LettersOctober 2021

Severe Exacerbations of Systemic Capillary Leak Syndrome After COVID-19 Vaccination: A Case Series

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    Background: Flares of systemic capillary leak syndrome (SCLS) release plasma into peripheral tissues, which typically leads to hypotensive shock and multiple organ dysfunction (1). Anasarca and compartment syndromes may develop as a result of excessive intravenous (IV) fluid administration (2). Between episodes, patients are typically asymptomatic. The diagnosis of SCLS is based on characteristic clinical findings that include hypotension, hemoconcentration, and hypoalbuminemia. Prophylaxis with IV immunoglobulin (IVIG) is disease sparing and improves survival (3).

    We describe 3 patients who had severe flares of SCLS immediately after receiving standard doses of the COVID-19 vaccines that have emergency use authorization from the U.S. Food and Drug Administration. These events were classified as non–dose-related, unexpected, and serious adverse events according to the World Health Organization.

    Objective: To alert clinicians to the possibility of SCLS-like events immediately after COVID-19 vaccination.

    Case Reports: Patient demographic characteristics and hospital experiences are detailed in Table 1, and the results of selected laboratory tests are summarized in Table 2.

    Table 1 Patient Demographic Characteristics and Hospital Experiences

    Table 1

    Table 2 Laboratory Abnormalities

    Table 2

    Patient 1 was diagnosed with SCLS with monoclonal gammopathy of unknown significance in 2006 after 2 characteristic episodes. She declined IVIG treatment but had no disease relapses during 15 years of treatment with oral theophylline and terbutaline. In March 2021, she presented to the emergency department of Exeter Hospital 2 days after receiving a single dose of the Ad26.COV2.S vaccine (Janssen). She had hypotension and tachycardia and developed protracted shock and anasarca. Results of blood cultures and nasal swab polymerase chain reaction tests for SARS-CoV-2 were negative. After she developed additional SCLS-related complications and continued to deteriorate, care was discontinued on hospital day 7.

    Patient 2 had a normal vaginal delivery in 2002 followed by hypotension and edema, which was attributed to amniotic fluid embolism. In 2018, she had another episode of hypotension (systolic blood pressure was approximately 50 mm Hg) and anasarca after several days of upper respiratory symptoms. This episode was attributed to sepsis, although blood culture results were negative. In February 2021, she presented to the emergency department of Virginia Hospital Center 2 days after receiving the second dose of the mRNA-1273 vaccine (Moderna). She had hypotension and tachycardia and later developed shock and anasarca. Results from a nasal swab polymerase chain reaction test for SARS-CoV-2 and a screen for other common respiratory pathogens (Table 1) were negative. All symptoms resolved with supportive treatment. Treatment with IVIG was started; monoclonal gammopathy of unknown significance (IgG κ) was detected during an asymptomatic period.

    Patient 3 had syncope and seizures in December 2020 and again in February 2021. His neurologic work-up, which included an electroencephalogram and magnetic resonance imaging of the brain, was normal. In April 2021, he presented to the local emergency department 1 day after receiving the second dose of the BNT162b2 vaccine (Pfizer-BioNTech). He had tachycardia and developed status epilepticus and was transferred to Maine Medical Center. During transport, he developed a cardiac arrest with pulseless electrical activity, which responded to cardiopulmonary resuscitation and epinephrine. Blood and urine cultures were negative, as were results from multiple nasal swab polymerase chain reaction tests for SARS-CoV-2. Monoclonal gammopathy of unknown significance was not detected by serum or urine immunofixation during the hospitalization.

    Discussion: We describe 3 patients with SCLS or a history suggestive of SCLS who developed life-threatening flares 1 to 2 days after COVID-19 vaccination. We believe these patients identify SCLS as a risk factor for the development of serious adverse reactions after COVID-19 vaccination. However, we recognize that these observations do not rule out other causes of these flares. For example, infection-related symptoms precede 44% to 64% of all acute flares (1, 4), and flares have been reported with SARS-CoV-2 infection (5). However, we were unable to identify any of these other triggers.

    Systemic capillary leak syndrome is a rare disease, and persons without a diagnosis of SCLS or a history suggestive of SCLS are unlikely to develop a flare after COVID-19 vaccination. However, some persons with unexplained episodes of hypotension and edema may have undiagnosed SCLS. In addition, we note that none of the 3 patients we describe were receiving IVIG prophylaxis when they were vaccinated and that we have received no reports of SCLS flares after COVID-19 (or other antiviral) vaccinations among our 78 patients with SCLS, most of whom are receiving IVIG prophylaxis. Therefore, we recommend that patients with a diagnosis or a suspected diagnosis of SCLS should receive IVIG prophylaxis before vaccination.



    Jos WM van der Meer16 June 2021
    Severe capillary leak and paraprotein

    These patients seem to suffer from Clarkson syndrome, in which usually a paraproteinemia is present (like in 2 of these patients). The role of the paraprotein in the bouts of severe capillary leakage is enigmatic. I would suggest to check whether the paraprotein of these patients binds the vaccine used. 


    Maddalena Alessandra Wu 1, Manuela Nebuloni 2, Riccardo Colombo 325 June 2021
    COVID-19 vaccination in Systemic Capillary Leak Syndrome: an unresolved dilemma

    TO THE EDITOR: We read with interest the case series of severe Systemic Capillary Leak Syndrome (SCLS) flares after COVID-19 vaccination by Matheny and colleagues (1). They warn about the risk of severe, potentially fatal, attacks after both adenoviral vector-based and mRNA-based vaccine administration in patients with a history of SCLS. Thus, they suggest treating them with intravenous immunoglobulin (IVIg) before vaccination, deriving their recommendation from the currently used prophylactic regimen in such patients (2). The reported cases are of exceptional value because the disease is extremely rare, and two out of three patients received mRNA vaccines. SCLS is usually preceded by mild upper airway infections, likely of viral origin. Therefore, when the European Medicines Agency’s Pharmacovigilance Risk Assessment Committee advised against use of Vaxzevria in SCLS patients (3), we hypothesized that vaccination with adenovirus-based vaccines could be harmful. We are currently strictly following 9 SCLS patients, and 7 received mRNA-based vaccines. Two patients were not receiving IVIg prophylaxis at the time of vaccination, and they did not develop symptoms of SCLS flare. The efficacy of IVIg preparations is probably due, at least partially, to the content of virus-specific immunoglobulins against seasonal viral infections, which trigger SCLS attacks (4). The prevalence of SARS-CoV-2-specific immunoglobulins in available preparations remains unknown, but it will likely increase according to the prevalence of immunization in donors. On the other hand, the immunization of SCLS patients is mandatory because they show high mortality during crises triggered by SARS-CoV-2 infection. Pineton De Chambrun described a severe SCLS flare in a patient receiving IVIg prophylaxis, triggered by SARS-CoV-2 infection without COVID-19 symptoms that lead to the patient’s death (4). Similarly, we treated a patient who developed a severe SCLS attack after SARS-CoV-2 infection without respiratory symptoms, which rapidly led to multiple organ failure and death because of massive bowel infarct. Thus, in SCLS patients, SARS-CoV-2 infection seems to have very high mortality. We wonder whether prophylactic administration of IVIg, which may have a high titer of SARS-CoV-2-specific immunoglobulins from recently immunized donors, might partially influence the immunogenicity of vaccines and, ultimately, leave patients at risk of severe SARS-CoV-2 infection. Conversely, intensified IVIg treatment has also been suggested (4). Therefore, the risks and benefits of IVIg prophylaxis before SARS-CoV-2 vaccination, the most appropriate dose regimen, and the timing of administration still need to be elucidated.


    1. Matheny M, Maleque N, Channell N, Eisch AR, Auld SC, Banerji A, et al. Severe Exacerbations of Systemic Capillary Leak Syndrome After COVID-19 Vaccination: A Case Series. Ann Intern Med. 2021.
    2. Pineton de Chambrun M, Gousseff M, Mauhin W, Lega JC, Lambert M, Riviere S, et al. Intravenous Immunoglobulins Improve Survival in Monoclonal Gammopathy-Associated Systemic Capillary-Leak Syndrome. The American journal of medicine. 2017;130(10):1219.e19-.e27.
    3. https://www.ema.europa.eu/en/news/vaxzevria-ema-advises-against-use-people-history-capillary-leak-syndrome.
    4. Pineton de Chambrun M, Cohen-Aubart F, Donker DW, Cariou PL, Luyt CE, Combes A, et al. SARS-CoV-2 Induces Acute and Refractory Relapse of Systemic Capillary Leak Syndrome (Clarkson's Disease). The American journal of medicine. 2020;133(11):e663-e4.