Capillary leak syndrome

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Capillary leak syndrome
Other namesSCLS, Clarkson's Disease, Capillary hyperpermeability syndrome
montelukast

Capillary leak syndrome, or vascular leak syndrome, is characterized by the escape of

monoclonal antibodies, can also cause capillary leaks.[1][2]
These conditions and factors are sources of secondary capillary leak syndrome.

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.

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 (

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

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,

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.

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

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.

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

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

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

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]

References

  1. ^
    PMID 28318633
    .
  2. PMID 9091576
    .
  3. ^
    PMID 20643990
    .
  4. ^
    PMID 28012935
    .
  5. ^
    S2CID 198448
    .
  6. ^
    PMID 22411873
    .
  7. PMID 24787070
    .
  8. ^
    PMID 1580299
    .
  9. PMID 36119848
    .
  10. PMID 20634497
    .
  11. ^
    PMID 25193271
    .
  12. ^
    PMID 28602874
    .
  13. ^
    S2CID 41357732
    .
  14. S2CID 250970743
    .
  15. PMID 13693909
    .

External links

Additional links:

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