About the Author Dr. Santiago is a lead research microbiologist at the Centers for Disease Control and Prevention in San Juan, Puerto Rico. His research is focused on the development of molecular diagnostic tests and genomic epidemiology of dengue virus and severe acute respiratory syndrome coronavirus 2. References 1. Sharp TM, Quandelacy TM, Adams LE, Aponte JT, Lozier MJ, Ryff K, et al. Epidemiologic and spatiotemporal trends of Zika virus disease during the 2016 epidemic in Puerto Rico. PLoS Negl Trop Dis. 2020;14:e0008532. https://doi.org/10.1371/journal.pntd.0008532 2. Quick J, Grubaugh ND, Pullan ST, Claro IM, Smith AD, Gangavarapu K, et al. Multiplex PCR method for MinION and Illumina sequencing of Zika and other virus genomes directly from clinical samples. Nat Protoc. 2017;12:1261–76. https://doi.org/10.1038/nprot.2017.066 3. Grubaugh ND, Gangavarapu K, Quick J, Matteson NL, De Jesus JG, Main BJ, et al. An amplicon-based sequencing framework for accurately measuring intrahost virus diversity using PrimalSeq and iVar. Genome Biol. 2019;20:8. https://doi.org/10.1186/s13059-018-1618-7 4. Santiago GA, Vázquez J, Courtney S, Matías KY, Andersen LE, Colón C, et al. Performance of the Trioplex real-time RT-PCR assay for detection of Zika, dengue, and chikungunya viruses. Nat Commun. 2018;9:1391. https://doi.org/10.1038/s41467-018-03772-1 5. Metsky HC, Matranga CB, Wohl S, Schaffner SF, Freije CA, Winnicki SM, et al. Zika virus evolution and spread in the Americas. Nature. 2017;546:411–5. https://doi.org/10.1038/ nature22402 6. Faria NR, Quick J, Claro IM, Thézé J, de Jesus JG, Giovanetti M, et al. Establishment and cryptic transmission of Zika virus in Brazil and the Americas. Nature. 2017;546:406–10. https://doi.org/10.1038/nature22401 7. Black A, Moncla LH, Laiton-Donato K, Potter B, Pardo L, Rico A, et al. Genomic epidemiology supports multiple introductions and cryptic transmission of Zika virus in Colombia. BMC Infect Dis. 2019;19:963. https://doi.org/ 10.1186/s12879-019-4566-2 8. Grubaugh ND, Saraf S, Gangavarapu K, Watts A, Tan AL, Oidtman RJ, et al.; GeoSentinel Surveillance Network. Travel surveillance and genomics uncover a hidden Zika outbreak during the waning epidemic. Cell. 2019;178:1057–1071.e11. https://doi.org/10.1016/j.cell.2019.07.018 9. Peters R, Stevenson M. Zika virus diagnosis: challenges and solutions. Clin Microbiol Infect. 2019;25:142–6. https://doi.org/10.1016/j.cmi.2018.12.002 Address for correspondence: Jorge L. Muñoz-Jordan, Centers for Disease Control and Prevention, 1324 Cañada St, San Juan, PR 00920, USA; email jmunoz@cdc.gov. RESEARCH LETTERS Fatal Systemic Capillary Leak Syndrome after SARS-CoV-2 Vaccination in Patient with Multiple Myeloma Gwang-Jun Choi, Seon Ha Baek, Junmo Kim, Jung Ho Kim, Geun-Yong Kwon, Dong Keun Kim, Yeon Haw Jung, Sejoong Kim Author affiliations: Daegu Metropolitan Government, Daegu, South Korea (G.-J. Choi); Hallym University Dongtan Sacred Heart Hospital, Hwaseong, South Korea (S.H. Baek); National Forensic Service Daegu Institute, Daegu (J. Kim); Yeungnam University College of Medicine, Daegu (J.H. Kim); Korea Disease Control and Prevention Agency, Cheongju, South Korea (G.-Y. Kwon, D.K. Kim, Y.H. Jung); Seoul National University Bun- dang Hospital, Seongnam, South Korea (S. Kim) DOI: https://doi.org/10.3201/eid2711.211723 A young man with smoldering multiple myeloma died of hypotensive shock 2.5 days after severe acute respirato- ry syndrome coronavirus 2 vaccination. Clinical findings suggested systemic capillary leak syndrome (SCLS); the patient had experienced a previous suspected flare epi- sode. History of SCLS may indicate higher risk for SCLS after receiving this vaccine. Systemic capillary leak syndrome (SCLS) is an ex- tremely rare disease of unknown incidence (1). Typical manifestations of SCLS include hypotension, edema, hemoconcentration, and hypoalbuminemia after nonspecific prodromal illnesses (1,2). Increased capillary vascular permeability is the commonly ac- cepted pathophysiology (1,2). However, the exact pathogenesis remains unclear. As part of the efforts to combat the ongoing pan- demic of coronavirus disease (COVID-19), caused by se- vere acute respiratory syndrome coronavirus 2, the US Food and Drug Administration on February 27, 2021, gave emergency use authorization to the Ad26.COV2.S vaccine (Johnson & Johnson/Janssen, https://www.jnj. com). An SCLS case series reported 1 case of SCLS in a patient who received the Ad26.COV2.S vaccine (3). The European Medicines Agency reviewed 3 cases of SCLS in Ad26.COV2.S vaccine recipients and issued a report, published July 9, 2021, advising against administering the vaccine in persons with previous SCLS experiences (4). We describe a case of SCLS after Ad26.COV2.S vac- cination in a patient with smoldering multiple myeloma. A 38-year-old man reporting vomiting and dizzi- ness sought treatment at an emergency department. Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 27, No. 11, November 2021 2973 RESEARCH LETTERS Smoldering multiple myeloma had been diagnosed 1.5 years before, but no laboratory abnormalities had been found in his most recent hospital visit 5 months earlier. He had received the Ad26.COV2.S vaccine 2 days before the emergency department visit and expe- rienced fever, chills, and myalgia 12–24 hours postvac- cination, then nausea, recurrent vomiting, and general weakness 24–48 hours postvaccination. At admission, he was afebrile, his heart rate was 130 beats/min, and his blood pressure was 100/90 mm Hg, with no notice- able edema. We administered isotonic saline and initi- ated diagnostic evaluations: laboratory tests, imaging, and COVID-19 reverse transcription PCR. Test results (Table) showed marked hemoconcentration and hypo- albuminemia. Chest and abdominal computed tomog- raphy results were unremarkable. Six hours after ad- mission, the patient was hypotensive (blood pressure 60/40 mm Hg), had a heart rate of 132 beats/min, and reported dyspnea. We obtained blood cultures and treated the patient with broad-spectrum antimicrobi- als, intravenous fluids, and inotropes. Despite these measures, the patient’s hypotensive shock worsened, and he died 10 hours after admission. Although at admission the patient showed neither peripheral edema nor severe hypoalbuminemia, we suspected SCLS for several reasons. First, we could not entirely rule out infection, but results of blood cultures and COVID-19 testing were negative. Second, autopsy results showed no evidence of acute infection or car- diovascular disease in the internal organs. We identi- fied pulmonary edema, pleural effusion, and pericardi- al effusion. Although pulmonary edema is atypical in acute SCLS attacks (leak phase), prolonged cardiopul- monary resuscitation and fluid administration might have affected the autopsy findings. Histopathologic findings in both kidneys suggested autolysis or acute tubular necrosis, which helped exclude other possi- ble etiologies of refractory hypotensive shock. Third, through medical chart review, we found that the pa- tient in our study had been admitted 1.5 years earlier for fever, vomiting, myalgia, generalized edema, and hypotension (blood pressure 90/60 mm Hg). Labora- tory results showed hemoconcentration (hematocrit 58.4%) and hypoalbuminemia (3.03 g/dL at nadir), but diagnosis was unclear, and the patient recovered spon- taneously after fluid administration. We retrospec- tively assumed a flare episode of SCLS. Fourth, ≈80% of patients with SCLS have monoclonal gammopathy of undetermined significance (MGUS) (2,5), and there have also been other reports of SCLS in patients with multiple myeloma (2). The patient who had the previ- ous reported case of SCLS after Ad26.COV2.S vaccina- tion had MGUS (3), and the patient in our study had multiple myeloma. Recently, an additional report de- scribed a patient with MGUS who experienced severe SCLS 2 days after receiving the ChAdOx1 nCOV-19 vaccine (Oxford/AstraZeneca, https://www.astra- zeneca.com); that patient also had an unrecognized previous episode of presumed SCLS (6). We believe a life-threatening flare developed after COVID-19 vaccination in the patient in our study who had a history suggestive of SCLS. Clinical findings were compatible with a previous report in which life-threat- ening disease occurred 1–2 days after vaccination (3,6); we could identify no SCLS triggers other than receiv- ing the COVID-19 vaccine. Data from a review article Table. Results of laboratory tests in patient with smoldering multiple myeloma who had SCLS develop after vaccination for severe acute respiratory syndrome coronavirus, South Korea* Test results after SCLS episodes Clinical measures Leukocytes, 103/mm3 Hemoglobin, g/dL Hematocrit, % Platelet, 103/mm3 Albumin, g/dL Blood urea nitrogen, mg/dL Creatinine, mg/dL Aspartate transaminase, IU/L Alanine transferase, IU/L Total bilirubin, mg/dL Calcium, mg/dL Erythrocyte sedimentation rate, mm/h C-reactive protein, mg/dL Procalcitonin, ng/ml Troponin I, ng/mL Creatine kinase myocardial band, ng/mL N terminal-pro B-type natriuretic peptide, pg/mL Lactic acid, mmol/L Creatine phosphokinase, IU/L *Vaccine was Ad26.COV2.S (Johnson & Johnson/Janssen, https://www.jnj.com). SCLS, systemic capillary leak syndrome. 2974 Reference range 4–10 13–17 40–52 140–440 3.5–5.0 8–23 0.7–1.2 10–35 0–40 0.1–1.2 8.6–10.6 0–20 0–0.5 0–5 0–0.04 0.6–6.3 0–125 0.5–1.6 1–171 5 mo earlier 6.88 14.7 44.3 259 4.8 13.6 0.94 22 14 0.5 10.0 Not done Not done Not done Not done Not done 35.1 Not done Not done Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 27, No. 11, November 2021 Postvaccination 29.42 22.7 63.7 133 3.3 33 2.0 30 4 1.46 8.9 13 2.371 0.641 0.017 3.5 4,427 5.4 276 indicated that 44% of 134 patients had identifiable SCLS triggers; 88% of those were infections, usually respira- tory, and 11% involved intense physical exertion or ex- tended travel (7). There was also a case report of pos- sible SCLS related to the influenza vaccine; although not clearly meeting all the criteria for SCLS, a peritoneal dialysis patient experienced recurrent episodes of hypo- tension, peripheral edema, and hypoalbuminemia after 2 consecutive seasons of influenza vaccination (8). Im- munologic response to vaccination has been proposed as a possible mechanism (8), but further studies are needed to verify factors predisposing patients to SCLS after COVID-19 immunization. In South Korea, 1,129,796 people had received the Ad26.COV2.S vaccine as of August 2, 2021 (9); we have found no other reports of possible SCLS in vaccine recipients in South Korea. Our report describes the clinical course and characteristics of SCLS after COVID-19 vaccination. SCLS is often dif- ficult to diagnose and may be misdiagnosed as other diseases, such as culture-negative sepsis. Therefore, clinicians should be aware of possible SCLS, espe- cially in at-risk populations, and medical histories should be examined before vaccine is administered. Acknowledgments The authors express our deepest condolences to the be- reaved family of the patient. RESEARCH LETTERS References 1. Siddall E, Khatri M, Radhakrishnan J. Capillary leak syndrome: etiologies, pathophysiology, and management. Kidney Int. 2017;92:37–46. https://doi.org/10.1016/ j.kint.2016.11.029 2. Druey KM, Greipp PR. Narrative review: the systemic capillary leak syndrome. Ann Intern Med. 2010;153:90–8. https://doi.org/10.7326/0003-4819-153-2-201007200-00005 3. 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 June 15 [Epub ahead of print]. https://doi.org/10.7326/L21-0250 4. European Medicines Agency. EMA advises against use of COVID-19 vaccine Janssen in people with history of capillary leak syndrome [cited 2021 July 9]. https://www.ema.europa. eu/en/news/ema-advises-against-use-covid-19-vaccine- janssen-people-history-capillary-leak-syndrome 5. Baek SH, Shin N, Kim HJ, Han MY, Choi DJ, Bang SM, et al. A case of chronic renal failure associated with systemic capillary leak syndrome. Yeungnam Univ J Med. 2012;29:145–9. https://doi.org/10.12701/yujm.2012.29.2.145 Julie Robichaud, Catherine Côté, Fanny Côté. Systemic capillary leak syndrome after ChAdOx1 nCOV-19 (Oxford–AstraZeneca) vaccination. CMAJ. 2021 Aug 6 [Epub ahead of print]. https://doi.org/10.1503/cmaj.211212 6. 7. Druey KM, Parikh SM. Idiopathic systemic capillary leak syndrome (Clarkson disease). J Allergy Clin Immunol. 2017;140:663–70. https://doi.org/10.1016/j.jaci.2016.10.042 8. Geerse DA, Meynen FM, Gelens MA, Kooman JP, Cornelis T. Systemic capillary leak syndrome after influenza vaccination in a peritoneal dialysis patient. Perit Dial Int. 2015;35:772–3. https://doi.org/10.3747/pdi.2014.00194 9. Korea Disease Control and Prevention Agency. Cumulative COVID-19 vaccine doses administered in Republic of Korea [cited 2021 August 2]. https://www.kdca.go.kr/board/ board.es?mid=a20501010000&bid=0015&list_no=714208&cg_ code=&act=view&nPage=7 About the Author Dr. Choi is an epidemic intelligence officer in the Daegu Metropolitan Government in Daegu, South Korea. His current research interest is adverse events following immunization. Address for correspondence: Sejoong Kim, Department of Internal Medicine, Seoul National University Bundang Hospital, 82, Gumi- ro 173beon-gil, Bundang-gu, Seongnam, Gyeonggi-do, South Korea; email: sejoong@snubh.org Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 27, No. 11, November 2021 2975