Keywords
SARS-CoV-2 - extracorporeal treatment - circuit failure - D-dimer
Introduction
About 102 years after the Spanish flu that took approximately 50 million lives, the
novel coronavirus (2019-nCoV), also known as severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2), leads to coronavirus disease 2019 (COVID-19) and is considered unprecedented
in its effect on global health and economy. Notwithstanding drastic measures to contain
the virus, its spread continues and the death toll rises. Even though an enormous
progress in clinical medicine has been made over the last century, we have currently
no efficient therapy in our toolbelt to treat COVID-19 except for dexamethasone.[1] Given the urgency of a public-health emergency, which has been declared a pandemic
by the World Health Organization, many therapeutic options above and beyond drug therapy
are currently explored. So far the extracorporeal strategies that have been discussed
and used in COVID-19 are mainly aimed to reduce the cytokine storm.[2] The Seraph 100 Microbind Affinity filter has recently been introduced for the elimination
of bacteria[3] and other pathogens from the blood.[4] Authorization for emergency use in patients with COVID-19 admitted to the intensive
care unit (ICU) with confirmed or imminent respiratory failure was granted by the
U.S. Food and Drug Administration on April 17, 2020. The rationale for the approval
was the fact that viral RNAemia is frequently (up to 78%) seen in critically ill patients
where it is related to the severity of the disease.[5] Moreover, the monomeric and trimeric SARS-CoV-2 spike glycoprotein binds tightly
to immobilized heparin,[6] the functional backbone of the Seraph 100.
Here, we describe the successful treatment of a critically ill COVID-19 patient with
the Seraph 100 Microbind affinity filter. The markedly elevated lactate dehydrogenase
(LDH), N-Terminal propeptide of brain natriuretic peptide (NT-proBNP), and D-dimer
fell during the treatment. In total, 3 days after treatment with Seraph 100, the patient
could be extubated and left the ICU after just 9 days of treatment.
Case Report
In early April 2020, a 53-year-old Caucasian firefighter presented to the emergency
department of our tertiary care hospital with fever (temperature 40.5°C). Main symptoms
were nausea, vomiting, and diarrhea accompanied by dry cough, headache, and muscle
pain for 7 days. Shortness of breath was denied. He had returned from skiing in Brixen,
Southern Tyrol, Italy 7 days prior to hospital admission. Five people in his skiing
group had been tested positive for SARS CoV-2. Besides a reflux esophagitis years
ago, the patient has no significant medical history.
The general condition of the febrile male was significantly reduced. The pulmonary
examination remained unremarkable. Vital signs showed a blood pressure of 129/84 mmHg,
a heart rate of 75 bpm and a temperature of 40.5°C. Peripheral oxygen saturation under
room air was 98%. Respiratory rate was 16/minute. The capillary blood gas analysis
showed a respiratory alkalosis due to hyperventilation (pH 7.599, pCO2 21.1 mmHg, pO2 71.2 mmHg, base excess (BE) 0.8 mmol/L). Laboratory evaluation on admission is summarized
in [Table 1]. A decreased transparency in left lower lung field was seen in the chest X-ray.
Table 1
Course of Vital signs and laboratory data
|
Vital signs
|
Admission to the hospital
|
Transfer to the ICU
|
Intubation
|
Start of Seraph 100
|
After Seraph 100
|
2 days after Seraph 100
|
|
|
Blood pressure (mmHg)
|
129/94
|
165/73
|
140/60
|
122/70
|
112/70
|
|
|
|
Heart rate (bpm)
|
75
|
67
|
80
|
62
|
62
|
|
|
|
Body temperature (°C)
|
40.5
|
38.7
|
38.0
|
37.7
|
38.5
|
|
|
|
Respiratory rate (/minute)
|
15
|
20
|
30
|
BiPAP
|
BiPAP
|
cPAP/BiPAP
|
|
|
O2 saturation (%)
|
98
|
88
|
98
|
94
|
94
|
|
|
|
FiO2 (%)
|
|
|
|
35
|
35
|
21
|
|
|
Laboratory data
|
|
|
|
|
|
|
Normal range
|
|
Hemoglobin (g/dL)
|
16.1
|
12.7
|
12.0
|
|
11.8
|
11.9
|
13.7–17.5
|
|
Leukocytes (Tds/µL)
|
4.82
|
5.48
|
6.16
|
|
8.01
|
7.97
|
4.24–9.07
|
|
Lymphocytes (Tds/µL)
|
1.54
|
0.53
|
0.89
|
|
1.85
|
1.80
|
1.32–3.57
|
|
CRP (mg/L)
|
47.5
|
234
|
256
|
|
243
|
172
|
<5
|
|
LDH (U/L)
|
380
|
745
|
|
|
505
|
467
|
135–225
|
|
D-dimer (mg/L)
|
Not done
|
3.39
|
|
15.8
|
2.34
|
1.63
|
<0.5
|
|
NT-Pro BNP (pg/mL)
|
Not done
|
306
|
|
517
|
189
|
48
|
<125
|
Abbreviations: BiPAP, bilevel positive airway pressure; cPAP, continuous positive
airway pressure; CRP, C-reactive protein; LDH, lactate dehydrogenase; NT-Pro BNP,
N-terminal propeptide of brain natriuretic peptide.
Based on the travel history, the throat swab, and the chest X-ray, the diagnosis of
a viral pneumonia with COVID-19 was made. The patient was isolated on the pulmonary
ward. He initially received symptomatic treatment with IV fluids, antiemetic (granisetron
IV) and antipyretic (metamizole IV) therapy. About 3 days after admission, the patient
developed lymphopenia (0.96 × 103/µL), and the CRP increased to 191.1 mg/L. At this point, azithromycine and supplemental
oxygen via nasal cannulas were started. Due to respiratory deterioration, the patient
was transferred to the ICU and hydroxychloroquin was started with 200 mg b.i.d. on
the 5th day after admission. Respiratory exhaustion with increasing respiratory rate
and beginning of desaturation occurred 24 hours after admission to the ICU requiring
intubation. At the beginning of the COVID pandemic, invasive ventilation was preferred
over noninvasive ventilation as the fear of virus-containing aerosols prevailed over
the assumed benefit of noninvasive ventilation. An echocardiography did not show signs
of pulmonary embolism or right heart failure. Due to the lack of a specific pharmacological
therapy, an extracorporeal treatment using the Seraph 100 Microbind Affinity Blood
Filter was established as a rescue therapy. The rationale for this approach was the
fact that viral RNAemia was already seen reported in severly ill COVID-19 patients,
which according to recent data account for up to 78% of all patients in the intensive
care unit.[5] The decrease of viral RNA or viremia by the Seraph 100 seemed not far fetched as
the coronaviruses, and especially SARS-CoV-2 with its spike glycoprotein has been
shown to bind exquisitely well to immobilized heparin,[6] the functional backbone of the Seraph 100.
We informed the patient about the possibility of treatment with Seraph 100, and he
consented to this treatment prior to his intubation. It is a single use extracorporeal
broad-spectrum sorbent hemoperfusion device for the reduction of pathogens from the
bloodstream.[4] Vascular access was obtained via double lumen catheter in the right femoral vein.
The Seraph 100 was used as hemoperfusion, that is, there was no concomitant renal
replacement therapy. Using an Octo-Nova (DIAMED Medizintechnik GmbH, Cologne, Germany),
a blood flow of 200 mL/minute was established. After a bolus of 2,500 IE unfractionated
heparin, the continuous anticoagulation consisted of 2,000 IE unfractionated heparin
per hour. Treatment was well tolerated and the mean arterial pressure with inotropic
support (noradrenalin 0.06 µg/kg/min or 3.33 µg/kg/h) was maintained between 122/70
and 112/70 mmHg. Oxygen saturation during the treatment was 94%, while the respirator
settings remained unchanged in bilevel positive airway pressure (BiPAP) mode with
an FiO2 of 35% and a positive end-expiratory pressure of 7 mbar and inspiratory pressure
of 24 mbar, respiratory rate of 15/min.
After initiation of the therapy patient who was under propofol sedation, became more
agitated, so that the dose was increased from 120 to 200 mg/h within the first 30 minutes
of therapy. Additional sedation was changed to midazolam. After 70 minutes of treatment,
venous return pressure of the hemoperfusion device increased and the filter clotted
before the blood could be given back to the patient. The inotropic support could be
stopped at this time. There were no acute changes in ventilation parameters or oxygenation.
After the hemoperfusion with Seraph 100, the patients previously rapidly deteriorating
clinical status stabilized so that no further intensification of ICU care was necessary.
Over the next 3 days, he was weaned off the ventilator. The elevated LDH, NT-proBNP,
and D-dimer levels fell. About 3 days later, the patient could be extubated and left
the ICU after a total stay of 9 days.
Discussion
Apheresis can be considered in a variety of clinical circumstances including viral
infections and the overwhelming response to them.[7] To our knowledge, this is the first case of hemoperfusion with the Seraph 100 Microbind
Affinity in a critically ill patient COVID- 19 in Europe. A report from two patients
in the United States had been published.[8] What is the rationale to use such a device patient with severe pulmonary SARS-CoV-2
infection?
The Seraph 100 filter has been licensed in the European Union in 2019 for the removal
of pathogens from the blood. The functional basis of the device are ultra-high molecular
weight polyethylene beads with end point-attached heparin. Bacteria, viruses, fungi,
and toxins have been shown to bind to the immobilized heparin in a similar way to
the interaction with heparan sulfate on the cell surface.[4] Due to this biomimetic action, pathogens binds irreversibly to the heparin on the
polyethylene beads and are thereby removed from the bloodstream.
Heparin binding is a frequent feature in viruses as this ability is important to bind
heparan sulfate proteoglycans on the surface of host cells – a precondition to enter
the cells through internalization. For SARS-CoV-2, it has been shown that it not only
binds to heparin but also that ACE2-mediated coronavirus entry can be mitigated by
heparin, a heparan sulfate-related glycan, or by genetic ablation of biosynthetic
enzymes for the cell surface heparan sulfate proteoglycans.[9]
Although viremia is demonstrated in a small percentage of patients, 8% in one case
series,[10] detectable SARS-CoV-2 viral RNA in the blood has been shown to be a strong indicator
for the clinical course.[11] Indeed SARS-CoV-2 RNA in serum at hospital admission indicates a high risk of progression
to critical disease and death.[12] Moreover, patients with severe COVID-19 tend to have a high-viral load and a long
virus-shedding period.[13] Platelets can be hyperactivated in association with SARS-CoV-2 RNA and thus presumably
contribute to trigger the hypercoagulation and thrombosis,[14] which is however a multifaceted process that involves several pathways.[15]
We suggest that D-dimers could be a surrogate parameter of ongoing and aggravating
thromboembolism. We made the observation that D-dimers levels increase simultaneously
at clinically deterioration and decrease with improvement. But further investigation
is needed to clarify this assumption. Another mechanism that might be beneficial is
the reduction of proinflammatory cytokines that had been shown for the Seraph 100
in vitro,[16] highlighting further potential therapeutic benefit.
Of note, there were two clinical findings during the Seraph 100 treatment. The first
one was the agitation of the patient potentially aggravated through the removal of
the sedating agents. Indeed, so far the effect of the S Seraph 100 Microbind Affinity
treatment had only been investigated for anti-infective agents[17] as well as for chloroquine and hydroxychloroquine.[18] An effect on hypnotics and sedatives has not been evaluated.
The second clinical finding of interest was the rapid circuit failure due to clotting
of the Seraph 100 that is packed with immobilized heparin. We know that COVID-19 patients
exhibit a deranged coagulation function that might explain this finding.[19] One report from the United States in which the use of the Seraph 100 Microbind affinity
filter was also reported clotting (of the vascular access) that resulted in the premature
end of the treatment after 3.5 hours.[8] In contrast to this publication, we did not see a drop on body temperature.
D-dimer level has been repeatedly shown to be associated with poor outcome in COVID-19
patients.[20] As the normal half-life of D-dimers is approximately 5 hours; hence, the dramatic
reduction in D-dimer levels during the Seraph treatment has to be attributed to their
removal that might have caused the filter clotting. We can only speculate about the
effect of the immobilized heparin on the coagulation problems in our patient. Interestingly,
a recent study suggested that anticoagulant therapy seems to be associated with an
improved outcome in severe COVID-19 patients.[21] The reduction of NT-ProBNP by approximately 64% can be in part attributed to the
normal decay of this marker with a half-life of 120 minutes.[22] The potential effect of the Seraph 100 on NT-ProBNP could not be established as
pre- and post-Seraph 100 blood samples drawn at the same to calculate the actual device
clearance had not been obtained. As the clinical effectiveness of the Seraph 100 Microbind
affinity filter in critically ill patients cannot be evaluated based on anecdotal
reports, an online registry has been recently established (Registry for the Evaluation
of Safety and Effectiveness of the Seraph 100 Microbind Affinity Blood Filter in the
Therapy of COVID-19 Patients (COSA) ClinicalTrials.gov Identifier: NCT04361500). We
noticed in subsequent treatments with Seraph 100 Microbind Affinity Filter a significant
decrease in D-dimers without clotting of the circuit. It can be speculated that the
use of propofol contributed to the clotting of the circuit. Taking midazolam for sedation
and without increasing the amount of heparin, we did not see any clotting of the Seraph
100.
The intention of this case report is to show that hemoperfusion with the Seraph 100
in patients with COVID-19 is feasible, and the device is easy to handle by using standard
dialysis equipment and requires no laborious preparation other than rinsing with normal
saline. We would like to encourage other centers to participate in the online register
COSA to obtain reliable data on effectiveness of Seraph 100 in critically ill COVID-19
patients with the goal to gain more evidence on its use in this disease. In future,
randomized controlled trials with Seraph 100 will have to provide the scientific basis
for the evaluation of its effect on hard clinical endpoints in COVID-19 patients.
