NORD gratefully acknowledges Mario Melika, NORD Editorial Intern from the Massachusetts College of Pharmacy and Health Sciences, and Kirk Druey, MD, Chief, Molecular Signal Transduction Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases/National Institutes of Health, for assistance in the preparation of this report.
Systemic capillary leak syndrome (SCLS) is a rare disorder characterized by acute and severe recurrent attacks associated with a rapid fall in blood pressure as a result of fluid leaks from smaller vessels called capillaries. Attacks often last several days and require emergency care. They are sometimes life threatening. SCLS occurs most often in adults and the disease is very rare in children.
Symptoms of SCLS usually involve a brief warning, which can include nasal congestion and cough that might be associated with a viral upper respiratory infection. Patients may develop malaise, nausea, lightheadedness, a faint feeling, abdominal pain, headache and swelling of extremities. Fever, chills, rash, or signs of infection may be absent. Patients may also exhibit elevated white blood cell count (leukocytosis) which may produce a false diagnosis when blood is tested. Spontaneous resolution of symptoms is uncommon without treatment.
A chronic form of SCLS has been reported that is manifested by swelling of the extremities and fluid accumulation around the heart and lungs. The characteristic increase in hemoglobin and blood cell count (hematocrit) may be absent in such cases, but serum albumin is characteristically decreased due to loss of fluid in the tissues. Low blood volume with a decrease in blood pressure are uncommon in the chronic form. These patients may respond to glucocorticoids, diuretics, and aminophylline, or IVIG.
The cause of SCLS is not yet known, but there appears to be no hereditary predisposition for the condition. More than half of patients have a monoclonal or M protein detected in the blood. The level of M protein is usually low. The M protein is produced by plasma cells in the marrow. The role of the M protein in acute attacks is unknown. Many possible explanations for the production of M protein in SCLS patients have been suggested including an autoimmune mechanism in which the immune system mistakenly attacks the body. Recently it has been suggested that capillary lining cells may be damaged by a factor in the blood which is produced during the acute attack.
There are less than 500 patients with SCLS reported in the world literature since its first description in 1960 by Clarkson. Although most clinical studies were performed in Caucasians, SCLS has been recognized in a range of racial backgrounds and nationalities. SCLS seems to occur slightly more often in older male adults, but females have also been affected. Most diagnoses are made at the median age of 48 years of age. The disease may be more frequent than the literature suggests because the diagnosis is often missed or delayed.
SCLS can be diagnosed with three parameters: low blood pressure, increased hematocrit and low protein in the blood (hypoalbuminemia). However, these three features are not absolutely conclusive of SCLS. Other tests must be done in order to rule out other possible causes of the symptoms such as infection and C-1 esterase inhibitor deficiency.
To confirm the diagnosis, several key laboratory features are critical. The sudden and profound capillary leak causes a sharp decrease in serum albumin level (hypoalbuminemia) and a similarly sharp increase in the level of hemoglobin and hematocrit. The red blood cells which contribute to measurements of hemoglobin and hematocrit are not actually increased. Rather, the blood becomes concentrated due to the loss of fluid. This hemoconcentration is a classic feature of the syndrome and proof of hemoconcentration is essential for the diagnosis. Some patients are mistakenly diagnosed as having polycythemia, a condition in which the hematocrit is increased due to excessive marrow production of red blood cells.
A search for an M protein should be undertaken but the absence of an M protein does not exclude the diagnosis.
Currently, there is no known cure for SCLS. Treatment is directed at prevention of attacks using agents aimed at decreasing capillary leakage and aimed at interfering with hormone like cytokines that induce the leakage. Once an attack is underway, treatment is directed toward supportive care, specifically controlling blood pressure to maintain blood flow to vital organs as well as preventing excessive swelling and fluid accumulation.
Treatment of a fully developed SCLS episode requires recognition that there are two phases of the acute attack. The first phase, which often lasts several days is called the resuscitation phase aimed at controlling the capillary leaks and maintaining blood pressure. In that phase, an albumin and fluid leak from the capillaries into the tissue spaces causes swelling. This loss of fluid has similar effects on the circulation as dehydration, which slows the flow of oxygen carrying blood to tissues. The blood pressure falls, and the red cells concentrate. Intravenous fluid replacement is usually required, but should be minimized due to its propensity to leak into tissues. Although the blood pressure may still be low, it is important to avoid overly aggressive intravenous fluid administration that could result in massive swelling of the extremities requiring surgical decompression. In this procedure, the skin of the arm of leg is cut to release the compressive pressure from the retained fluids and improve blood flow to and from the extremities. Excessive intravenous fluids may also cause accumulation of fluid in the lungs and around other vital organs. The goal during the acute phase is NOT to attempt to maintain absolutely normal blood pressure or urine flow but to maintain the blood pressure at just sufficiently high enough levels to avoid permanent damage to vital organs yet spare the patient from the risks of excess fluid administration. Measurement of central venous or arterial pressure in an intensive care unit is often necessary to achieve this delicate balance. Intravenous albumin and colloid may be used. Keeping up with the fluid loss is important because sustained low blood pressure can damage vital organs such as the kidneys.
The second phase of treatment is sometimes called the recruitment phase as fluids and albumin are reabsorbed from the tissues. In this phase, the capillary leak has lessened and the main threat is fluid overload. Diuretics may be required for excess fluid overload.
Glucocorticoids (steroids) are often used during the acute attack, especially early in the recruitment phase in an attempt to reduce the capillary leak, but their efficacy is unknown. Albumin and colloids administered with the intravenous fluids may have temporary benefit to increase blood flow to vital organs like the kidneys.
Maintenance therapy is given in an attempt to reduce the frequency and severity of the acute attacks. Administrating immunoglobulins intravenously once per month for an indefinite period of time is currently the standard of care for SCLS. IVIG for prevention has been shown to significantly improve survival in patients with monoclonal gammopathy-associated SCLS, but it is also highly effective in cases of SCLS without monoclonal gammopathy.
Secondary medications may include a combination of theophylline and terbutaline. These are administered by mouth. The level of theophylline must be maintained in the therapeutic range as determined by regular blood tests. Patients who do not tolerate these drugs may benefit by leukotriene inhibitors such as montelukast (Singulair). Occasionally, an ACE inhibitor such as lisinopril may be of benefit. The role of these secondary medications is uncertain.
The National Institute of Allergy and Infectious Disease (NIAID) is sponsoring a study to investigate mechanisms that may cause systemic capillary leak syndrome. Patients between 16 and 65 years of age who have been diagnosed with SCLS are eligible. The following link provides details: http://clinicaltrials.gov/ct2/show/NCT00936325
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
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