Elisabeth H. Adam and Benedikt Schmid share first authorship.
Kai Zacharowski and Patrick Meybohm share senior authorship.
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Abkürzungen
ARDS
Acute respiratory distress syndrome
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2
ICU
Intensive care unit
IL-6
Interleukin 6
ECMO
Extracorporeal membrane oxygenation
To the editor,
After SARS-CoV-2 first occurred in China in December of 2019, it set out to become a global pandemic. Critically ill patients constitute about 2–9% of all infected patients and progress from pneumonia and hypoxemia to multi-organ dysfunction, for which acute treatment options are scarce [1]. Currently, there is no clinical evidence supporting the efficacy and safety of a drug against any coronavirus in humans, including SARS-CoV-2. Here, we describe the empirical salvage treatment of critically ill COVID-19 patients in two German tertiary care University Hospitals with FX06 (F4 Pharma, Vienna, Austria), a naturally occurring peptide derived from the neo-N-terminus of fibrin (Bβ15-42). FX06 is known for its immunomodulatory properties [2] and was already investigated in clinical trials demonstrating convincing efficacy while being tolerated well with a favorable safety profile [3].
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This observational case series includes six patients during their treatment in the intensive care unit. The respective institutions’ ethics committees approved the post hoc analysis of patient records for scientific purposes. The diagnosis of ARDS was based on the criteria put forth by the Berlin Definition.
Six mechanically ventilated patients suffering from moderate to severe ARDS upon ICU admission were treated with i.v. FX06 (400–600 mg per day; 3–7 days). Five out of these six patients additionally needed ECMO treatment during the course of their illness. Detailed clinical information is given in Table 1.
Table 1
Demographics and clinical characteristics at admission and treatment of patients
Demographics and clinical characteristics at admission and treatment of patients
Y years, BMI body mass index, ARDS acute respiratory distress syndrome, SAPS simplified acute physiology score, LDH lactate dehydrogenase, U units, aPTT activated partial Thromboplastin time, VWF AG von Willebrand factor antigen, SAPS II Simplified Acute Physiology Score, PaO2 partial pressure arterial oxygen, FiO2 fraction of inspired oxygen, vv veno-venous, ECMO extracorporeal membrane oxygenation
Mean oxygenation ratio improved over the first 3 days after the beginning of FX06 application, returned to baseline and increased steadily afterwards from day seven on (Fig. 1a). IL-6 serum concentrations as a marker of inflammation activity were instantly declining from day one (Fig. 1b). Norepinephrine dosages decreased initially after the initiation of FX06 therapy before returning to near-baseline values after some days (data not shown). Renal replacement therapy was necessary in four patients. Overall, four out of six patients survived. Both deceased patients (pats. 2 and 4 in Table 1) died from multi-organ failure due to septic shock most likely from secondary bacterial (co)infection. Hence, we saw no indication that the application of FX06 was in any way related to a patient’s death.
Fig. 1
Oxygenation and IL-6 serum concentrations after FX06 treatment. a The difference in oxygenation compared to baseline (before FX06 treatment). paO2, partial pressure arterial oxygen; FiO2, fraction of inspired oxygen. b The course of interleukin 6 during the treatment with FX06. Data are presented as mean ± standard deviation
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In summary, we observed substantial improvement in lung function following FX06 administration, which may be attributed to its immunomodulatory properties [3] and its function to preserve the endothelial barrier [4]. Patients treated with FX06 displayed a remarkable increase of their oxygenation indices, which we consider to be indicative of the normalization of the pulmonary vascular walls through the aforementioned underlying mechanisms. This was also mirrored in the radiographic diagnostics in five out of all six patients, reflecting a normalization of the interface between the alveolar space and an enhanced tissue integrity. Various coagulation factors, including fibrin degradation products, modulate the inflammatory response by influencing leukocyte migration and cytokine production [5, 6]. The decrease in IL-6 after FX06 is therefore considered to be attributed to these immunomodulatory effects.
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Based on our experience, the salvage use of FX06 in severe COVID-19-associated ARDS could be an effective therapy to improve pulmonary function and vascular leakage in the most severely ill patients. A prospective randomized, controlled study to better elucidate this hypothesis is on preparation.
Acknowledgements
We are extremely thankful for all our staff nurses and support personal enabling us to successfully treat the high number of patients with Sars-Cov-2-induced ARDS.
This work was performed at Frankfurt University Hospital, Department of Anesthesiology and Intensive Care Medicine, Frankfurt, Germany, and Wuerzburg University Hospital, Department of Anesthesiology, Wuerzburg, Germany.
Ethics approval and consent to participate
The study was approved by the local ethics committee (University Hospital Frankfurt, Frankfurt, Germany) (#20-643).
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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