Capillary leak syndrome

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Capillary leak syndrome
Other namesSCLS, Clarkson's Disease, Capillary hyperpermeability syndrome
Specialty Hematology, immunology, intensive care medicine
Symptoms hemoconcentration, hypotension, hypoalbuminemia, edema, compartment syndromes
Differential diagnosis polycythemia, polycythemia vera, hyperviscosity syndrome, sepsis, disseminated intravascular coagulation, other cases involving internal blood loss
Treatment IVIG, theophylline, terbutaline, montelukast

Capillary leak syndrome, or vascular leak syndrome, is characterized by the escape of blood plasma through capillary walls, from the blood circulatory system to surrounding tissues, muscle compartments, organs or body cavities. It is a phenomenon most commonly witnessed in sepsis, and less frequently in autoimmune diseases, differentiation syndrome, engraftment syndrome, hemophagocytic lymphohistiocytosis, the ovarian hyperstimulation syndrome, viral hemorrhagic fevers, and snakebite and ricin poisoning. [1] Pharmaceuticals, including the chemotherapy medications gemcitabine and denileukin diftitox, as well as certain interleukins and monoclonal antibodies, can also cause capillary leaks. [1] [2] These conditions and factors are sources of secondary capillary leak syndrome.

Contents

Systemic capillary leak syndrome (SCLS), also called Clarkson's disease, or primary capillary leak syndrome, is a rare, grave and episodic medical condition observed largely in otherwise healthy individuals mostly in middle age. [3] It is characterized by self-reversing episodes during which the endothelial cells which line the capillaries, usually of the extremities, separate for one to three days, causing a leakage of plasma mainly into the muscle compartments of the arms and legs. The abdomen, the central nervous system, and the organs (including the lungs) are typically spared, but the extravasation in the extremities is sufficiently massive to cause circulatory shock and compartment syndromes, with a dangerous hypotension (low blood pressure), hemoconcentration (thickening of the blood) and hypoalbuminemia (drop in albumin, a major protein) in the absence of other causes for such abnormalities. [3] [4] SCLS is thus a limb- and life-threatening illness, because each episode has the potential to cause damage to limb muscles and nerves, as well as to vital organs due to limited perfusion. [3] [4] It is often misdiagnosed as polycythemia, polycythemia vera, hyperviscosity syndrome, or sepsis. [3]

Symptoms

Most SCLS patients succumb to viral infections manifesting themselves by way of flu-like symptoms (like a runny nose), gastro-intestinal disorders (diarrhea or vomiting), or general weakness or pain in the limbs, but others get no particular or consistent warning signs ahead of their episodes. They subsequently develop thirst and lightheadedness and the following conditions measurable in a hospital emergency-room setting: [3] [4] [5]

Cause

Although the precise molecular cause of SCLS remains undetermined, scientific research in recent years, conducted mainly at a unit (NIAID) of the U.S. National Institutes of Health, has shed some light on its biological and chemical roots. The study of the peripheral microvasculature from patients’ biopsy specimens has not evidenced gross anomalies, disrupted angiogenesis, or inflammatory cells or other factors suggestive of a disorder prone to damage the blood vessels by inflammation. [4] The absence of structural abnormalities is thus consistent with the hypothesis of some kind of defective but curiously reversible cellular phenomenon in the capillaries. [6]

Studies suggest that the presence of various inflammatory factors during episodes of SCLS may explain the temporarily abnormal permeability of the endothelial cells lining the inner surface of the capillaries. These include transient spikes in monocyte- and macrophage-associated inflammatory mediators [4] and temporary increases in the proteins vascular endothelial growth factors (VEGF) and angiopoietin-2. [6] The impairment of endothelial cells in laboratory conditions provoked by serum taken from patients who were having episodes of SCLS is also suggestive of biochemical factors at work. [6] [7]

There is no evidence that SCLS is hereditary, and the role of specific gene defects in patients with SCLS, which might program their endothelial cells for an overreaction to external stimuli such as viral infections, has not been established. [4] The significance, if any, of the paraprotein (MGUS) present in most patients with SCLS is unknown, other than it has been a precursor to multiple myeloma in a minority (7% in the largest reported cohort) of SCLS patients. [4] [8]

Diagnosis

SCLS is often difficult to recognize and diagnose on initial presentation, and thus misdiagnoses are frequent. The characteristic triad of profound arterial hypotension, hemoconcentration (elevated hematocrit, leukocytosis, and thrombocytosis), and hypoalbuminemia in the absence of secondary causes of shock and infection, requires diagnosis in a monitored hospital setting during or after an acute episode. The fact that the condition is exceedingly rare – an estimated one per million inhabitants – and that several other diseases exhibit features akin to SCLS, including secondary capillary-leak syndrome or hypoproteinemia, militate against early identification. [3] [8] Preserved consciousness, despite severe shock and hypotension, is an additional and most intriguing clinical manifestation often reported during episodes at hospital admission. [5]

Treatment

The natural history of SCLS episodes indicates they usually resolve spontaneously within 2-to-4 days, and that they consist of two distinct phases: [3] [4] [5]

The capillary leak phase

The initial stage is the capillary leak phase, lasting from 1 to 3 days, during which up to 70% of total plasma volume invades body cavities, especially in the extremities. [3] [4] The most common clinical features are flu-like symptoms such as fatigue; runny nose; lightheadedness up to and including syncope (fainting); limb, abdominal or generalized pain; facial or other edema; dyspnea; and hypotension that results in circulatory shock and potentially in cardiopulmonary collapse and other organ distress or damage. [3] [4] [5] Acute kidney injury or failure is a common risk due to acute tubular necrosis consequent to hypovolemia and rhabdomyolysis. [3] [4] [5] The escape of fluid out of the capillaries has similar effects on the circulation as dehydration, slowing both the flow of oxygen delivered to tissues and organs as well as the output of urine, causing oliguria.

Urgent medical attention in this phase often features fluid resuscitation efforts, mainly the intravenous administration of saline solution plus hetastarch or albumin and colloids (to increase the remaining blood flow to vital organs like the kidneys), as well as glucocorticoids (steroids like methylprednisolone, to reduce or stop the capillary leak). [3] However, the impact of such fluid therapy is always transient and leads to increased extravascular fluid accumulation, engendering multiple complications especially compartment syndrome and thus limb-destructive rhabdomyolysis.

Consequently, fluid resuscitation should be minimized as much as possible in patients experiencing episodes of SCLS, and they should be closely monitored in a hospital intensive-care setting including for orthopedic complications requiring surgical decompression. [3] [4] [5] Recent clinical experience suggests that administration of immunoglobulins (IVIG) with minimal additional intravenous fluids, close to the start of an episode of SCLS, is a safe way to support patients during their leak phase and is associated with rapid clinical improvement. [9]

The recruitment phase

The second stage features the reabsorption of the initially extravasated fluid and albumin from the tissues, and it usually lasts 1 to 2 days. Intravascular fluid overload leads to polyuria and can cause flash pulmonary edema and cardiac arrest, with possibly fatal consequences. [3] [4] Death from SCLS typically occurs during this recruitment phase because of pulmonary edema arising from excessive intravenous fluid administration during the earlier leak phase. [3] [4] The severity of the problem depends on the quantity of fluid supplied in the initial phase, the damage that may have been sustained by the kidneys, and the promptness with which diuretics are administered to help the patient discharge the accumulated fluids quickly. [3] A recent study of 59 acute episodes occurring in 37 hospitalized SCLS patients concluded that high-volume fluid therapy was independently associated with poorer clinical outcomes, and that the main complications of SCLS episodes were recovery-phase pulmonary edema (24%), cardiac arrhythmia (24%), compartment syndrome (20%), and acquired infections (19%). [5]

The prevention of episodes of SCLS has involved two approaches. The earliest was advocated by the Mayo Clinic, and it recommended treatment with high doses of beta agonists such as terbutaline, phosphodiesterase-inhibitor theophylline, and leukotriene-receptor antagonists montelukast sodium. [8] [10]

The rationale for use of these drugs was their ability to increase intracellular cyclic AMP (adenosine monophosphate) levels, which might counteract inflammatory signaling pathways that induce endothelial permeability. [4] It was the standard of care until the early 2000s, but was sidelined afterwards because patients frequently experienced renewed episodes of SCLS, and because these drugs were poorly tolerated due to their unpleasant side effects. [4] [11] [12]

The second, more recent approach pioneered in France during the early 2000s involves monthly intravenous infusions of immunoglobulins (IVIG), with an initial dose of 1-2 gr/kg/month of body weight, which has proven very successful as per abundant case-report evidence from around the world. [4] [11] [12] [13]

IVIG has long been used for the treatment of autoimmune and MGUS-associated syndromes, because of its potential immunomodulatory and anticytokine properties. The precise mechanism of action of IVIG in patients with SCLS is unknown, but it is likely that it neutralizes their proinflammatory cytokines that provoke endothelial dysfunction. [6] [11] [12] [13]

A review of clinical experience with 69 mostly European SCLS patients found that preventive treatment with IVIG was the strongest factor associated with their survival, such that an IVIG therapy should be the first-line preventive agent for SCLS patients. [12] According to an NIH survey of patient experience, IVIG prophylaxis is associated with a dramatic reduction in the occurrence of SCLS episodes in most patients, with minimal side effects, so it may be considered as frontline therapy for those with a clear-cut diagnosis of SCLS and a history of recurrent episodes. [11]

A recent study involving 59 patients to evaluate the safety of IVIG tapering and withdrawal in French and Italian patients with SCLS concluded that the incidence of severe flares was not statistically different across the different dosages of IVIG, but that withdrawal was associated with increased mortality and higher rates of recurrence, such that lifelong treatment with IVIG is recommended for patients with SCLS. [14]

Prognosis

In mostly European experience with 69 patients during 1996–2016, the 5- and 10-year survival rates for SCLS patients were 78% and 69%, respectively, but the survivors received significantly more frequent preventive treatment with IVIG than did non-survivors. Five- and 10-year survival rates in patients treated with IVIG were 91% and 77%, respectively, compared to 47% and 37% in patients not treated with IVIG. [12] Moreover, better identification and management of this condition appears to be resulting in lower mortality and improving survival and quality-of-life results as of late. [4]

History

The syndrome was first described by a team of New York City physicians led by Dr. Bayard D. Clarkson in 1960, [15] after whom it was later informally named. Beyond numerous case reports published since then, three comprehensive reviews of clinical and research experience were published in 2017. [4] [5] [12]

Related Research Articles

<span class="mw-page-title-main">Edema</span> Accumulation of excess fluid in tissue

Edema, also spelled oedema, and also known as fluid retention, dropsy and hydropsy, is the build-up of fluid in the body's tissue, a type of swelling. Most commonly, the legs or arms are affected. Symptoms may include skin that feels tight, the area feeling heavy, and joint stiffness. Other symptoms depend on the underlying cause.

<span class="mw-page-title-main">Nephrotic syndrome</span> Symptoms resulting from kidney damage

Nephrotic syndrome is a collection of symptoms due to kidney damage. This includes protein in the urine, low blood albumin levels, high blood lipids, and significant swelling. Other symptoms may include weight gain, feeling tired, and foamy urine. Complications may include blood clots, infections, and high blood pressure.

<span class="mw-page-title-main">Pleural effusion</span> Accumulation of excess fluid in the pleural cavity

A pleural effusion is accumulation of excessive fluid in the pleural space, the potential space that surrounds each lung. Under normal conditions, pleural fluid is secreted by the parietal pleural capillaries at a rate of 0.6 millilitre per kilogram weight per hour, and is cleared by lymphatic absorption leaving behind only 5–15 millilitres of fluid, which helps to maintain a functional vacuum between the parietal and visceral pleurae. Excess fluid within the pleural space can impair inspiration by upsetting the functional vacuum and hydrostatically increasing the resistance against lung expansion, resulting in a fully or partially collapsed lung.

<span class="mw-page-title-main">Cerebral edema</span> Excess accumulation of fluid (edema) in the intracellular or extracellular spaces of the brain

Cerebral edema is excess accumulation of fluid (edema) in the intracellular or extracellular spaces of the brain. This typically causes impaired nerve function, increased pressure within the skull, and can eventually lead to direct compression of brain tissue and blood vessels. Symptoms vary based on the location and extent of edema and generally include headaches, nausea, vomiting, seizures, drowsiness, visual disturbances, dizziness, and in severe cases, death.

<span class="mw-page-title-main">Pulmonary edema</span> Fluid accumulation in the tissue and air spaces of the lungs

Pulmonary edema, also known as pulmonary congestion, is excessive fluid accumulation in the tissue or air spaces of the lungs. This leads to impaired gas exchange, most often leading to shortness of breath (dyspnea) which can progress to hypoxemia and respiratory failure. Pulmonary edema has multiple causes and is traditionally classified as cardiogenic or noncardiogenic.

<span class="mw-page-title-main">Septic shock</span> Dangerously low blood pressure due to damage from an organ infection

Septic shock is a potentially fatal medical condition that occurs when sepsis, which is organ injury or damage in response to infection, leads to dangerously low blood pressure and abnormalities in cellular metabolism. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defines septic shock as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by requiring a vasopressor to maintain a mean arterial pressure of 65 mm Hg or greater and having serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40%.

<span class="mw-page-title-main">Macular edema</span> Medical condition

Macular edema occurs when fluid and protein deposits collect on or under the macula of the eye and causes it to thicken and swell (edema). The swelling may distort a person's central vision, because the macula holds tightly packed cones that provide sharp, clear, central vision to enable a person to see detail, form, and color that is directly in the centre of the field of view.

<span class="mw-page-title-main">Kawasaki disease</span> Disease found in young children

Kawasaki disease is a syndrome of unknown cause that results in a fever and mainly affects children under 5 years of age. It is a form of vasculitis, where medium-sized blood vessels become inflamed throughout the body. The fever typically lasts for more than five days and is not affected by usual medications. Other common symptoms include large lymph nodes in the neck, a rash in the genital area, lips, palms, or soles of the feet, and red eyes. Within three weeks of the onset, the skin from the hands and feet may peel, after which recovery typically occurs. The disease is the leading cause of acquired heart disease in children in developed countries, which include the formation of coronary artery aneurysms and myocarditis.

<span class="mw-page-title-main">POEMS syndrome</span> Paraneoplastic syndrome

POEMS syndrome is a rare paraneoplastic syndrome caused by a clone of aberrant plasma cells. The name POEMS is an acronym for some of the disease's major signs and symptoms, as is PEP.

<span class="mw-page-title-main">Nephritic syndrome</span> Symptoms resulting from kidney inflammation

Nephritic syndrome is a syndrome comprising signs of nephritis, which is kidney disease involving inflammation. It often occurs in the glomerulus, where it is called glomerulonephritis. Glomerulonephritis is characterized by inflammation and thinning of the glomerular basement membrane and the occurrence of small pores in the podocytes of the glomerulus. These pores become large enough to permit both proteins and red blood cells to pass into the urine. By contrast, nephrotic syndrome is characterized by proteinuria and a constellation of other symptoms that specifically do not include hematuria. Nephritic syndrome, like nephrotic syndrome, may involve low level of albumin in the blood due to the protein albumin moving from the blood to the urine.

<span class="mw-page-title-main">Hypoalbuminemia</span> Abnormally low levels of albumin in the blood

Hypoalbuminemia is a medical sign in which the level of albumin in the blood is low. This can be due to decreased production in the liver, increased loss in the gastrointestinal tract or kidneys, increased use in the body, or abnormal distribution between body compartments. Patients often present with hypoalbuminemia as a result of another disease process such as malnutrition as a result of severe anorexia nervosa, sepsis, cirrhosis in the liver, nephrotic syndrome in the kidneys, or protein-losing enteropathy in the gastrointestinal tract. One of the roles of albumin is being the major driver of oncotic pressure in the bloodstream and the body. Thus, hypoalbuminemia leads to abnormal distributions of fluids within the body and its compartments. As a result, associated symptoms include edema in the lower legs, ascites in the abdomen, and effusions around internal organs. Laboratory tests aimed at assessing liver function diagnose hypoalbuminemia. Once identified, it is a poor prognostic indicator for patients with a variety of different diseases. Yet, it is only treated in very specific indications in patients with cirrhosis and nephrotic syndrome. Treatment instead focuses on the underlying cause of the hypoalbuminemia. Albumin is an acute negative phase respondent and not a reliable indicator of nutrition status.

<span class="mw-page-title-main">Selective immunoglobulin A deficiency</span> Medical condition

Selective immunoglobulin A (IgA) deficiency (SIgAD) is a kind of immunodeficiency, a type of hypogammaglobulinemia. People with this deficiency lack immunoglobulin A (IgA), a type of antibody that protects against infections of the mucous membranes lining the mouth, airways, and digestive tract. It is defined as an undetectable serum IgA level in the presence of normal serum levels of IgG and IgM, in persons older than 4 years. It is the most common of the primary antibody deficiencies. Most such persons remain healthy throughout their lives and are never diagnosed.

Catastrophic antiphospholipid syndrome (CAPS), also known as Asherson's syndrome, is a rare autoimmune disease in which widespread, intravascular clotting causes multi-organ failure. The syndrome is caused by antiphospholipid antibodies that target a group of proteins in the body that are associated with phospholipids. These antibodies activate endothelial cells, platelets, and immune cells, ultimately causing a large inflammatory immune response and widespread clotting. CAPS was first described by Ronald Asherson in 1992. The syndrome exhibits thrombotic microangiopathy, multiple organ thromboses, and in some cases tissue necrosis and is considered an extreme or catastrophic variant of the antiphospholipid syndrome.

Guillain–Barré syndrome (GBS) is a rapid-onset muscle weakness caused by the immune system damaging the peripheral nervous system. Typically, both sides of the body are involved, and the initial symptoms are changes in sensation or pain often in the back along with muscle weakness, beginning in the feet and hands, often spreading to the arms and upper body. The symptoms may develop over hours to a few weeks. During the acute phase, the disorder can be life-threatening, with about 15% of people developing weakness of the breathing muscles requiring mechanical ventilation. Some are affected by changes in the function of the autonomic nervous system, which can lead to dangerous abnormalities in heart rate and blood pressure.

Extravasation is the leakage of a fluid out of its contained space into the surrounding area, especially blood or blood cells from vessels. In the case of inflammation, it refers to the movement of white blood cells through the capillary wall, into the surrounding tissues. This is known as leukocyte extravasation, also called diapedesis. In the case of cancer metastasis, it refers to cancer cells exiting the capillaries and entering other tissues, where secondary tumors may form. The term is commonly used in a medical context.

<span class="mw-page-title-main">Systemic vasculitis</span> Medical condition

Necrotizing vasculitis, also called systemic necrotizing vasculitis, is a general term for the inflammation of veins and arteries that develops into necrosis and narrows the vessels.

<span class="mw-page-title-main">Cerebrospinal fluid leak</span> Leakage of fluid surrounding the brain and spinal cord through tears in the dura mater

A cerebrospinal fluid leak is a medical condition where the cerebrospinal fluid (CSF) that surrounds the brain and spinal cord leaks out of one or more holes or tears in the dura mater. A CSF leak is classed as either spontaneous (primary), having no known cause, or nonspontaneous (secondary) where it is attributed to an underlying condition. Causes of a primary CSF leak are those of trauma including from an accident or intentional injury, or arising from a medical intervention known as iatrogenic. A basilar skull fracture as a cause can give the sign of CSF leakage from the ear, nose or mouth. A lumbar puncture can give the symptom of a post-dural-puncture headache.

Drug-Induced Aseptic Meningitis (DIAM) is a type of aseptic meningitis related to the use of medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) or biologic drugs such as intravenous immunoglobulin (IVIG). Additionally, this condition generally shows clinical improvement after cessation of the medication, as well as a tendency to relapse with resumption of the medication.

<span class="mw-page-title-main">Lupus vasculitis</span> Medical condition

Lupus vasculitis is one of the secondary vasculitides that occurs in approximately 50% of patients with systemic lupus erythematosus (SLE).

Immunoglobulin therapy is the use of a mixture of antibodies to treat several health conditions. These conditions include primary immunodeficiency, immune thrombocytopenic purpura, chronic inflammatory demyelinating polyneuropathy, Kawasaki disease, certain cases of HIV/AIDS and measles, Guillain–Barré syndrome, and certain other infections when a more specific immunoglobulin is not available. Depending on the formulation it can be given by injection into muscle, a vein, or under the skin. The effects last a few weeks.

References

  1. 1 2 Siddall, Eric; Khatri, Minesh; Radhakrishnan, Jai (16 March 2017). "Capillary leak syndrome: etiologies, pathophysiology, and management". Kidney International. 92 (1): 37–46. doi: 10.1016/j.kint.2016.11.029 . PMID   28318633.
  2. ↑ Izzedine, Hassan; Mathian, Alexis; Amoura, Zahir; Ng, Jia; Jhaveri, Kenar (25 February 2022). "Anticancer Drug-Induced Capillary Leak Syndrome". Kidney International Reports. 7 (5): 945–953. doi: 10.1016/j.ekir.2022.02.014 . PMC   9091576 . PMID   9091576.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Druey, Kirk M.; Greipp, Philip R. (2010). "Narrative Review: Clarkson Disease-Systemic Capillary Leak Syndrome". Annals of Internal Medicine. 153 (2): 90–8. doi:10.7326/0003-4819-153-2-201007200-00005. PMC   3017349 . PMID   20643990.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Druey, Kirk; Parikh, Samir M. (22 December 2016). "Idiopathic systemic capillary leak syndrome (Clarkson disease)". Journal of Allergy and Clinical Immunology. 140 (3): 663–670. doi:10.1016/j.jaci.2016.10.042. PMC   5481509 . PMID   28012935.
  5. 1 2 3 4 5 6 7 8 Pineton de Chambrun, Marc; et al. (2017). "The Clinical Picture of Severe Systemic Capillary-Leak Syndrome Episodes Requiring ICU Admission". Critical Care Medicine. 45 (7): 1216–23. doi:10.1097/CCM.0000000000002496. PMID   28622216. S2CID   198448.
  6. 1 2 3 4 Xie, Zhihui; Gosh, Chandra C.; et al. (2012). "Vascular endothelial hyperpermeability induces the clinical symptoms of Clarkson disease (the systemic capillary leak syndrome)". Blood. 119 (18): 1145–7. doi:10.1182/blood-2011-08-375816. PMC   3359743 . PMID   22411873.
  7. ↑ Xie, Zhihui; Ghosh, Chandra C.; Parikh, Samir M.; Druey, Kirk M. (2014). "Mechanistic Classification of the Systemic Capillary Leak Syndrome: Clarkson Disease". American Journal of Respiratory and Critical Care Medicine. 189 (9): 1145–7. doi:10.1164/rccm.201310-1746LE. PMC   4098109 . PMID   24787070.
  8. 1 2 3 Droder, Robert M.; Kyle, Robert A.; Greipp, Philip R. (1992). "Control of systemic capillary leak syndrome with aminophylline and terbutaline". The American Journal of Medicine. 92 (5): 523–6. doi:10.1016/0002-9343(92)90749-2. PMID   1580299.
  9. ↑ Pecker, Mark; Hammudi, Mustafa; Melchio, Remo; et al. (2 August 2022). "Management of Acute Episodes of Clarkson Disease (Monoclonal Gammopathy-Associated Systemic Capillary Leak Syndrome) With Intravenous Immunoglobulins". AIM Clinical Cases. 1 (6). doi: 10.7326/aimcc.2022.0496 . PMC   9481058 . PMID   36119848.
  10. ↑ Kapoor, Prashant; Greipp, Patricia T.; Schaefer, Eric W.; Mandrekar, Sumithra J.; Kamal, Arif H.; Gonzalez-Paz, Natalia C.; Kumar, Shaji; Greipp, Philip R. (2010). "Idiopathic Systemic Capillary Leak Syndrome (Clarkson's Disease): The Mayo Clinic Experience". Mayo Clinic Proceedings. 85 (10): 905–12. doi:10.4065/mcp.2010.0159. PMC   2947962 . PMID   20634497.
  11. 1 2 3 4 Xie, Zhihui; Chan, Eunice; et al. (2015). "High dose intravenous immunoglobulin therapy of the Systemic Capillary Leak Syndrome (Clarkson disease)". The American Journal of Medicine. 128 (1): 91–5. doi:10.1016/j.amjmed.2014.08.015. PMC   4282822 . PMID   25193271.
  12. 1 2 3 4 5 6 Pineton de Chambrun, Marc; et al. (June 8, 2017). "Intravenous immunoglobulins improve survival in monoclonal gammopathy-associated systemic capillary-leak syndrome". The American Journal of Medicine. 130 (10): 1219.e19–1219.e27. doi: 10.1016/j.amjmed.2017.05.023 . PMID   28602874.
  13. 1 2 Lambert, Marc; Launay, David; Hachulla, Eric; Morell-Dubois, Sandrine; Soland, Vincent; Queyrel, Viviane; Fourrier, François; Hatron, Pierre-Yves (2008). "High-dose intravenous immunoglobulins dramatically reverse systemic capillary leak syndrome". Critical Care Medicine. 36 (7): 2184–7. doi:10.1097/CCM.0b013e31817d7c71. PMID   18552679. S2CID   41357732.
  14. ↑ Moyon, Quentin; et al. (2022). "Intravenous Immunoglobulins Tapering and Withdrawal in Systemic Capillary Leak Syndrome (Clarkson Disease)". The Journal of Allergy and Clinical Immunology:In Practice. 10 (11): 2889–95. doi: 10.1016/j.jaip.2022.07.006 . PMID   35870726. S2CID   250970743.
  15. ↑ Clarkson, Bayard; Thompson, David; Horwith, Melvin; Luckey, E.Hugh (1960). "Cyclical edema and shock due to increased capillary permeability". The American Journal of Medicine. 29 (2): 193–216. doi:10.1016/0002-9343(60)90018-8. PMID   13693909.

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