Capillary Leak Syndrome - Causes and Symptoms

Introduction

Capillaries are minute vascular vessels that interlink arteries and veins. They exist as a network system finely interconnected with the tissues. These capillaries play a prime role in the exchange of gases (oxygen, carbon dioxide), nutrients, and other metabolites between the blood and tissue cells. About 5 percent of the total blood volume circulates in the capillaries at a given time. The walls of the capillaries are made of a specialized selectively permeable membrane that allows passage of only specific components. Sometimes any disease or injury condition alters its permeability resulting in capillary dysfunction.

What Is Capillary Leak Syndrome?

Capillary leak syndrome is a rare but life-threatening clinical condition caused by the movement of intravascular fluid (plasma-containing proteins) into the surrounding tissues (interstitial space). The term capillary leak syndrome encompasses a spectrum of disorders characterized by an enhanced capillary permeability to plasma proteins. Three forms of capillary leak syndrome exist

• Idiopathic systemic capillary leak syndrome (Clarkson’s disease).

• Capillary leak syndrome is associated with cutaneous diseases (pustular psoriasis, papuloerythroderma, leukemia).

• Drug-induced (Docetaxel, Acitretin, Gemcitabine, Sirolimus).

What Causes Capillary Leak Syndrome?

Capillary leak syndrome is caused due to the damage in layers of blood vessels (endothelium) by the products of inflammation (cytokines). The predominant causes resulting in capillary leak syndrome are

• Viral hemorrhagic fevers (Ebola and Marburg viruses).

• Engraftment syndrome (occurs after hematopoietic stem cell transplantation).

• Sepsis and septic shock (infection due to the growth of microbes in the bloodstream).

• Toxic shock syndrome (due to toxins produced by bacteria - Staphylococcus aureus).

• Differentiation syndrome (seen in acute promyelocytic leukemia).

• Hemophagocytic lymphohistiocytosis (a rare and potentially life-threatening disorder characterized by an overactive immune system).

• Ovarian hyperstimulation syndrome.

• Autoimmune disorders.

• Envenomation from snakebite.

• Ricin poisoning.

• Administration of interleukins (IL-2), and monoclonal antibodies (G-CSF and anti-CD22 antibodies).

• Intake of drugs such as Gemcitabine.

What Are the Signs and Symptoms of Capillary Leak Syndrome?

Most of the disorders causing capillary leak syndrome are rare and uncommon. The resulting clinical manifestations vary in proportion to the existing predisposing condition and its eventual development into capillary dysfunction. Also, the severity ranges from mild symptoms to severe complications.

The clinical presentation of capillary leak syndrome is usually manifested in three stages:

• Prodromal phase.

• Status (leak) phase.

• Recovery phase.

Prodromal Phase - It lasts for one to two days and shows nonspecific symptoms like

• Irritability.

• Increased thirst.

• Fatigue.

• Weakness.

• Nausea.

• Abdominal pain.

• A sudden increase in body weight.

• Myalgias (muscle pain).

• Fever with chills.

• Rashes.

Status (Leak) Phase - At this stage, most of the clinical complications arise due to decreased oxygen supply and reduced nutrient availability to the tissues.

• Generalized pitting edema.

• A marked decrease in blood pressure (hypotension).

• Localized and diffuse skin edema.

• Massive edema.

• Decreased urine output.

• Accumulation of fluids in tissues surrounding lungs and heart.

• Ischemia-induced organ failure.

• Hypovolemic shock.

• Rhabdomyolysis (muscle breakdown releasing muscle protein into the blood).

• Acute kidney injury.

• Pulmonary edema and lung failure.

• Muscle compartment syndromes (increased pressure around muscle tissues leading to decreased blood flow).

• Liver failure.

• Heart failure.

• Stroke.

• Venous thromboembolism (a condition in which blood clots form in the veins, typically in the legs or pelvis, and lungs).

• Proteinuria (protein in urine).

Recovery (Post Leak) Phase - This stage occurs within five to seven days of initial onset.

• Gradual normalization of blood pressure.

• Urine output increases.

• Generalized swelling decreases.

• Reduction in body weight.

How Is Capillary Leak Syndrome Diagnosed?

Diagnosis is done mostly by clinical examination and by excluding other disease conditions that present with similar symptoms. The clinical triad of hypotension (drop in blood pressure), hemoconcentration, and hypoalbuminemia (in the absence of secondary causes for shock) is highly suggestive of capillary leak syndrome. Blood tests are done as confirmatory procedures.

• Increased respiratory rate (more than 20/ minute).

• Blood pressure falls below 95/45 mm Hg.

• Pulmonary lung congestion.

• Hemoconcentration (increased concentration of cellular components of blood).

• Increased neutrophil count and total white blood cell count (due to decreased blood volume).

• Increased platelet count (thrombocytosis).

• Increased hematocrit values (due to decreased total blood volume).

• Hypoalbuminemia.

• Culture negativity (in case of sepsis).

• Hepatomegaly and ascites.

• Respiratory and metabolic acidosis.

• Presence of abnormal proteins in the blood in case of repeated episodes.

• Elevated liver enzymes.

• Myoglobinuria (presence of muscle breakdown products in urine)

• Vascular endothelial growth factors (VEGF) are increased causing endothelial damage and are detected by immunoassay.

How Is Capillary Leak Syndrome Treated?

The symptoms that are mild to moderate are usually reversible and require continuous monitoring to prevent progression into fatal complications. There is no specific treatment for capillary leak syndrome and management includes stabilization of clinical symptoms. Their management is usually done in the intensive care unit (ICU).

• Vasopressor therapy and fluid replacement are done in acute episodes.

• Colloidal solutions are given to prevent under-perfusion.

• High molecular weight starches (10 percent pentastarch) are preferred for fluid resuscitation.

• Terbutaline and theophylline are given between the episodes to reduce their severity as well as frequency.

• Monitoring of central venous pressure is mandatory since the increase in central venous pressure is suggestive of recovery.

• Oxygen therapy to prevent ischemic injury in tissues.

• In severe cases, mechanical ventilation is given.

• After establishing normal blood pressure, diuretics are administered to increase urinary output to prevent pulmonary edema.

• Administration of corticosteroids (steroid therapy) is given to minimize inflammation and immune reactions.

• Immunomodulating agents, thalidomide and lenalidomide are proved effective.

• anti-VEGF antibodies are given to reduce endothelial damage.

• Prophylactic doses of intravenous immunoglobulins (IVIG) are also recommended to prevent auto-immune antibody-mediated reactions.

• Anticoagulants are administered to prevent venous thromboembolism.

What Is the Prognosis of Capillary Leak Syndrome?

The prognosis is uncertain and varies depending on the recovery phase. With early detection and immediate management, more than 70 percent of a ten-year survival rate is reported even in patients with severe episodes. Immunoglobulin (Ig) therapy is commonly recommended for prevention. Oral medications of terbutaline and theophylline are also used as prophylactic therapy. The average survival age of 15 to 30 years is reported with regular follow-up and prophylaxis.

Conclusion

Diverse groups of diseases cause capillary leak syndrome. Common clinical symptoms include hypotension and shock, followed by edema and organ damage. Diagnosis and treatment of capillary leak syndrome are challenging due to the absence of specific diagnostic criteria. However, increased awareness in suspicion of its occurrence and correlating with clinical symptoms helps in early identification and management. This condition is usually self-recovering where regular monitoring reduces fatal complications.