Idiopathic Capillary Leak Syndrome Research Articles

A MISLEADING FORM OF IDIOPATHIC CAPILLARY LEAKAGE SYNDROME (CLARKSONS DISEASE): A CASE REPORT

The idiopathic capillary leak syndrome, commonly referred to as Clarksons disease, is an uncommon and severe disorder that frequently necessitates intensive care intervention due to recurring episodes of shock.With no established treatment available during the acute phase, the primary approach to management revolves around symptom relief. It seems that the use of vascular fluid resuscitation has an adverse effect on patient outcomes in intensive care, and therefore, there should be endeavors to restrict its usage.As an illustrative case, this article describes the case of a 53-year-old patient who presented to the emergency department with edema following the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and was initially misdiagnosed as anaphylaxis.Laboratory tests revealed hypoproteinemia in contrast to hemoconcentration, and the absence of serum albumin, which raised suspicion of Clarksons syndrome. This suspicion was confirmed through serum protein electrophoresis, ruling out other diagnoses.

Ovarian hyperstemulation syndrome as a private case of iatrogenic capillary leak syndrome

Idiopathic capillary leak syndrome was first described in 1960 and later received its name in honor of the discoverer - Clarkson's Disease. However, in the past two decades, more cases have been reported than in the previous 35 years, most likely due to improved recognition, the widespread use of assisted reproductive technologies in the treatment of infertility and the emergence of targer therapy - monoclonal antibodies for the treatment of cancer and autoimmune diseases. Except for Clarkson's disease, capillary leak syndrome can occur in engraftment syndrome, differentiation syndrome after bone marrow transplantation, ovarian hyperstimulation syndrome, hemophagocytic lymphohistiocytosis, viral infections, mostly hemorrhagic fevers, some autoimmune diseases, administration of recombinant interleukins, cytostatics, some monoclonal antibodies including treatment with the latest anticancer drugs - immune checkpoint inhibitors, snakebite envenomation, and ricin poisoning. This syndrome is characterized by a sharp increase in vascular permeability for fluid and protein molecules that leads to the loss of fluid into the interstitium, and presents with acute onset of severe edema, often asymmetric, hypotension, polyserositis, hemoconcentration and low blood protein level. In assisted reproductive technology programs, the introduction of gonadotropins results in an increase in estradiol levels, which leads to the development of immunopathological process, accompanied by leukocyte infiltration of blood vessels and secondary hypercytokinemia. Subsequently, the secondary «wave» of cytokines and vasoactive substances secreted in response to the introduction of human chorionic gonadotropin as an ovulation trigger, leads to disruption of interendothelial contacts and the development of ovarian hyperstimulation syndrome. It is necessary to conduct a further study of the pathogenesis of capillary leak syndrome, in order to develop promising methods for the prevention and correction of ovarian hyperstimulation syndrome in assisted reproductive technology programs.

Weird and wonderful ICU cases: Unusual causes of shock

During their practice, intensivists are ought to face challenging cases that are rare. Intensivists need to be aware of the rare causes of shock beyond common presentations. In each category of shock, there are rare causes that require prompt identification and management. Certain clues in the patient's presentation might point to those rare causes.Classically shock is classified into: distributive, hypovolemic, cardiogenic, and obstructive. In this era of bedside point-of-care ultrasound, intensivists are able to promptly identify the cause of shock and institute a resuscitation plan. However, there are cases when the diagnosis is still obscure and the cause of shock is not easily identified. For example, in a study of patients admitted with presumed septic shock, 7.4% had no identified cause of shock and 11% had sepsis mimickers.1 Hypovolemic shock occurs secondary to a reduction in the effective circulating volume secondary to fluid loss or third spacing. A rare cause of hypovolemic shock is idiopathic capillary leak syndrome (Clarkson Syndrome).2 The syndrome is characterized by recurrent episodes of rapidly progressive generalized edema, shock, renal failure and high hematocrit. The episode usually resolves in 3-7 days where the capillary leak resolves and a phase of pulmonary edema occurs. Several treatment options such as intravenous immunoglobulin (IVIG) and aminophylline were used in case reports.3 Vasodilatory shock occurs secondary to peripheral vasodilation and decrease in blood flow. It occurs as part of the systemic inflammatory response syndrome for which sepsis, acute pancreatitis, acute liver failure, and major trauma are common causes. Rare causes that need to be considered include: hemophagocytic lymphohistiocytosis (HLH), systemic mastocytosis, and toxic shock syndrome.Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome characterized by macrophage activation and engulfment of hemopoetic cells which leads to pancytopenia. It is also characterized by cytokines storm that lead to a vasodilatory shock, multi-organ failure, and acute respiratory distress syndrome (ARDS). The most common triggers are infection, malignancy, and autoimmune diseases. Pointers to this diagnosis in the intensive care unit include: pancytopenias, hypofibrinogenemia, high triglycerides, and high ferritin. Treatment necessitates treating the underlying cause as well as using immune modifying therapies.4 Systemic mastocytosis is a rare cause of recurrent anaphylaxis shock. It results from the accumulation of mast cells in tissues and can present with anaphylaxis and vascular collapse. An important clue to the diagnosis is the presence of urticarial pigmentosa and the absence of an allergen history.5 Toxic shock syndrome is a unique cause of sepsis. It is caused by a pre-formed toxin produced by Staphylococcus aureus and Streptococcus pyrogenes. The clue to the diagnosis include the rapid onset after the precipitating factor, erythroderma, and skin desquamation. Treatment includes IVIG and Clindamycin.6

Idiopathic Capillary Leak Syndrome

Capillary leak can be the underlying mechanism of a number of clinical syndromes, especially in severe shock states including anaphylaxis. The hallmarks of the idiopathic capillary leak syndrome (ICLS) include edema, hypotension and hemoconcentration and can mimic type 1 allergic disorders.

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Introduction: Diagnosing factitious disorders can be expensive, time consuming, and challenging. We present a clinical conundrum of refractory hypotension that ultimately led to a diagnosis of surreptitious AV-nodal agent abuse. Case: A 41 year-old female with a diagnosis of idiopathic capillary leak syndrome (ICLS), s/p demand pacemaker for intermittent symptomatic bradycardia, was admitted for elective administration of intravenous immunoglobulin (IVIG). Development of hypoalbuminemia, bilateral pleural effusion, and peripheral edema on a background of refractory hypotension during a preceding hospital admission (6 months prior to the index admission) aided the diagnosis of ICLS [1]. A diagnosis of ICLS was made following an extensive 2-year evaluation by multiple specialties for a constellation of symptoms that had escaped clinical diagnosis. She was committed to IVIG, after failure of first line therapy (Terbutaline) [2] by an autonomic dysfunction expert, in consultation with an allergist, pulmonologist, general cardiologist, and electrophysiologist. On evaluation, her physical examination, biochemical profile, echocardiogram, pacemaker evaluation, and radiology were all unremarkable. Within one hour of admission, the patient developed acute refractory hypotension and bradycardia prompting pacemaker activation and vasopressors. Hemodynamic improvement noted during the course of the day was followed by a precipitous decline at night, only to improve dramatically again with short periods of vasopressor therapy. This was the pattern of her clinical course during her admission. Inconsistencies in her clinical presentation (no evidence of hemoconcentration or third spacing - a hallmark of ICLS) and intermittent pacemaker activation for bradycardia, prompted a reevaluation of her clinical diagnosis. The evanescent nature of the symptoms in an otherwise healthy individual was intriguing. Our belief in the medical adage 'All other things being equal the simplest answer is usually the best' prompted us to consider surreptitious AV-nodal blocker abuse. We requested serum beta and calcium-channel blocker levels during the throes of these acute hypotensive episodes while the patient was on norepinephrine. A two year search for a medical dilemma that escaped clinical diagnosis came to fruitition when a Metoprolol level of 95 ng/ml (therapeutic limit 20 to 340 ng/ml) and a Verapamil level of 380 ng/ml (therapeutic limit 70 to 350 ng/ml) was reported. A case for Munchausen's Syndrome - Factitious disorder was thus made. Patient was confronted with the data and reluctantly admitted to surreptitious use of Metoprolol and Verapamil. She elected to have her pacemaker removed and psychiatry services were consulted. Discussion: Factitious Disorder is a mental disorder in which a person acts as if he or she has a physical or mental illness when, in fact, he or she has consciously created their symptoms. Idiopathic capillary leak syndrome is a rare disease of unknown cause. It results in reversible plasma extravasation and vascular collapse. Diagnosis is made clinically and by exclusion of other diseases that cause similar signs and symptoms [1]. Factitious disorders must also be considered as part of the differential diagnosis when there are inconsistencies in the patient's history, laboratory tests, and physical examination findings [3]. Conclusion: Factitious disorders could be the simplest explanation for medical conundrums that baffle physicians. "When you hear hoofbeats, think horses, not zebras." Reference #1: Druey KM et al. Narrative review: the systemic capillary leak syndrome. Ann Intern Med 2010; 153-90. Reference #2: Gousseff M, et al. The systemic capillary leak syndrome: a case series of 28 patients from a European registry. Ann Intern Med 2011; 154:464. Reference #3: Krahn LE, Li H, et al. Patients who strive to be ill: factitious disorder with physical symptoms. Am J Psychiatry. Jun 2003;160(6):1163-8

Acute Renal Endothelial Injury During Marrow Recovery in a Cohort of Combined Kidney and Bone Marrow Allografts

An idiopathic capillary leak syndrome ('engraftment syndrome') often occurs in recipients of hematopoietic cells, manifested clinically by transient azotemia and sometimes fever and fluid retention. Here, we report the renal pathology in 10 recipients of combined bone marrow and kidney allografts. Nine developed graft dysfunction on day 10-16 and renal biopsies showed marked acute tubular injury, with interstitial edema, hemorrhage and capillary congestion, with little or no interstitial infiltrate (≤10%) and marked glomerular and peritubular capillary (PTC) endothelial injury and loss by electron microscopy. Two had transient arterial endothelial inflammation; and 2 had C4d deposition. The cells in capillaries were primarily CD68(+) MPO(+) mononuclear cells and CD3(+) CD8(+) T cells, the latter with a high proliferative index (Ki67(+) ). B cells (CD20(+) ) and CD4(+) T cells were not detectable, and NK cells were rare. XY FISH showed that CD45(+) cells in PTCs were of recipient origin. Optimal treatment remains to be defined; two recovered without additional therapy, six were treated with anti-rejection regimens. Except for one patient, who later developed thrombotic microangiopathy and one with acute humoral rejection, all fully recovered within 2-4 weeks. Graft endothelium is the primary target of this process, attributable to as yet obscure mechanisms, arising during leukocyte recovery.

Syndrome de fuite capillaire idiopathique

Idiopathic capillary leak syndrome (ICLS) is a rare and poorly known condition. Since the first description in 1960, about hundred cases have been reported. A French register that was initiated in 1997 provides a better knowledge of the natural course of the disease and highlights some therapeutic issues. ICLS mainly affects middle-aged adults. The prognosis is poor with a 10-year mortality rate around 34%. Severe crisis and complications occurring in intensive care units account for 80% of the mortality. Diagnosis relies on an almost pathognomonic association: recurrent attacks of hypotension and hemoconcentration with paradoxical hypoalbuminemia. A monoclonal gammopathy is found in about 80% of patients. Physiopathology still remains unclear. Paraprotein toxicity has never been demonstrated. As a result, no evidence-based treatment is available neither for acute crisis nor for prophylaxis. Management of acute episodes is mainly symptomatic. Fluid infusion must be cautious because it can induce complications during the recovery phase. Patient education is a major measure to prevent recurrent attacks. Beta-2 stimulants were reported to reduce the frequency and severity of episodes and were considered as the recommended prophylactic measure. However, early data from the French register suggest that intravenous immunoglobulins are more effective in reducing both frequency and severity of the attacks. Inclusion of patients with ICLS in a register is crucial to improve the knowledge about aetiology and treatment of this disorder.

Le syndrome d’hyperperméabilité capillaire idiopathique : à propos de deux cas

We report on two cases of severe hypovolemic shock related to the diagnosis of idiopathic capillary leak syndrome (SCLS). Two patients – a 34-year old man and a 47-year old woman – were admitted in an intensive care unit with circulatory failure. One patient had abdominal pain. The association of elevated hematocrit, decreased albumin serum concentration and the presence of monoclonal IgG kappa immunoglobulins confirmed the diagnosis of SCLC. SCLC is a rare disease with a poor prognosis, the pathophysiology of which remains unexplained. It is characterized by acute periods of hypotension subsequent to a shift of fluid and proteins from the intravascular to the interstitial space. During an attack, a paradoxical hypoproteinaemia in the context of major haemoconcentration suggests the diagnosis. Between attacks, a benign monoclonal gammapathy is often present and appears to be a cornerstone of the diagnosis. Currently, betamimetics and phosphodiesterase inhibitors are proposed as a prophylactic therapy.

Encephalopathy Due to Capillary Leak Syndrome

Systemic capillary leak syndrome (SCLS) is characterized by intermittent attacks of leakage of intravascular fluids into the extravascular space. Hypovolemia, hemoconcentration, weakness, edema, and visceral congestion are resulting manifestations of SCLS. Most patients with SCLS have clear mentation during attacks, and encephalopathy is not a known manifestation of the syndrome. We report a patient with acute idiopathic capillary leak syndrome manifested in an acute encephalopathy. The possibility of SCLS should be considered in patients who have an encephalopathy and hemoconcentration.

Idiopathic capillary leak syndrome: Evidence of CD8-positive lymphocytes surrounding damaged endothelial cells

J Allergy Clin Immunol 1997;99:417-9.

Idiopathic Capillary Leak Syndrome Complicated by Massive Rhabdomyolysis

Idiopathic systemic capillary leak syndrome (Clarkson's disease) is characterized by recurring attacks of increased capillary permeability, resulting in severe hypovolemic shock due to plasma extravasation. Additional laboratory features include association with a monoclonal gammopathy, extreme hemoconcentration, and hypoalbuminemia. Rare manifestations of this syndrome are renal damage and rhabdomyolysis due to increased compartment pressure and ischemic myonecrosis. We present the findings in two patients with capillary leak syndrome complicated by severe rhabdomyolysis, in one case leading to acute renal failure. We review therapeutic aspects of this rare syndrome and emphasize the importance of early diagnosis and of prompt and aggressive fluid replacement.