Systemic Capillary Leak Syndrome · What Is It, Causes, Symptoms, Diagnosis, and More

Systemic capillary leak syndrome (SCLS), also known as Clarkson disease, is a rare disorder in which considerable amounts of plasma and proteins leak from capillaries into surrounding tissue, muscle, and body cavities. As a result, there is a sharp drop in blood pressure, potentially resulting in hypovolemic shock, hypoalbuminemia, and thickened blood due to a decrease in plasma volume.  

If left untreated, organ failure and death can occur. The frequency of attacks can range from several a year to a single occurrence in a lifetime. The average age of onset is 45 years of age with the sexes affected equally. Of note, there have only been approximately 250 cases reported in medical literature to date.  

The cause of systemic capillary leak syndrome is often unknown, however, it is thought to be an abnormal response of the immune system to an infection or illness mediated by cytokines (e.g., VEGF and IL-2) and endothelial injury.  

In SCLS, the endothelium, or the inner lining of blood vessels, becomes abnormally permeable, which allows fluid, albumin, and other proteins to leak from capillaries into interstitial space. However, red blood cells remain inside the blood vessels, which results in hemoconcentration. 

Attacks of systemic capillary leak syndrome may be triggered by viral infections or through intense physical exertion. It has recently been reported that COVID-19 vaccines and SARS-CoV-2 infection can also induce this disorder in those who have never had an attack, as well as induce recurring episodes in those who have previously experienced SCLS. In many cases, SCLS is associated with monoclonal gammopathy of unknown significance (MGUS), an immune cell disorder characterized by excessive amounts of a dysfunctional immunoglobulin protein.   

Finally, some chemotherapeutic agents and biologic therapies have also been linked with SCLS, either as a direct cause or as a trigger in predisposed individuals. 

The signs and symptoms of systemic capillary leak syndrome vary from person to person. SCLS typically occurs in recurrent episodes, ranging from weeks to years apart. Each attack progresses in three phases: prodromal phase, leak phase, and recovery.   

During the prodromal phase, there are non-specific symptoms, including irritability, fatigue, abdominal pain, nausea, muscle aches, increased thirst, and sudden increases in body weight. Symptoms such as fever, chills, rash, or signs of infection may or may not be present. This phase typically lasts 1 to 2 days. 

The leak phase follows and is characterized by general swelling, significantly low blood pressure, fluid build-up in the lungs and around the heart, and decreased urine output. Other complications may include rhabdomyolysis, which is the breakdown of muscle tissue causing release of proteins and electrolytes into the blood, and compartment syndrome of the extremities. Compartment syndrome is a rare and painful condition that occurs when a build-up of pressure around the muscle leads to decreased blood flow and potential loss of the affected limb.  

During recovery, which usually takes place between the fifth and seventh day, blood pressure normalizes, urine output increases, and the swelling reduces. Weight loss also occurs. During this phase, fluid rapidly re-enters blood vessels, so there’s a risk of fluid overload and pulmonary edema. 

These characteristic features often vary, with some people experiencing more severe symptoms than others. Over time, as fluid leaks out from the bloodstream, organs may be starved of adequate blood flow. For example, the kidneys, brain, and liver may be deprived of oxygen and other critical nutrients they need for normal function. If left untreated, kidney failure, lung failure, heart failure, and stroke can occur.

Diagnosis of systemic capillary leak syndrome is primarily clinical, based on the presence of recurrent episodes of hemoconcentration, hypotension and hypoalbuminemia in the absence of other explanations (e.g., sepsis, anaphylactic shock).   

There are no specific tests to confirm SCLS, however, laboratory findings typically reveal an elevated hematocrit and hemoglobin and low protein levels in the blood (i.e., hypoalbuminemia). Additionally, blood cultures and infection markers are usually negative, and serum protein electrophoresis often shows increased levels of paraprotein, consistent with MGUS. Finally, imaging may show edema, pleural effusion, or ascites during the leak phase. 

There is currently no known cure, so treatment of systemic capillary leak syndrome is focused on managing and stabilizing the symptoms during an episode and preventing future episodes and complications.  

Given the serious nature of the disorder, acute treatment usually occurs in an intensive care unit (ICU). During an episode, treatment involves stabilizing the airway, administering medications, providing hydration, and delivering oxygen therapy. Intravenous fluids are often administered with caution as too much can worsen edema in recovery phase. After a variable number of days, vascular permeability spontaneously improves, and the blood pressure stabilizes.  

There are prophylactic treatments that can help prevent future episodes, including monthly infusions of intravenous immunoglobulin (IVIG). Those who do not improve with IVIG or who cannot tolerate the therapy may have success with theophylline and terbutaline, which are oral medications designed to treat asthma that were used historically when IVIG was not available.