PRACTICE | CASES CPD Systemic capillary leak syndrome after ChAdOx1 nCOV-19 (Oxford–AstraZeneca) vaccination Julie Robichaud MD PhD, Catherine Côté BPharm MSc, Fanny Côté MD n Cite as: CMAJ 2021 August 30;193:E1341-4. doi: 10.1503/cmaj.211212; early-released August 6, 2021 A 66-year-old man presented to the emergency depart- ment with a 1-day history of generalized malaise, nau- sea, abdominal pain and dizziness. On presentation the patient’s body temperature was 36.5° C, blood pressure 112/78 mm Hg, heart rate 112 beats/min and oxygen saturation 96% (room air), and his respiratory rate was normal. He reported no allergies, no drug or alcohol misuse, and no current use of any medications or over-the-counter products. Two  days earlier, he had received his first dose of the ChAdOx1 nCOV-19 (Oxford– AstraZeneca) vaccine. The patient’s medical history included monoclonal gammo- pathy of uncertain significance (immunoglobulin G [IgG] κ) and a cardiac arrest in 2017. At that time, he presented with general- ized weakness and a syncopal episode. Because his hemoglobin level was elevated (210 [normal 130–180] g/L), polycythemia was suspected and phlebotomy was performed. Soon after, the patient became hypotensive and went into pulseless electrical activity arrest. He was successfully resuscitated, recovered with- out substantial deficits and was discharged home 5 weeks later. His test result for influenza type  A was positive, and his shock was attributed to the viral infection. At this presentation, the patient’s hemoglobin level was increased markedly at 224  g/L. He had hypoalbuminemia (28  [normal 34–55]  g/L) and an elevated creatinine level (133  [normal 62–115] μmol/L). Coagulation parameters, cardiac and liver enzymes, C-reactive protein and procalcitonin were normal. Screening results for SARS-CoV-2 and extended respira- tory virus panel were negative. Examinations using chest radiog- raphy, abdominal computed tomography, electrocardiography and focussed assessment with sonography for trauma echocar- diography were unremarkable (Table 1 and Table 2). We started intravenous fluids and empiric treatment with piperacillin–tazobactam, despite the unlikelihood of an infec- tious process. Twelve hours later, the patient had received more than 6  L of fluid, but his blood pressure had deteriorated to 93/60  mm  Hg, his heart rate was 125  beats/min and his poly- cythemia persisted (hemoglobin 223  g/L). We admitted the patient to the intensive care unit (ICU). In the absence of other causes of impending shock, we diagnosed systemic capillary leak syndrome (SCLS). Key points • Rare cases of systemic capillary leak syndrome (SCLS) have been reported worldwide after vaccination with adenoviral vector and mRNA vaccines against SARS-CoV-2; a number have occurred in patients with a history of SCLS. • Systemic capillary leak syndrome is a potentially life- threatening immune disorder that is characterized by transient, recurrent episodes of vascular endothelial hyperpermeability that are often triggered by viral upper respiratory infections. • Hypotension, hemoconcentration, hypoalbuminemia and anasarca are prominent features of SCLS, reflecting the massive leakage of fluids and proteins into peripheral tissues. • Acute SCLS can rapidly evolve into shock and multiorgan failure, and treatment is mostly aimed at correcting hypovolemia and avoiding end-organ damage; prophylactic monthly administration of immunoglobulins can help prevent further episodes. • Adenoviral vector vaccines against SARS-CoV-2 are not advised for patients with a history of SCLS. During the first 24 hours of his admission, the patient received more than 10 L of intravenous fluid, but his hemoglobin and lactic acid levels remained elevated (Table 1), and his creatinine level con- tinued to rise. Central venous pressure was consistently 0–1 mm Hg. He did not need vasopressors and he required oxygen therapy only transiently. He developed substantial anasarca and gained 15 kg. Eventually, his hemodynamic status improved, laboratory abnor- malities resolved, and he was discharged 4 days later. We considered various causes of hypotension, polycythemia and hypoalbuminemia, and eliminated all of them (Table  2). Because his SCLS developed 2  days after vaccination against SARS-CoV-2 and we identified no other triggers, we suspected a possible adverse reaction to the ChAdOx1 nCOV-19 vaccine and reported the reaction to our local department of public health. Interpretation Systemic capillary leak syndrome is a rare disorder associated with recurrent episodes of extravasation of fluid and protein into the interstitial space.1,2 Fewer than 500  cases have been © 2021 CMA Joule Inc. or its licensors CMAJ | AUGUST 30, 2021 | VOLUME 193 | ISSUE 34 E1341 Table 1: Laboratory test results for the patient during his 4-day stay in hospital Laboratory test Hemoglobin, g/L (normal 130–180 g/L) Hematocrit, % (normal 39%–52%) White blood cell count, × 109/L (normal 4.4–11.0 × 109/L) Neutrophil count, × 109/L (normal 1.8–7.0 × 109/L) Lymphocyte count, × 109/L (normal 1.0–4.0 × 109/L) Platelets, × 109/L (normal 140–440 × 109/L) Albumin, g/L (normal 34–55 g/L) Creatinine, μmol/L (normal 62–115 μmol/L) Lactate level, mmol/L (normal 0.5–2.2 mmol/L) D-dimer level, μg/L (normal 0–500 μg/L) Prothrombin time, INR (normal 0.9–1.1) Partial prothrombin time, s (normal 20.1–26.4 s) Note: ND = not done, INR = international normalized ratio. At admission 224 65 14.5 10.5  2.4 222 28 133 ND 353 1.1 28.4 4 h 226 68.8 19.7 15.7  2.2 237 ND 133 ND ND ND ND Test result 24 h 184 54.8 21.5 16.7  3.2 202 25 122 3.3 ND ND ND 12 h 223 68 24.5 21.3  2.4 251 ND 159 3.8 ND ND ND 48 h 142 41.9 11.4 7.6  2.5 173 ND 90 1.1 ND ND ND 72 h 131 38.4 7.6 4.6  2.1 164 ND 71 ND ND ND ND 96 h 136 40 6.9 4.3  2 174 38 79 ND ND ND ND reported. Recognizing SCLS may be challenging, because presen- tation has often been preceded by a prodrome of flu-like symp- toms and may be mistaken for sepsis. There are no specific diag- nostic criteria for SCLS. Once other causes of shock have been excluded, the classical triad of hypotension, hemoconcentration and hypoalbuminemia supports the diagnosis of SCLS.2 Together with generalized edema, those 3  features are manifestations of the vascular hyperpermeability and extreme hypovolemia that occur with this syndrome. The exact pathophysiology of SCLS is mostly unknown. Typic- ally, exacerbations can be triggered by viral upper respiratory infections.1,3–5 An overwhelming immune response and upregula- tion of soluble inflammatory and angiogenic mediators during flares appear to be linked to vascular endothelial hyperperme- ability.2 Monoclonal gammopathy of uncertain significance (pre- dominantly IgG κ) is observed in 68%–85% of patients with SCLS, although a pathogenic role for the paraprotein has yet to be established.2 Reports exist of patients with SCLS who had a car- diac arrest triggered by influenza type  A, similar to the experi- ence of our patient in 2017.5,6 It is likely that his cardiac arrest at that time occurred during an unrecognized episode of SCLS; he had hypoalbuminemia (29 g/L), hemoconcentration and hypovo- lemia. However, SCLS was not suspected until this admission. Our patient’s near-fatal episodes illustrate that unrecognized SCLS can be life-threatening; SCLS is associated with an esti- mated 10-year mortality rate of 25%–34%.1,4 In addition to shock and renal and cardiopulmonary failure arising from intravascu- lar volume depletion, thromboembolic events and compartment syndrome can occur. Systemic capillary leak syndrome can be classified as grade 1 (hypotension responding to oral hydration), grade 2 (intravenous fluids without hospital admission), grade 3 (life threatening and requiring admission to an ICU) and grade 4 (fatal).1 No interventions other than fluid resuscitation have been shown to halt or delay progression of a flare of SCLS.2 Most epi- sodes are self-limited and resolve within 4 days.1 The frequency of recurrence of SCLS varies, ranging from once weekly to once every 10  years. Administration of prophylactic monthly intra- venous Igs can reduce the frequency of episodes.1,2 The World Health Organization (WHO) reports that 3.8 bil- lion  doses of vaccines against SARS-CoV-2 have been adminis- tered worldwide (as of July 29, 2021; WHO Coronavirus [COVID-19] Dashboard, available at https://covid19.who.int). Adverse effects are usually mild and local in nature; however, rare serious adverse reactions can occur, such as pericarditis or myocarditis, anaphylaxis, Guillain–Barré syndrome and thromboembolic events with concurrent low platelet levels (the latter occurring mostly with adenoviral vector vaccines).7 In April 2021, the European Medicines Agency (EMA) reported 6 cases of SCLS following receipt of the ChAdOx1 nCOV-19 vac- cine (including 1 fatality).8 Three of those patients had a previous history of SCLS. More than 78  million doses of the ChAdOx1 nCOV-19 vaccine have been administered in Europe, with a reported rate of 1  case of SCLS per 13  million doses.8 In June 2021, Health Canada issued the first report of SCLS in a patient who had received a ChAdOx1 nCOV-19 vaccine in Canada.9 The United Kingdom’s Medicines & Healthcare products Regulatory Agency (MHRA) reported 8 potential cases of SCLS that occurred shortly after administration of the ChAdOx1 nCOV-19 vaccine.7 Our patient had a score of at least 4 on the Naranjo Adverse Drug Reaction Probability Scale, 10 making this a possible case of exacer bation of SCLS induced by the ChAdOx1 nCOV-19 vaccine. Many health agencies have concluded that SCLS, albeit rare, should be considered a serious and potentially fatal adverse effect of the ChAdOx1 nCOV-19 vaccine, and are now advising against its use in patients with known SCLS.7–9 After the EMA’s E1342 CMAJ | AUGUST 30, 2021 | VOLUME 193 | ISSUE 34 E C I T C A R P Table 2: Causes of polycythemia, hypoalbuminemia and hypotension and the reasons for exclusion in our patient Presentation Differential diagnosis Reason for exclusion Inherited: Congenital heart defects • Normal transthoracic echocardiogram Polycythemia Primary polycythemia Secondary polycythemia Acquired: Polycythemia vera Leukemia Chronic hypoxia or cardiopulmonary abnormalities Erythropoietin-secreting tumours Dehydration Capillary leak syndrome Relative polycythemia Hypoalbuminemia Nephrotic syndrome Hypotension and shock Sepsis • Absence of Janus kinase 2 (JAK-2) mutation (Val671Phe) • Absence of BCR-ABL t(9;22) mutation • No clinical symptoms of obstructive sleep apnea and low risk according to the STOP-BANG score • No known chronic pulmonary disease • No obesity hypoventilation syndrome and no daytime hypercapnia • No elevation of erythropoietin level: 4.6 (normal range 5.0–16.0) IU/L • Normal hemoglobin and hematocrit levels between acute episodes • No history of high-altitude travel • Level of erythropoietin not high • Not excluded • No proteinuria, negative urine protein-to-creatinine ratio: undetectable (normal < 0.15 g • No evidence of hyperlipidemia that may be associated with nephrotic syndrome (normal protein/g creatinine) fasting lipid profile) nutrition or cirrhosis Poor nutrition or liver cirrhosis • Rapid correction of serum albumin levels is inconsistent with hypoalbuminemia from poor • No features of liver cirrhosis or ascites on abdominal CT • Normal procalcitonin level 0.28 (normal 0.00–0.39) μg/L and C-reactive protein level 4.9 (normal 0.0–10.0) mg/L • No evidence of infection on chest radiography and abdominal CT • Two negative results for blood cultures • Negative result for urine culture • Negative result for screening (RT–PCR) test for SARS-CoV-2 (COVID-19 direct diagnostic kit) • Negative result for serology screening test for SARS-CoV-2 IgG • Negative results for screening for common respiratory viruses and pathogens: syncytial respiratory virus; influenza type A (H1 and H3); influenza type B; parainfluenza viruses 1, 2, 3 and 4; human metapneumovirus; entero-rhinovirus, coronavirus NL 63, HKU1, OC43 and 229E; adenovirus; Bordetella pertussis and parapertussis; Chlamydophilia pneumoniae; or Mycoplasma pneumoniae • Negative results for serology screening test for HIV-1 and -2 (p24 combo) • Normal FAST ultrasonography in the emergency department • Normal electrocardiogram • Normal transthoracic echocardiography and negative result for exercise stress test (recent outpatient investigations) • Absence of pulmonary edema and raised central venous pressure • Normal cardiac enzymes (troponin < 3 [normal 0–18] ng/L) and D-dimer levels (353 [normal < 500] μg/L) • Negative V/Q • Absence of typical clinical signs or symptoms associated with anaphylaxis (e.g., respiratory compromise, rash, pruritus, angioedema or persistent gastrointestinal symptoms) • Normal tryptase level: 3.0 (normal < 11) μg/L Normal C4 esterase activity (0.20 [normal 0.13–0.40] g/L) and C1 esterase activity (0.97 [normal 0.69–1.42] g/L) Absence of the epidemiologic factors usually associated with these diagnoses Cardiogenic and obstructive shock Anaphylaxis Hereditary angioedema Cancer drug reactions Hemophagocytic lymphohistiocytosis Viral hemorrhagic fever Snakebite envenomation Other diseases excluded Note: CT = computed tomography, FAST = focussed assessment with sonography for trauma, IgG = immunoglobulin G, RT–PCR = reverse transcription–polymerase chain reaction. CMAJ | AUGUST 30, 2021 | VOLUME 193 | ISSUE 34 E1343 P R A C T I C E July 2021 report of 3 cases of severe SCLS, 2 with fatal outcomes, which were potentially linked to the Ad26.COV2.S vaccine (John- son & Johnson–Janssen; an adenoviral vector vaccine), similar advice against using the Ad26.COV2.S vaccine in patients with a history of SCLS was made.8 In June 2021, a case series described 3 patients who pre- sented with acute SCLS within 2 days of receiving a SARS-CoV-2 vaccine.11 They all had monoclonal gammopathy of uncertain significance and pre-existing SCLS. The 3 patients received differ- ent vaccines: Ad26.COV2.S, mRNA-1273 (Moderna) and BNT162b2 (Pfizer–BioNTech). To our knowledge, no other cases of SCLS have been reported that were associated with mRNA SARS-CoV-2 vaccines, and thus far no warnings or recommenda- tions related to SCLS have been released regarding the mRNA- 1273 or BNT162b2 vaccines. Whether exacerbations are triggered by adenoviral vectors themselves or by SARS-CoV-2 antigen (spike protein) remains to be determined. Administration of mRNA SARS-CoV-2 vaccines can still be used in patients with a history of SCLS, if the benefits are considered to outweigh the risks. After vaccination, physicians and patients must be extra vigilant, because exacerbations can develop quickly and patients may require urgent medical assessment. In our opinion, patients should be monitored closely during the 7–10 days after vaccination with home surveillance of blood pressure, heart rate, weight and urine output; hemoglobin and albumin levels should be measured at least once or twice. We also suggest that prophylaxis with intravenous immunoglobulins be started before vaccination, if not already given monthly. Conclusion We presented the case of a patient with an acute exacerbation of SCLS after ChAdOx1 nCOV-19 vaccination. Early recognition and treatment of acute SCLS is crucial. When a patient presents with generalized edema, malaise, hypotension, hemoconcentration or hypoalbuminemia shortly after administration of a SARS-CoV-2 vaccine, regardless of which vaccine was administered, SCLS should be considered. A history of SCLS is now considered a con- traindication to adenoviral vector vaccines against SARS-CoV-2. Health care professionals should report any suspected adverse reactions to SARS-CoV-2 vaccines to their public health agency. References 1. Druey KM, Greipp PR. Narrative review: the systemic capillary leak syndrome. Ann Intern Med 2010;153:90-8. 2. Druey KM, Parikh SM. Idiopathic systemic capillary leak syndrome (Clarkson disease). J Allergy Clin Immunol 2017;140:663-70. 3. Sousa A, Len O, Escola-Verge L, et al. Influenza A virus infection is associated with systemic capillary leak syndrome: case report and systematic review of the literature. Antivir Ther 2016;21:181-3. 4. 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: 464-71. 5. Ebdrup L, Druey KM, Druey K, et al. Severe capillary leak syndrome with cardiac arrest triggered by influenza virus infection. BMJ Case Rep 2018 Aug.  29; 2018:bcr2018226108. doi: 10.1136/bcr-2018-226108. 6. Lawrence JL, Hindi H. Capillary leak syndrome aggravated by influenza type A infection. Cureus 2018;10:e2554. 7. Coronavirus vaccine — weekly summary of Yellow Card reporting. London (UK): Medicines & Healthcare products Regulatory Agency (MHRA); 2021. Avail- able: https://assets.publishing.service.gov.uk/government/uploads/system/ uploads/ attachment_data/file/1005194/Coronavirus_vaccine_-_summary_ of_Yellow_Card_reporting_14.07.21_clean.pdf (accessed 2021 July 18). 8. Pharmacovigilance Risk Assessment Committee (PRAC). COVID-19 pandemic. Amsterdam (Netherlands): European Medicines Agency (EMA). Available: https://www.ema.europa.eu/ (accessed 2021 June 11). 9. Recalls and safety alerts: Health Canada issues label change on the AstraZeneca and COVISHIELD COVID-19 vaccines. Ottawa: Health Canada; 2021 June 29. Available: https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc -sc /2021 /75389a-eng.php (accessed 2021 July 28). 10. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45. 11. Matheny M, Maleque N, Channell N, et al. Severe exacerbations of systemic cap- illary leak syndrome after COVID-19 vaccination: a case series. Ann Intern Med 2021 Jun 15;L21-0250 [Epub ahead of print]. doi: 10.7326/L21-0250. Competing interests: None declared. This article has been peer reviewed. The authors have obtained patient consent. Affiliations: Departments of Critical Care Medicine and Internal Medicine (Robichaud), Pharmacy (C.  Côté) and Internal Medicine (F. Côté), CIUSSS Saguenay-Lac-Saint-Jean, Chicoutimi, Que. Contributors: All of the authors interpreted the data and partici- pated equally in writing the manuscript, gave final approval of the version to be published and agreed to be accountable for all aspects of the work. Content licence: This is an Open Access article distributed in accor- dance with the terms of the Creative Commons Attribution (CC BY-NC- ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is noncommercial (i.e., research or educational use), and no modifi- cations or adaptations are made. See: https://creativecommons.org/ licenses/by-nc-nd/4.0/ Correspondence to: Julie Robichaud, julie.robichaud.med@ssss.gouv.qc.ca The section Cases presents brief case reports that convey clear, practical lessons. Preference is given to common presentations of important rare conditions, and important unusual presentations of common problems. Articles start with a case presentation (500 words maximum), and a discussion of the underlying condition fol- lows (1000 words maximum). Visual elements (e.g., tables of the dif- ferential diagnosis, clinical features or diagnostic approach) are encouraged. Consent from patients for publication of their story is a necessity. See information for authors at www.cmaj.ca. E1344 CMAJ | AUGUST 30, 2021 | VOLUME 193 | ISSUE 34 E C I T C A R P