Case 1

Figure

Figure. Chest computed tomography from hospital day 3 for a 59-year-old woman (case-patient 1) with new-onset systemic capillary leak syndrome and coronavirus disease showing A)...

A 59-year-old woman with a history of hypertension but no known history of SCLS or prior episodes of peripheral edema was admitted to a hospital in January 2021 with a 6-day history of cough, shortness of breath, and lower extremity pain. She was hypotensive, with a blood pressure of 96/70 mm Hg, but her initial physical exam was otherwise unremarkable and included normal results for a pulmonary examination. Laboratory examination revealed hemoconcentration (hemoglobin 17.1 g/dL, hematocrit of 52%) and a lactic acid level of 3.7 mmol/L. Despite resuscitation with 5.5 L Ringer’s lactate and 2.5 L normal saline IV fluids over the first 3 days of admission, serum lactate levels remained elevated at 5.7 mmol/L on day 4 of hospitalization (Table 1). Lower extremity pain worsened, and anasarca without hypoxemia developed. SARS-CoV-2 PCR testing of a nasal swab specimen taken at the time of admission returned positive results; daily treatment with 6 mg dexamethasone and 40 mg enoxaparin was initiated. Remdesivir was not administered because of a developing acute kidney injury. The patient’s lung examination results remained unremarkable, but she became intermittently hypoxemic (SpO₂ of 88% on 2L nasal cannula), requiring ongoing nasal cannula support. A chest computed tomography revealed bilateral scattered ground glass opacities consistent with mild-to-moderate SARS-CoV-2 infection (Figure). A transthoracic echocardiogram performed on day 3 of hospitalization showed a normal left ventricular ejection fraction (70%–75%), no left ventricular dilation or geometric changes, and no wall motion abnormalities. Other laboratory abnormalities included increased creatinine phosphokinase levels, peaking at 15,094 units/L; elevated lactate at 6.3 mmol/L; and hypoalbuminemia at 2.4 g/dL, which raised concerns for SCLS.

The patient was transferred to the intensive care unit for further monitoring on day 4 of hospitalization. Pain increased in her extremities and tense anasarca developed; however, because compartment pressures were 18 mm Hg in her right arm and 15 mm Hg in her left arm, she did not meet criteria for a diagnosis of compartment syndrome. Apart from edema and tachypnea while on 2 L nasal cannula, her cardiopulmonary examination was otherwise normal. On hospitalization day 5, she suffered a cardiac arrest; spontaneous circulation returned after 2 rounds of cardiopulmonary resuscitation. She was intubated at the time of cardiac arrest and empirically started on vancomycin and cefepime. Because of concern for microvascular thrombi in the setting of SARS-CoV-2 infection, an argatroban infusion was started. Although the patient had remained afebrile and hemodynamically stable up to this point, shock rapidly developed, and she required vasopressor support with norepinephrine, vasopressin, epinephrine, and stress-doses of hydrocortisone. Continuous renal replacement therapy was initiated for oliguric renal failure.

The next day, edema in the extremities intensified, and creatinine phosphokinase levels increased further to >45,000 units/L, but compartment pressures were 17 mm Hg in her right arm and 16 mm Hg in her left arm, suggestive of rhabdomyolysis without compartment syndrome. No MGUS was detected. Serum SARS-CoV-2 IgG was not detected, prompting treatment with convalescent plasma. Given the patient’s grave condition and lack of proven interventions for acute SCLS, empiric treatments were also administered, including IVIg; methylene blue, an agent that suppresses downstream effects of nitric oxide (7); and icatibant, a bradykinin receptor antagonist used to treat vascular leakage associated with hantavirus infection (8). Bradycardia developed and ultimately required transvenous pacing. Within hours, her hemoglobin decreased to 6.8 g/dL although there was no obvious source of hemorrhage. Because she was anticoagulated with argatroban and had a prolonged activated partial thromboplastin time in the setting of acute liver failure, the patient was transfused with packed erythrocytes. She suffered cardiac arrest, and ventricular fibrillation deteriorated into pulseless electrical activity. Transthoracic echocardiography performed during ACLS revealed no pericardial effusion. The patient received additional units of erythrocytes, IV fluids, fresh frozen plasma, and prothrombin complex concentrate during the cardiac arrest. However, spontaneous circulation was not restored, and the patient died on day 6 of her hospitalization.

Case 2

A 36-year-old man with no notable medical history first sought treatment in 2015 for transient hypotension and severe bilateral lower-extremity edema; laboratory testing showed hemoconcentration (hemoglobin 20.2 g/dL, hemocrit 59.4%) and a serum hypoalbuminemia level of 2.2 g/dL after several days of fevers and upper respiratory symptoms. SCLS was diagnosed on the basis of characteristic clinical presentation and an IgG lambda MGUS. His course was complicated by acute kidney injury and compartment syndromes in both legs, which required bilateral fasciotomies. He also had deep vein thromboses in the right internal jugular and left cephalic veins. He was treated transiently with anticoagulants, but a full evaluation for hypercoagulability was negative. Muscle biopsies taken at the time of fasciotomies provided no evidence of inflammatory myositis. All symptoms resolved before he was discharged from the hospital, although a bilateral sensorimotor neuropathy developed, presumably as a residual effect of compartment syndrome.

The patient was treated with IVIg (2 g/kg) within 24 hours of the 2015 hospitalization and monthly thereafter with no recurrence of his SCLS-related symptoms. In November 2016, IVIg prophylaxis was discontinued at the patient’s request. In 2017 and 2018, the patient experienced 2 episodes of bilateral lower extremity swelling, in both cases after several days of upper respiratory symptoms. Blood pressure and laboratory tests were normal at the time of these episodes, and swelling resolved without further treatment.

In February 2020, the patient sought treatment for a several-day history of fevers (40°C) and productive cough. He was noted to be hypoxemic (SpO₂ of 87% on room air). Mycoplasma pneumonia was diagnosed on the basis of chest radiographic evidence of lung infiltrates and positive Mycoplasma serologic testing. He was hospitalized and treated with IV antimicrobial drugs and fluids (10.5 L total). Although the fevers and respiratory symptoms resolved, bilateral leg swelling and serum hypoalbuminemia developed, prompting treatment with 1 dose of IVIg (2 g/kg) for empirically presumed SCLS-related edema in the absence of any other proven treatment options. He ultimately recovered and experienced no residual symptoms.

In January 2021, the patient was transported to the emergency department because of disorientation after several days of upper respiratory symptoms, fever (40.6°C), and back pain. Upon arrival, he was hypotensive, with a blood pressure of 94/20 mm Hg, and tachycardic at 140 beats/min. Upon initial examination, he showed no signs of apparent dyspnea (respiratory rate of 19 breaths/min) or respiratory distress (SpO₂ of 99% on room air). A PCR nasal swab test for SARS-CoV-2 performed on the day before he sought treatment was reported by the family to be positive. Laboratory tests taken at the time of hospital admission revealed severe hemoconcentration (hemoglobin >25 g/dL, 75% hemocrit), leukocytosis (leukocyte count 43.3K/μL blood), and lactic acidosis (lactate level 9.2 mmol/L). Other laboratory values included brain natriuretic peptide at 12 pg/mL, troponin at <0.02 ng/mL, and a fingerstick glucose level of 197 mg/dL. There was no ST elevation suggesting myocardial infarction or dysrhythmia on his electrocardiogram.

In the emergency department, his condition deteriorated rapidly. His blood pressure became unobtainable manually, and he exhibited an Sp0₂ of 73% on a 15-L nonrebreather mask. A bedside echocardiogram revealed a flat inferior vena cava, intact bilateral ventricular function, and pericardial effusion with no evidence of right heart strain or tamponade. He was intubated emergently but ultimately experienced cardiac arrest with pulseless electrical activity. Despite aggressive cardiopulmonary resuscitation and pharmacological interventions including boluses of epinephrine, bicarbonate, calcium, and magnesium, refractory ventricular tachycardia developed, followed by Torsade de Pointes, and he died shortly thereafter.