Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the underlying cause of the coronavirus disease 2019 (COVID-19) pandemic (1,2). The early mortality for COVID-19 patients admitted to the ICU and requiring mechanical ventilation approaches 88% (3–5). Both SARS-CoV-2 and the resulting overactive dysregulated inflammatory response contribute to severe COVID-19 (6,7). In a larger cohort of 50 critically ill Germany, half of those that were tested had viral RNA in the serum (8). High SARS-CoV-2 viral loads in nasopharyngeal samples and SARS-CoV-2 viremia have been associated with more severe COVID-19 in small case series (9–12). Clearance of SARS-CoV-2 virus and inflammatory mediators from the blood could therefore provide a better environment for the innate immune system to clear SARS-CoV-2 and establish lasting immunity. The Seraph-100 Microbind Affinity Blood Filter (Seraph-100; Exthera Medical Corporation, Martinez, CA) is a broad-spectrum extracorporeal sorbent hemoperfusion device that can bind bacteria, viruses, fungi, and cytokines present in blood, including SARS-CoV-2 (Table 1). The Seraph-100 was previously granted a Conformite Europeene Mark for sale in the European Economic Area under a broad indication for use and recently an emergency use authorization (EUA) by the Food and Drug Administration (FDA) for treatment of severe COVID-19. The FDA review for the EUA included two patients with severe COVID-19 requiring mechanical ventilation and vasopressor support who were treated at Walter Reed National Military Medical Center under the Emergency Use provision of the FDA.
A 67-year-old male with noninsulin-dependent diabetes, hypertension, hyperlipidemia, and hypothyroidism presented with nasopharyngeal swab confirmed COVID-19 requiring mechanical ventilation and vasopressor support. Initial blood and urine cultures were negative. Despite treatment with ceftriaxone, azithromycin, hydroxychloroquine, and tocilizumab, he developed worsening circulatory shock requiring increasing vasopressor support. His oxygenation deteriorated despite maximal ventilatory support with increasing oxygen (Fio2), neuromuscular blockade and prone positioning.
On hospital day (HD) 3, the patient received a Seraph-100 treatment for approximately 24 hours at an average blood flow rate of 293 mL/min for a total filtered blood volume of 426 L. The norepinephrine dose precipitously declined from a peak of 0.3 µg/kg/min and was discontinued by treatment completion (Fig. 1). Vasopressin was also discontinued over the next 6 hours. There was no fluid resuscitation or new antimicrobials during or immediately preceding Seraph-100 use.
After 48 hours, he again became hypotensive requiring norepinephrine to maintain a mean arterial pressure (MAP) of greater than 60 mm Hg. A second Seraph-100 treatment was initiated. Treatment was interrupted after 3.5 hours due clotting of the femoral catheter. After placement of an internal jugular line and transition from prone to supine position, treatment resumed for 12 hours at an average blood flow rate of 210 mL/min for a total filtered blood volume of 182 L. At the completion of this interrupted treatment his norepinephrine was weaned off (Fig. 1). SARS-CoV-2 was detected in stored blood samples from before and after the first treatment, but not before and after the second treatment. C-reactive protein (CRP), interleukin-6 (IL-6), Pro-B-type natriuretic peptide and ferritin all declined after Seraph-100 treatment (Table 2).
The day after his second treatment, oxygenation remained difficult. Given the lack of other manifestations of end organ failure, the decision was made to transfer to an outside center for consideration of extracorporeal membrane oxygenation.
A 59-year-old male with a history of hypertension and obesity presented with nasopharyngeal swab confirmed COVID-19 requiring mechanical ventilation and vasopressor support. Despite treatment with ceftriaxone, azithromycin, hydroxychloroquine, vancomycin, piperacillin-tazobactam, and acalabrutinib, the patient’s clinical status declined.
On hospital day 7, the patient received a Seraph-100 treatment for approximately 8 hours with average flow rates of 213 mL/min for a total filtered blood volume of 106 L. The norepinephrine dose, ventilatory requirements, and temperature decreased after the first treatment, without volume resuscitation or the addition of new antimicrobials.
On hospital day 8, the patient’s temperature rose to 102° despite treatment with acetaminophen and his norepinephrine dose increased to maintain hemodynamic stability. Micafungin was added to his antimicrobial regimen, but repeat blood, urine, and respiratory cultures later returned negative. The patient received a second 8-hour Seraph-100 treatment at average blood flows of 243 mL/min for a total filtered blood volume of approximately 125 L. Approximately 12 hours after treatment, MAP rose above 90 mm Hg, norepinephrine was weaned off and his temperature was normal. Serum CRP, IL-6 levels, and d-dimer levels declined after his treatments, but stored samples were not available for SARS-CoV-2 testing (Table 2).
Over hospital days 9–20, he remained hemodynamically stable and afebrile without further Seraph-100 treatment. His ventilatory requirements persistently decreased. He was extubated on HD 21, transferred out of the ICU on HD 22, and discharged on HD 30.
We present the first cases of severe COVID-19 treated with the novel Seraph-100 device in the United States. While it is not possible to make definitive conclusions based on case reports, there were no significant adverse events and both patients experienced quantitative clinical improvement after each of the four total Seraph-100 treatments administered. Improvements in hemodynamics, temperature, and inflammatory biomarkers were the most significant observed benefits. It is possible that these clinical improvements would have occurred independent of Seraph-100 treatments, but seems unlikely because there was a consistent and rapid clinical improvement after Seraph-100 treatment despite ongoing clinical decline prior to treatment initiation. It is possible that the Seraph-100 contributed to clinical and biomarker improvement through sequestration of SARS-CoV-2, cytokines from a pathologic “cytokine storm,” or a combination of both given the absence of another etiology for septic shock in our patients. SARS-CoV-2 viremia was present in the one patient we were able to test, but we cannot yet reliably quantify viral load to determine the amount of SARS-CoV-2 clearance after Seraph-100 treatment. The IL-6 levels declined with Seraph-100 treatments in both patients. There is ongoing debate about the contribution of SARS-CoV-2 viremia in COVID-19 cases. Viremia was present in approximately 30% of Middle East respiratory syndrome and severe acute respiratory syndrome cases and associated with more severe disease (13–15). There is minimal data currently about quantitative serologic SARS-CoV-2 viral loads, but small COVID-19 case series report a wide variance of viremia between 10% and 50% (8–12). Overall, viremia prevalence is difficult to estimate in COVID-19. Early assays my not have ideal sensitivity. It is possible that only severe COVID-19 cases with hemodynamic instability experience SARS-CoV-2 viremia. Early viremia could dissipate, giving rise to the “cytokine storm” before the initial serum SARS-CoV-2 viral load measurement. Also, viremia could be transient due to cyclical SARS-CoV-2 shedding.
The Seraph-100 is unique from other extracorporeal therapies in that it can directly binds SARS-CoV-2 and other pathogens to heparin moieties on a nonporous media which mimics the natural heparin sulfate brush boarder on endothelial cells (16). In addition, the Seraph-100 has the capability to bind potential secondary pathogens while not binding common antibiotic, antifungal, or antiviral medications which may be required (17). These effects may account for the observed rapid discontinuation of vasopressor support in these patients subsequent to institution of Seraph-100, potentially faster than observed after other extracorporeal therapies for sepsis (18). In addition, we experienced minimal clotting problems using the Seraph-100 in these two patients, despite COVID-19 producing a hypercoagulable state. This may be due to the intrinsic heparin moieties present in the device. Previous reports of other extracorporeal sorbent hemoperfusion devices that nonspecifically target endotoxins and cytokines have reported this as a potential problem (18–20).
As mentioned previously, other extracorporeal devices are available for critically ill patients. For example, CytoSorb (Cytosorbents Inc., Monmouth Junction, NJ), another extracorporeal device with an EUA from the FDA for COVID-19, uses a nonspecific molecular size based adsorptive mechanism with binding to device polymer within porous beads by nonpolar interactions, hydrogen bonding, and van der Waals forces. It has not been shown to directly bind SARS-CoV-2 or other pathogens (21). Additional extracorporeal strategies have been attempted to treat sepsis not associated with SARS-CoV-2 such as plasmapheresis, high-volume hemofiltration (HVHF), high cutoff (HCO) membranes, and coupled plasma filtration and adsorption (CPFA) (18,19,22,23). All of these therapies effectively remove middle molecular weight molecules such as cytokines. Compared to the Seraph-100, each has limitations in addition to not directly binding pathogens such as SARS-CoV-2. Plasmapheresis clears albumin, coagulation factors, and immunoglobulins. While these can theoretically be replaced, even transient reduction in intravascular oncotic pressure or immunosuppression can be deleterious in sepsis. While neither HCO nor HVHF filter large molecular weight immunoglobulins (> 150 kD), they do remove albumin. They also provide overall convective clearance which would otherwise not be needed in patients without acute kidney injury requiring renal replacement therapy. Significant convective clearance in patients with relatively preserved renal function could cause adverse events to include hypophosphatemia which could result in diaphragm paralysis or rhabdomyolysis. The effects of CPFA are variable and depend on contents of the sorbent cartridge, the hemofilter permeability, and if HVHF is used. No large prospective studies have demonstrated a mortality benefit for any of these treatments despite cytokine removal. This is potentially due to not directly removing the culprit pathogen or the above discussed potential adverse effects of the treatments. The Seraph-100 provides no convective clearance and does not remove albumin, coagulation factors, or immunoglobulins which potentially reduces the possibility of adverse events.
Although the Seraph-100 is unlikely to cure COVID-19, it is possible that it could reduce the viral burden and blunt the cytokine storm to provide additional time and a more favorable environment for the innate immune system to clear the SARS-CoV-2 virus and establish lasting immunity or “immune hemostasis.” The intermediate outcomes in these cases are promising. They support the need for the prospective study of a larger cohort with longer clinical follow-up to evaluate the relationship between Seraph-100 treatments and hard outcomes such as mortality, number of days intubated, number of days in the ICU, and number of days in the hospital.
The authors like to thank ExThera Medical Corporation for providing the Seraph-100 filters under the emergency use extended access pathway and overseeing in vitro testing. They also would like to highlight the invaluable contributions from the dialysis nurses that treated the patients with the Seraph-100 to include Christine Fifarek, Ethan Cole, Sukwon Koh, Kevin Sukkum, Jean Duplex Nkweni, Christian Pimentel, Anna Choi, Barbara Cooper, and Luz Munoz. Donna Rodrick, in addition to treating patients, helped conceive, design, and draft the standard operating procedures, and train other nurses. Nurses remain the backbone of patient care.
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