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The Systemic Capillary Leak Syndrome: A Case Series of 28 Patients From a European Registry

Marie Gousseff, MD; Laurent Arnaud, MD; Marc Lambert, MD, PhD; Arnaud Hot, MD; Mohamed Hamidou, MD; Pierre Duhaut, MD, PhD; Thomas Papo, MD; Martin Soubrier, MD, PhD; Marc Ruivard, MD, PhD; Giuseppe Malizia, MD; Nathalie Tieulié, MD; Sophie Rivière, MD; Jacques Ninet, MD, PhD; Pierre-Yves Hatron, MD; Zahir Amoura, MD, for the Capillary Leak Syndrome Registry
[+] Article and Author Information

From Pitié-Salpêtrière Hospital, Assistance Publique–Hôpitaux de Paris, Institut National de la Santé et de la Recherche Médicale, Hôpital Bichat, and Université Pierre et Marie Curie, Paris, France; Université Nord de France, Lille, France; Hôpital Edouard Herriot, Université Claude Bernard Lyon I, Lyon, France; Centre Hospitalier Universitaire Hôtel-Dieu, Nantes, France; Hôpital Nord, Amiens, France; Centre Hospitalier Universitaire de Clermont-Ferrand and Centre Hospitalier Universitaire Estaing, Clermont-Ferrand, France; Ospedali Riuniti Villa Sofia-Ospedale V. Cervello, Palermo, Italy; Hôpital l'Archet, Nice, France; and Centre Hospitalier Universitaire Montpellier, Montpellier, France.


Note: Drs. Gousseff and Arnaud contributed equally to this work.

Acknowledgment: The authors thank the physicians caring for the patients and who referred them to the registry: Drs. Abgueguen, Carano, Choukroun, Decaux, Godmer, Hachulla, Ibouanga, Lavigne, Le Quellec, Mathian, Moulin, Rondeau, and Thebault, among others.

Grant Support: Primarily by Université Pierre et Marie Curie (Paris, France) and in part by Laboratoire Français du Fractionnement et des Biotechnologies (Les Ulis, France).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-2267.

Reproducible Research Statement:Study protocol and statistical code: Not applicable. Data set: Full access to the data set is limited to the physicians contributing to the Capillary Leak Syndrome Registry.

Requests for Single Reprints: Zahir Amoura, MD, Service de Médecine Interne 2, Groupe Hospitalier Pitié-Salpêtrière, 47-83 boulevard de l'Hôpital, 75013 Paris, France; e-mail, zahir.amoura@psl.aphp.fr.

Current Author Addresses: Drs. Gousseff, Arnaud, and Amoura: Service de médecine interne 2, Groupe Hospitalier Pitié-Salpêtrière, 47-83 boulevard de l'Hôpital, 75013 Paris, France.

Drs. Lambert and Hatron: Service de Médecine Interne, Hôpital Huriez, Rue Michel Polonovski, 59037 Lille Cedex, France.

Drs. Hot and Ninet: Service de Médecine Interne, Centre Hospitalier Régional Universitaire Hôpital Edouard Herriot, 5 Place d'Arsonval, 69437 Lyon Cedex 03, France.

Dr. Hamidou: Service de Médecine Interne, Centre Hospitalier Universitaire Hôtel Dieu, Place Alexis Ricordeau, 44093 Nantes, France.

Dr. Duhaut: Service de Médecine Interne du Pr Jean-Pierre Ducroix, Centre Hospitalier Universitaire Nord, Place Victor Pauchet, 80000 Amiens, France.

Dr. Papo: Service de Médecine Interne, Hôpital Bichat, 46 rue Henri Huchard, 75877 Paris Cedex 18, France.

Dr. Soubrier: Service de Rhumatologie, Hôpital Gabriel Montpied, 58 rue Montalembert, 63003 Clermont-Ferrand, France.

Dr. Ruivard: Service de Médecine Interne, Centre Hospitalier Universitaire de Clermont-Ferrand—Hôtel Dieu, Boulevard Léon Malfreyt, 63058 Clermont-Ferrand Cedex 01, France.

Dr. Malizia: Divisione di Gastroenterologia, Ospedali Riuniti Villa Sofia-Ospedale V. Cervello, Via Trabucco 180, 90146 Palermo, Italy.

Dr. Tieulié: Service de Médecine Interne, Hôpital l'Archet, 151 route de Saint Antoine de Ginestière, BP 3079, 06202 Nice Cedex 3, France.

Dr. Rivière: Service de Médecine Interne A, Centre Hospitalier Universitaire de Montpellier, Hôpital Saint-Éloi, 80 avenue Augustin Fliche, 34295 Montpellier Cedex 5, France.

Author Contributions: Conception and design: M. Gousseff, L. Arnaud, Z. Amoura.

Analysis and interpretation of the data: M. Gousseff, L. Arnaud, T. Papo, Z. Amoura.

Drafting of the article: M. Gousseff, L. Arnaud, Z. Amoura.

Critical revision of the article for important intellectual content: M. Gousseff, L. Arnaud, M. Lambert, T. Papo, M. Ruivard, G. Malizia, P.Y. Hatron, Z. Amoura.

Final approval of the article: M. Gousseff, L. Arnaud, M. Lambert, A. Hot, M. Hamidou, T. Papo, M. Soubrier, M. Ruivard, G. Malizia, N. Tieulié, S. Rivière, Z. Amoura.

Provision of study materials or patients: M. Gousseff, M. Lambert, A. Hot, M. Hamidou, P. Duhaut, M. Ruivard, G. Malizia, S. Rivière, J. Ninet, P.Y. Hatron, Z. Amoura.

Statistical expertise: M. Gousseff, P. Duhaut.

Obtaining of funding: Z. Amoura.

Administrative, technical, or logistic support: M. Gousseff, Z. Amoura.

Collection and assembly of data: M. Gousseff, L. Arnaud, M. Lambert, A. Hot, P. Duhaut, T. Papo, N. Tieulié, S. Rivière, J. Ninet, Z. Amoura.


Ann Intern Med. 2011;154(7):464-471. doi:10.7326/0003-4819-154-7-201104050-00004
Text Size: A A A

Background: The systemic capillary leak syndrome (SCLS) is a rare disease characterized by life-threatening attacks of capillary hyperpermeability.

Objective: To describe the clinical characteristics, laboratory findings, treatments, and outcomes of patients with SCLS who were not previously reported in the literature.

Design: Case series.

Setting: Patients referred to a European multicenter SCLS registry between January 1997 and July 2010.

Patients: 28 patients with SCLS.

Measurements: Frequency, severity of attacks, and vital status were assessed every 6 months, from diagnosis to the end of the study.

Results: 13 men and 15 women referred to the registry who were not previously reported in the literature had 252 attacks. Median age at disease onset was 49.1 years (range, 5.4 to 77.7 years), and median annual frequency of attacks was 1.23 (range, 0.13 to 21.18) per patient. Monoclonal IgG gammopathy was observed in 25 patients (89%). Preventive treatment included intravenous immunoglobulin (n = 18), terbutaline (n = 9), and aminophylline (n = 10). Eight patients died (29%); 1-year survival was 89%, and 5-year survival was 73%. Death was directly related to SCLS attacks in 6 of 8 cases (75%). In 10 patients with a prediagnosis period greater than 6 months who received preventive treatment, the annual frequency of attacks after diagnosis decreased by a median of 1.55 (range, 0.14 to 8.84) per patient. Five years after diagnosis, survival was 85% in 23 patients who had received prophylactic treatment and 20% in 5 patients who had not.

Limitation: The benefits of preventive treatment could not be precisely ascertained because of the small sample size and because most patients received several treatments.

Conclusion: Clinical experience with these 28 patients with SCLS suggests that prophylactic treatment with β2-agonists or intravenous immunoglobulin may reduce the frequency and severity of attacks and may improve survival.

Primary Funding Source: Université Pierre et Marie Curie, Paris, France.

Figures

Grahic Jump Location
Figure 1.
Therapeutic sequences and outcomes in 28 new patients with the systemic capillary leak syndrome.

For each patient, follow-up since the first manifestation of the disease is represented by a horizontal arrow. The end of follow-up was 31 July 2010. For patients 6, 7, 12, and 19, the long follow-up could not be represented entirely in the figure. The number of attacks (and severe attacks) after diagnosis is indicated for each subsequent line of treatment. The number of attacks (and severe attacks) before diagnosis includes the attack that led to the diagnosis. IVIG = intravenous immunoglobulin.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Comparison of survival in patients with the systemic capillary leak syndrome who were receiving or not receiving prophylactic treatment.

Tick marks indicate censored patients. PT = prophylactic treatment.

Grahic Jump Location

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Systemic Capillary Leak Syndrome
Posted on April 11, 2011
Mark S Pecker
Weill Cornell Medical College
Conflict of Interest: None Declared

We read the important report of Gousseff et al (1) on The Systemic Capillary Leak Syndrome (SCLS) with great interest (1). We differ with their conclusion implying that beta-2 agonist therapy and IVIG therapy provide equivalent prophylaxis.

Review of the data of Gousseff et al. (1), shows that of the eight patients who died, six from severe episodes, none were receiving prophylactic treatment at the time of death. Eleven of the 20 survivors were treated initially with ?2-agonist therapy, but over time virtually all survivors were migrated to prophylaxis with IVIG. Eight of 18 patients receiving IVIG had no additional episodes of SCLS, and of the 14 patients who received the recommended dosage of 2gr/kg/month of IVIG, only one had a single severe episode. The remainder had either no or mild episodes, and most patients had far fewer or no severe episodes compared with the number prior to receiving IVIG. Even 2 of the 3 patients getting a low dose of IVIG had no further attacks.

We report two additional patients with SCLS who failed prophylaxis with terbutaline and theophylline, and subsequently have had no further attacks after initiation of IVIG therapy:

Patient 1: A 56 year old man had his first attack of SCLS when he presented with severe hypotension, oliguria and hemoglobin of 23 gm%. An MGUS was present. Complications included compartment syndromes in arms and legs, deep vein thromboses and acute renal failure. Terbutaline and theophylline were initiated, and continued despite ensuing personality changes. A second severe attack followed 16 months later, again requiring fasciotomies. Despite continued therapy, eight additional attacks occurred in the two years after the first episode. Theophylline levels were within the therapeutic range (10-20 mg%) over 80% of the time during this period. Levels did not correlate with the presence or severity of attacks. After the last attack, IVIG 2 gm/kg over 2 days every four weeks was initiated. Terbutaline and theophylline were stopped 5 months later. No attacks have occurred in more than 16 months since IVIG was initiated. Patient 2: A 53 year old man had his first attack of SCLS when he presented with hypotension, and hematocrit of 58.2%. Over the next 6 months, multiple episodes of hypotension ensued with hematocrits as high as 65.6%. Treatment with cetirizine, ranitidine, and zafirlukast was ineffective. An MGUS was discovered, and SCLS was diagnosed on his seventh hospitalization, six months after his initial attack. Terbutaline and theophylline were begun. Over the following 19 months, he experienced 25 episodes. Complications included atrial flutter, pericardial tamponade, recurrent pulmonary emboli, renal failure, pulmonary edema, and forearm compartment syndromes. Prednisone 5 mg daily and thalidomide were added 5 and 17 months after diagnosis, without obvious effect. 19 months after diagnosis, monthly IVIG 2 grams/kg over two days was initiated. He has had no episodes for the more than 20 months. Renal failure progressed and he is now on permanent dialysis.

There are additional published reports of successful prophylaxis with IVIG (2,3,4). We are also aware of another case (Personal Communication, J. Barrett). In at least two of these patients, instability occurred 5 weeks after treatment with IVIG, suggesting that the dosing interval may be important.

We agree with Gousseff et al that patients with SCLS require prophylactic therapy. However, given our present state of knowledge, we strongly feel that, despite its expense, IVIG is the optimal prophylaxis, and should be the initial choice to prevent attacks of SCLS. That we are not alone is implied by the authors' observation that "IVIG became a common first-line treatment in more recent years."

Mark Pecker, MD Weill Cornell Medical College New York, NY

Michael Adams, MD Georgetown University School of Medicine Washington, DC

Walter Graham, MD Burley, Idaho

References:

1. Gousseff M, Arnaud L, Lambert M, et al. The Systemic Capillary Leak Syndrome: A Case Series of 28 Patients From A European Registry. Annals of Internal Medicine 2011; 154: 464-471.

2. Lambert M, Launay D, Hachulla E, et al. High-dose intravenous immunoglobulins dramatically reverse systemic capillary leak syndrome. Critical Care Medicine 2008; 36: 2184-2187.

3. Abueguen P, Chennebault JM, Pichard E. Immunoglobulins for the Treatment of Systemic Capillary Leak Syndrome. American Journal of Medicine 2010; 123: e3-4.

4. Govig BA, Javaheri S. The Systemic Capillary Leak Syndrome (Letter). Annals of Internal Medicine 2010; 153:764.

Conflict of Interest:

None declared

Should intravenous immunoglobulins be used as the first line treatment in the Systemic Capillary Leak Syndrome?
Posted on May 11, 2011
Zahir Amoura
Service de Medecine Interne, 2,Centre National de Ref Lupus,Groupe Hosp Pitie-Salpetriere, Paris, FR
Conflict of Interest: None Declared

Dear Editor,

We read with great interest the comments by Pecker and colleagues regarding our recent study about Systemic Capillary Leak Syndrome (SCLS) (1). Based on previously published data, a careful review of our study, and at least two personal cases, they argue that beta-2 agonists and intravenous immunoglobulins (IVIG) do not provide equivalent prophylaxis, and that IVIG should be the initial choice to prevent attacks of SCLS.

In the past, many treatments have been claimed to be effective in SCLS. However, because SCLS is a rare disease with an unpredictable course, drawing clear conclusions is often difficult, and many of these treatments are not used anymore. To circumvent these caveats, we chose to draw our conclusions using only robust data such as survival (and not mortality). Based on the survival analysis, the major statistically valid conclusion we could draw was that prophylactic treatments, namely beta-2 agonists, IVIG, or both, improved survival in SCLS and reduced the frequency of attacks. We did not claim that beta-2 agonists and IVIG provide equivalent prophylaxis, but that the benefits of each preventive treatment could not be precisely ascertained in our study. Indeed, survival comparisons according to treatments were impeded because of the small sample size of this series including only new patients, but also because most patients received several lines of treatment. We thus believe that based on the limited data available, it is yet difficult to decide whether IVIG should be the initial choice to prevent attacks of SCLS. Whether IVIG could have a major prophylactic effect when used alone could only be formally assessed using a randomized controlled trial comparing prophylactic treatments, such as the one we are currently setting-up.

REFERENCES

(1) Gousseff M, Arnaud L, Lambert M, et al. The Systemic Capillary Leak Syndrome: A Case Series of 28 Patients From A European Registry. Ann Intern Med 2011; 154: 464-471.

Conflict of Interest:

None declared

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