolemia and hypotension can cause organ injury, whereas capillary leakage of administered fluid can worsen organ edema leading to progressive organ injury. The purpose of this article is to discuss the diseases other than sepsis that produce capillary leak and review their collective pathophysiology and treatment. In various human diseases, an increase in capillary permeability to proteins leads to the loss of protein-rich fluid from the intravascular to the interstitial space. Although sepsis is the disease most commonly associated with this phenomenon, many other diseases can lead to a “sepsis-like” syndrome with manifestations of diffuse pitting edema, exudative serous cavity effusions, noncardiogenic pulmonary edema, hypotension, and, in some cases, hypovolemic shock with multiple-organ failure. The term capillary leak syndrome has been used to describe this constellation of disease manifestations associated with an increased capillary permeability to proteins. Diseases other than sepsis that can result in capillary leak syndrome include the idiopathic systemic capillary leak syndrome (SCLS) or Clarkson’s disease, engraftment syndrome, differentiation syndrome, ovarian hyperstimulation syndrome (OHSS), hemophagocytic lymphohistiocytosis (HLH), viral hemorrhagic fevers (VHFs), autoimmune diseases, snakebite envenomation, and ricin poisoning. Drugs, including some interleukins (ILs), certain monoclonal antibodies, and gemcitabine can also cause capillary leak syndrome. Acute kidney injury (AKI) is commonly seen in all of these diseases. In addition to hypotension, cytokines are likely to be important in the pathophysiology of AKI in capillary leak syndrome. Fluid management is a critical part of the treatment of capillary leak syndrome; hypovolemia and hypotension can cause organ injury, whereas capillary leakage of administered fluid can worsen organ edema, leading to progressive organ injury. The purpose of this article is to discuss the diseases other than sepsis that produce capillary leak and review their collective pathophysiology and treatment. The true incidence of capillary leak syndrome is unknown. It is likely that many cases of capillary leak are unrecognized and labeled as culture-negative sepsis or are attributed to an alternate pathophysiology such as hypoalbuminemia. Many of the diseases leading to capillary leak syndrome are uncommon, and in only a variable proportion of those with a predisposing condition will a clinically significant capillary leak develop. Over a 26-year period at the Mayo Clinic, only 25 cases of SCLS (or Clarkson’s disease) were documented.1Kapoor 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: 905-912Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar Drug-induced capillary leak syndrome has a variable incidence depending on the specific drug studied. In a study of interleukin (IL)-2 administration to cancer patients, severe fluid retention developed in 16 of 25 patients.2Rosenberg S.A. Lotze M.T. Muul L.M. et al.Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer.N Engl J Med. 1985; 313: 1485-1492Crossref PubMed Scopus (2246) Google Scholar Conversely, there are only a handful of case reports of gemcitabine-induced capillary leak. In the case of rituximab treatment for chronic lymphocytic leukemia, the risk of severe capillary leak is universal when the lymphocyte count is >50.0 × 109/l.3Winkler U. Jensen M. Manzke O. et al.Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8).Blood. 1999; 94: 2217-2224Crossref PubMed Google Scholar Capillary leak due to engraftment syndrome following hematopoietic stem cell transplantation has an incidence of 7% to 55%, depending on the definition of engraftment syndrome used.4Spitzer T.R. Engraftment syndrome: double-edged sword of hematopoietic cell transplants.Bone Marrow Transplant. 2015; 50: 469-475Crossref PubMed Scopus (74) Google Scholar Capillary leak due to differentiation syndrome following the treatment of acute promyelocytic leukemia with retinoic acid or arsenic trioxide occurs in ∼25% of cases.5Luesink M. Jansen J.H. Advances in understanding the pulmonary infiltration in acute promyelocytic leukaemia.Br J Haematol. 2010; 151: 209-220Crossref PubMed Scopus (30) Google Scholar In the example of OHSS, severe capillary leak is seen in only 2% of cases.6Fabregues F. Balasch J. Gines P. et al.Ascites and liver test abnormalities during severe ovarian hyperstimulation syndrome.Am J Gastroenterol. 1999; 94: 994-999Crossref PubMed Google Scholar The incidence of adult HLH was estimated to be 1 in 800,000 in Japan.7Ishii E. Ohga S. Imashuku S. et al.Nationwide survey of hemophagocytic lymphohistiocytosis in Japan.Int J Hematol. 2007; 86: 58-65Crossref PubMed Scopus (301) Google Scholar Because the signs and symptoms of HLH overlap with those of many other diseases, it is likely that HLH is underdiagnosed. The proportion of individuals with HLH in whom capillary leak develops is unknown. Viral hemorrhagic fever is relatively uncommon, though most of these patients demonstrate capillary leak. In summary, the incidence of capillary leak syndrome varies from common to very rare, depending on the disease or drug in question. Patients with severe capillary leak syndrome are likely to cluster in the intensive care unit, and thus, practitioners who frequently round in the intensive care unit will encounter these patients. SCLS is a rare disorder characterized by episodic increases in vascular permeability resulting in acute losses of protein-rich fluid from the intravascular to the interstitial space.1Kapoor 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: 905-912Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 8Clarkson B. Thompson D. Horwith M. Luckey E.H. Cyclical edema and shock due to increased capillary permeability.Am J Med. 1960; 29: 193-216Abstract Full Text PDF PubMed Scopus (278) Google Scholar, 9Atkinson J.P. Waldmann T.A. Stein S.F. et al.Systemic capillary leak syndrome and monoclonal IgG gammopathy; studies in a sixth patient and a review of the literature.Medicine (Baltimore). 1977; 56: 225-239Crossref PubMed Scopus (142) Google Scholar A typical presentation begins with a prodrome of fatigue, dizziness, and flulike symptoms followed by the rapid-onset of shock, systemic pitting edema, hemoconcentration, and hypoalbuminemia. Other common disease manifestations include AKI, pleural and pericardial effusions, rhabdomyolysis, and sometimes compartment syndrome of the extremities.1Kapoor 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: 905-912Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar After a variable number of days, the vascular permeability spontaneously improves, and the blood pressure stabilizes. During this recovery phase, life-threatening pulmonary edema can develop.1Kapoor 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: 905-912Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 10Chihara R. Nakamoto H. Arima H. et al.Systemic capillary leak syndrome.Intern Med. 2002; 41: 953-956Crossref PubMed Scopus (30) Google Scholar, 11Tahirkheli N.K. Greipp P.R. Treatment of the systemic capillary leak syndrome with terbutaline and theophylline. A case series.Ann Intern Med. 1999; 130: 905-909Crossref PubMed Scopus (113) Google Scholar, 12Bouhaja B. Somrani N. Thabet H. et al.Adult respiratory distress syndrome complicating a systemic capillary leak syndrome.Intensive Care Med. 1994; 20: 307-308Crossref PubMed Scopus (15) Google Scholar The frequency of episodes can vary widely between patients, with intervals ranging from days to years.13Druey K.M. Greipp P.R. Narrative review: the systemic capillary leak syndrome.Ann Intern Med. 2010; 153: 90-98Crossref PubMed Scopus (196) Google Scholar The majority of patients have a detectable monoclonal protein in the serum, although the importance of the monoclonal protein in the disease pathogenesis is unclear.1Kapoor 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: 905-912Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 14Amoura 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: 514-519Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 15Gousseff M. Arnaud L. Lambert M. et al.The systemic capillary leak syndrome: a case series of 28 patients from a European registry.Ann Intern Med. 2011; 154: 464-471Crossref PubMed Scopus (105) Google Scholar SCLS is a diagnosis of exclusion and is often confused with sepsis, angioedema, or anaphylactic shock.16Xie Z. Chan E. Yin Y. et al.Inflammatory markers of the systemic capillary leak syndrome (Clarkson disease).J Clin Cell Immunol. 2014; 5: 1000213PubMed Google Scholar The elevation of multiple cytokines has been discovered in the acute serum of patients with SCLS, although only CXCL10 (C-X-C motif chemokine ligand 10) was shown to be elevated in both the quiescent and acute sera compared with controls.16Xie Z. Chan E. Yin Y. et al.Inflammatory markers of the systemic capillary leak syndrome (Clarkson disease).J Clin Cell Immunol. 2014; 5: 1000213PubMed Google Scholar In another study, angiopoietin-2 and vascular endothelial growth factor were increased in acute SCLS sera compared with control sera.17Xie Z. Ghosh C.C. Patel R. et al.Vascular endothelial hyperpermeability induces the clinical symptoms of Clarkson disease (the systemic capillary leak syndrome).Blood. 2012; 119: 4321-4332Crossref PubMed Scopus (126) Google Scholar The finding that acute serum from SCLS patients induces hyperpermeability in human microvascular endothelial cells suggests that a soluble factor is important in the capillary leak pathophysiology.17Xie Z. Ghosh C.C. Patel R. et al.Vascular endothelial hyperpermeability induces the clinical symptoms of Clarkson disease (the systemic capillary leak syndrome).Blood. 2012; 119: 4321-4332Crossref PubMed Scopus (126) Google Scholar The appropriate disease-specific treatment of SCLS is currently unknown. Successful abortive therapy with i.v. Ig has been described in 6 patients,18Lambert M. Launay D. Hachulla E. et al.High-dose intravenous immunoglobulins dramatically reverse systemic capillary leak syndrome.Crit Care Med. 2008; 36: 2184-2187Crossref PubMed Scopus (91) Google Scholar, 19Ledochowski S. Freichet M. Prieur C. et al.An uncommon cause of distributive shock: Lessons from two consecutive cases of idiopathic systemic capillary leak syndrome (Clarkson's disease).Anaesth Crit Care Pain Med. 2015; 34: 251-253Crossref PubMed Scopus (11) Google Scholar, 20Almagro P. Marti J.M. Garcia Pascual L. Rodriguez-Carballeira M. Successful treatment of systemic capillary leak syndrome with intravenous immunoglobulins.Rev Clin Esp. 2012; 212: 218-219Crossref PubMed Scopus (9) Google Scholar, 21Marra A.M. Gigante A. Rosato E. Intravenous immunoglobulin in systemic capillary leak syndrome: a case report and review of literature.Expert Rev Clin Immunol. 2014; 10: 349-352Crossref PubMed Scopus (15) Google Scholar whereas theophylline treatment to maintain high trough levels was successful in aborting attacks in 2 patients.22Dowden A.M. Rullo O.J. Aziz N. et al.Idiopathic systemic capillary leak syndrome: novel therapy for acute attacks.J Allergy Clin Immunol. 2009; 124: 1111-1113Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar Successful abortive therapy with the tumor necrosis factor-α (TNF-α) antagonist infliximab was described in a single case report.22Dowden A.M. Rullo O.J. Aziz N. et al.Idiopathic systemic capillary leak syndrome: novel therapy for acute attacks.J Allergy Clin Immunol. 2009; 124: 1111-1113Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar Prophylactic treatment with i.v. Ig prevented further attacks in 15 of 18 patients in 1 series23Xie Z. Chan E.C. Long L.M. et al.High-dose intravenous immunoglobulin therapy for systemic capillary leak syndrome (Clarkson disease).Am J Med. 2015; 128: 91-95Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar and successfully prevented recurrent attacks in multiple case series.18Lambert M. Launay D. Hachulla E. et al.High-dose intravenous immunoglobulins dramatically reverse systemic capillary leak syndrome.Crit Care Med. 2008; 36: 2184-2187Crossref PubMed Scopus (91) Google Scholar, 19Ledochowski S. Freichet M. Prieur C. et al.An uncommon cause of distributive shock: Lessons from two consecutive cases of idiopathic systemic capillary leak syndrome (Clarkson's disease).Anaesth Crit Care Pain Med. 2015; 34: 251-253Crossref PubMed Scopus (11) Google Scholar, 20Almagro P. Marti J.M. Garcia Pascual L. Rodriguez-Carballeira M. Successful treatment of systemic capillary leak syndrome with intravenous immunoglobulins.Rev Clin Esp. 2012; 212: 218-219Crossref PubMed Scopus (9) Google Scholar, 21Marra A.M. Gigante A. Rosato E. Intravenous immunoglobulin in systemic capillary leak syndrome: a case report and review of literature.Expert Rev Clin Immunol. 2014; 10: 349-352Crossref PubMed Scopus (15) Google Scholar, 24Scanvion Q. Lefevre G. Hachulla E. et al.Subcutaneous immunoglobulin therapy prevents systemic capillary leak syndrome attack.Am J Med. 2016; 129: e77-e78Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 25Lassoued K. Clauvel J.P. Similowski T. et al.Pulmonary infections associated with systemic capillary leak syndrome attacks in a patient with hypogammagloulinemia.Intensive Care Med. 1998; 24: 981-983Crossref PubMed Scopus (23) Google Scholar, 26Abgueguen P. Chennebault J.M. Pichard E. Immunoglobulins for treatment of systemic capillary leak syndrome.Am J Med. 2010; 123: e3-e4Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 27Govig B.A. Javaheri S. The systemic capillary leak syndrome.Ann Intern Med. 2010; 153: 764Crossref PubMed Scopus (7) Google Scholar, 28Pecker M. Adams M. Graham W. The systemic capillary leak syndrome.Ann Intern Med. 2011; 155 (author reply 335–336): 335Crossref PubMed Scopus (5) Google Scholar, 29Rabbolini D.J. Ange N. Walters G.D. et al.Systemic capillary leak syndrome: recognition prevents morbidity and mortality.Intern Med J. 2013; 43: 1145-1147Crossref PubMed Scopus (9) Google Scholar Combined treatment with terbutaline and aminophylline or theophylline decreased the frequency and severity of attacks in 2 small series,11Tahirkheli N.K. Greipp P.R. Treatment of the systemic capillary leak syndrome with terbutaline and theophylline. A case series.Ann Intern Med. 1999; 130: 905-909Crossref PubMed Scopus (113) Google Scholar, 22Dowden A.M. Rullo O.J. Aziz N. et al.Idiopathic systemic capillary leak syndrome: novel therapy for acute attacks.J Allergy Clin Immunol. 2009; 124: 1111-1113Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar although another series questioned the benefits of this combination therapy.14Amoura 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: 514-519Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar Several drugs have been shown to cause capillary leak syndrome. The cytokine IL-2 administered for the treatment of malignancy has been shown to cause edema, dyspnea, fever, chills, nausea, vomiting, and diarrhea.2Rosenberg S.A. Lotze M.T. Muul L.M. et al.Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer.N Engl J Med. 1985; 313: 1485-1492Crossref PubMed Scopus (2246) Google Scholar In an animal model, IL-2 caused an increase in the vascular permeability to albumin.30Rosenstein M. Ettinghausen S.E. Rosenberg S.A. Extravasation of intravascular fluid mediated by the systemic administration of recombinant interleukin 2.J Immunol. 1986; 137: 1735-1742PubMed Google Scholar The cytokines IL-11 and IL-12 have also been associated with capillary leak syndrome.31Kai-Feng W. Hong-Ming P. Hai-Zhou L. et al.Interleukin-11-induced capillary leak syndrome in primary hepatic carcinoma patients with thrombocytopenia.BMC Cancer. 2011; 11: 204Crossref PubMed Scopus (13) Google Scholar, 32Hurteau J.A. Blessing J.A. DeCesare S.L. Creasman W.T. Evaluation of recombinant human interleukin-12 in patients with recurrent or refractory ovarian cancer: a gynecologic oncology group study.Gynecol Oncol. 2001; 82: 7-10Abstract Full Text PDF PubMed Scopus (80) Google Scholar The use of gemcitabine for malignant diseases has resulted in systemic edema, hypotension, noncardiogenic pulmonary edema, and AKI.33Biswas S. Nik S. Corrie P.G. Severe gemcitabine-induced capillary-leak syndrome mimicking cardiac failure in a patient with advanced pancreatic cancer and high-risk cardiovascular disease.Clin Oncol (R Coll Radiol). 2004; 16: 577-579Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 34De Pas T. Curigliano G. Franceschelli L. et al.Gemcitabine-induced systemic capillary leak syndrome.Ann Oncol. 2001; 12: 1651-1652Crossref PubMed Scopus (47) Google Scholar, 35Casadei Gardini A. Aquilina M. Oboldi D. et al.Separate episodes of capillary leak syndrome and pulmonary hypertension after adjuvant gemcitabine and three years later after nab-paclitaxel for metastatic disease.BMC Cancer. 2013; 13: 542Crossref PubMed Scopus (10) Google Scholar, 36Pulkkanen K. Kataja V. Johansson R. Systemic capillary leak syndrome resulting from gemcitabine treatment in renal cell carcinoma: a case report.J Chemother. 2003; 15: 287-289Crossref PubMed Scopus (21) Google Scholar Studies of gemcitabine in lung cancer patients demonstrated significant increases in IL-2 and TNF-α in response to therapy.37Levitt M.L. Kassem B. Gooding W.E. et al.Phase I study of gemcitabine given weekly as a short infusion for non-small cell lung cancer: results and possible immune system-related mechanisms.Lung Cancer. 2004; 43: 335-344Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Monoclonal antibodies can acutely activate large numbers immune cells leading to abrupt increases in several cytokines.38Lee D.W. Gardner R. Porter D.L. et al.Current concepts in the diagnosis and management of cytokine release syndrome.Blood. 2014; 124: 188-195Crossref PubMed Scopus (1646) Google Scholar This form of capillary leak syndrome, or cytokine release syndrome, is characterized by the onset of symptoms minutes to hours after the monoclonal antibody has been administered. OKT3 is a monoclonal antibody that inhibits CD3 on T cells. OKT3 administration causes fever, chills, dyspnea, wheezing, hypotension, tachycardia, nausea, and vomiting.39Gaston R.S. Deierhoi M.H. Patterson T. et al.OKT3 first-dose reaction: association with T cell subsets and cytokine release.Kidney Int. 1991; 39: 141-148Abstract Full Text PDF PubMed Scopus (130) Google Scholar The first dose reaction to OKT3 is associated with increases in TNF-α, IL-2, and interferon-γ.40Abramowicz D. Schandene L. Goldman M. et al.Release of tumor necrosis factor, interleukin-2, and gamma-interferon in serum after injection of OKT3 monoclonal antibody in kidney transplant recipients.Transplantation. 1989; 47: 606-608Crossref PubMed Scopus (365) Google Scholar More severe reactions have been correlated with greater increases in serum TNF-α.39Gaston R.S. Deierhoi M.H. Patterson T. et al.OKT3 first-dose reaction: association with T cell subsets and cytokine release.Kidney Int. 1991; 39: 141-148Abstract Full Text PDF PubMed Scopus (130) Google Scholar The treatment of hematologic malignancies with the monoclonal antibodies rituximab and alemtuzumab has resulted in the cytokine release syndrome.38Lee D.W. Gardner R. Porter D.L. et al.Current concepts in the diagnosis and management of cytokine release syndrome.Blood. 2014; 124: 188-195Crossref PubMed Scopus (1646) Google Scholar Rituximab has been shown to increase TNF-α and IL-6 associated with capillary leak syndrome in B-cell leukemia patients,3Winkler U. Jensen M. Manzke O. et al.Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8).Blood. 1999; 94: 2217-2224Crossref PubMed Google Scholar whereas alemtuzumab has been shown to increase TNF-α, interferon-γ, and IL-6.41Wing M.G. Moreau T. Greenwood J. et al.Mechanism of first-dose cytokine-release syndrome by CAMPATH 1-H: involvement of CD16 (FcgammaRIII) and CD11a/CD18 (LFA-1) on NK cells.J Clin Invest. 1996; 98: 2819-2826Crossref PubMed Scopus (215) Google Scholar Perhaps the best example of acute drug-induced capillary leak with multiple-organ injury comes from the study of the anti–CD-28 monoclonal antibody TGN1412.42Suntharalingam G. Perry M.R. Ward S. et al.Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412.N Engl J Med. 2006; 355: 1018-1028Crossref PubMed Scopus (1660) Google Scholar Within hours of the administration of TGN1412 to 6 healthy volunteers, hypotension, bilateral pulmonary infiltrates, disseminated intravascular coagulation, and acute kidney injury with metabolic acidosis requiring continuous renal replacement therapy developed in all patients. There were large increases of multiple cytokines in all patients. In the 2 most critically ill patients, IL-6 and IL-4 were increased out of proportion to other patients. Steroids have been shown to be effective in ameliorating the signs and symptoms of drug-induced capillary leak syndrome.30Rosenstein M. Ettinghausen S.E. Rosenberg S.A. Extravasation of intravascular fluid mediated by the systemic administration of recombinant interleukin 2.J Immunol. 1986; 137: 1735-1742PubMed Google Scholar, 33Biswas S. Nik S. Corrie P.G. Severe gemcitabine-induced capillary-leak syndrome mimicking cardiac failure in a patient with advanced pancreatic cancer and high-risk cardiovascular disease.Clin Oncol (R Coll Radiol). 2004; 16: 577-579Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 34De Pas T. Curigliano G. Franceschelli L. et al.Gemcitabine-induced systemic capillary leak syndrome.Ann Oncol. 2001; 12: 1651-1652Crossref PubMed Scopus (47) Google Scholar, 35Casadei Gardini A. Aquilina M. Oboldi D. et al.Separate episodes of capillary leak syndrome and pulmonary hypertension after adjuvant gemcitabine and three years later after nab-paclitaxel for metastatic disease.BMC Cancer. 2013; 13: 542Crossref PubMed Scopus (10) Google Scholar, 38Lee D.W. Gardner R. Porter D.L. et al.Current concepts in the diagnosis and management of cytokine release syndrome.Blood. 2014; 124: 188-195Crossref PubMed Scopus (1646) Google Scholar, 42Suntharalingam G. Perry M.R. Ward S. et al.Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412.N Engl J Med. 2006; 355: 1018-1028Crossref PubMed Scopus (1660) Google Scholar Engraftment syndrome occurs after hematopoietic stem cell transplantation, usually within 4 days of granulocyte recovery, and is mediated by the release of inflammatory cytokines such as IL-1, TNF-α, and interferon-γ.4Spitzer T.R. Engraftment syndrome: double-edged sword of hematopoietic cell transplants.Bone Marrow Transplant. 2015; 50: 469-475Crossref PubMed Scopus (74) Google Scholar Clinical manifestations include fever, hypotension, edema, ascites, pleural effusions, noncardiogenic pulmonary edema, and variable renal dysfunction.4Spitzer T.R. Engraftment syndrome: double-edged sword of hematopoietic cell transplants.Bone Marrow Transplant. 2015; 50: 469-475Crossref PubMed Scopus (74) Google Scholar The incidence of engraftment syndrome varies with the type of transplant (e.g., autologous, allogeneic, syngeneic) and has widely discrepant estimations and outcome data due to differing definitions and overlap with other similar syndromes. AKI is common, with an incidence of 26% in 1 study of autologous stem cell transplantation patients.43Carreras E. Fernandez-Aviles F. Silva L. et al.Engraftment syndrome after auto-SCT: analysis of diagnostic criteria and risk factors in a large series from a single center.Bone Marrow Transplant. 2010; 45: 1417-1422Crossref PubMed Scopus (61) Google Scholar Capillary leak due to engraftment syndrome responds to treatment with steroids.44Spitzer T.R. Engraftment syndrome following hematopoietic stem cell transplantation.Bone Marrow Transplant. 2001; 27: 893-898Crossref PubMed Scopus (307) Google Scholar Differentiation syndrome is a complication occurring in ∼25% of patients with acute promyelocytic leukemia who undergo induction treatment with either all-trans retinoic acid or arsenic trioxide. This complication usually occurs 10 to 12 days after initiating treatment and is characterized by pulmonary infiltrates, fever, pulmonary edema, pleural effusions, systemic edema, hypotension, and AKI.5Luesink M. Jansen J.H. Advances in understanding the pulmonary infiltration in acute promyelocytic leukaemia.Br J Haematol. 2010; 151: 209-220Crossref PubMed Scopus (30) Google Scholar AKI can be seen in 28% of cases.5Luesink M. Jansen J.H. Advances in understanding the pulmonary infiltration in acute promyelocytic leukaemia.Br J Haematol. 2010; 151: 209-220Crossref PubMed Scopus (30) Google Scholar The pathophysiology of differentiation syndrome involves chemokine release from differentiated acute promyelocytic leukemia cells and the upregulation of integrins and adhesion molecules on differentiated acute promyelocytic leukemia cells as well as target tissues. These events facilitate the infiltration of leukemic cells into target organs, particularly the lungs.5Luesink M. Jansen J.H. Advances in understanding the pulmonary infiltration in acute promyelocytic leukaemia.Br J Haematol. 2010; 151: 209-220Crossref PubMed Scopus (30) Google Scholar Steroids are effective in the treatment of capillary leak caused by the differentiation syndrome.5Luesink M. Jansen J.H. Advances in understandi