Case Report

Long Covid Patients Successfully Treated by Means of Heparin-Mediated Extracorporeal LDL Precipitation (H.E.L.P.) Apheresis

Beate Roxane Jaeger1*, Hayley Emma Arron1,2, Renata Madre Booyens1, Christiane Kappert3,Josef van Helden3, Maud Weimer1, Oliver Weingärtner4, Rainer Seibel5, Franz Reichl6, Asad Khan7,8, Dietrich Seidel9

1Lipidzentrum Nordrhein, Mülheim an der Ruhr, Germany

2Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa

3Dr. Stein and Kollegen Medical Care Centre, Germany

4Klinik Fur Innere Medizin I, Universitätsklinikum Jena, Jena, Germany

5Diagnosticum, Mülheim, Germany

6Ludwig-Maximilians-Universität, Germany

7Directorate of Respiratory Medicine, Northwest Lung Centre, Manchester University Hospitals NHS Trust, Wythenshawe Hospital, Manchester, United Kingdom

8School of Medicine, Faculty of Medicine, Biology and Health, The University of Manchester, Oxford Road, Manchester, United Kingdom

9Institut für Klinische Chemie und Laboratoriumsmedizin, Ludwig-Maximilians-Universität München, Munich, Germany

*Corresponding author: Beate Roxane Jaeger, Lipidzentrum Nordrhein, Mülheim an der Ruhr, Germany

Received Date: 9 May 2023

Accepted Date: 22 May 2023

Published Date: 26 May 2023

Citation: Jaeger BR, Arron HE, Booyens RM, Kappert C, van Helden J, Weimer M, et al. (2023) Case Report: Long Covid Patients Successfully Treated by Means of Heparin-Mediated Extracorporeal LDL Precipitation (H.E.L.P.) Apheresis. Infect Dis Diag Treat 7: 216. https://doi.org/10.29011/2577-1515.100216

Abstract

Many COVID-19 infected patients develop a chronic state of disease that hinders them for months or even years due to severe persisting pulmonary, neurologic, cardiac, and other deficits. This debilitating condition was coined by patients as ‘Long COVID’, for which there is currently no proven effective treatment. It is increasingly apparent that a key mechanism of COVID-19 infection is a systemic endotheliitis and microembolization which affects various organs. Mounting evidence suggests that the plasma of individuals with acute COVID-19 or Long COVID contains fibrin amyloid-like microclots that are comparatively resistant to fibrinolysis. A biologically plausible explanation links the presence of such fibrin amyloid-like microclots to the blockage of capillaries, with the inhibition of oxygen transport to tissues. This may contribute to many of the Long COVID symptoms such as breathlessness, fatigue, cognitive dysfunction, post-exertional symptom exacerbation, and autonomic dysfunction. Thus, an extracorporeal method such as Heparin-mediated Extracorporeal Low-density lipoprotein (LDL) Precipitation (H.E.L.P.) apheresis that eliminates cholesterol, clotting factors, endotoxins, and inflammatory mediators such as cytokines and tumour necrosis factor-α toxins, could also potentially eliminate the SARS-CoV-2 spike protein and fibrin amyloid-like microclots present in Long COVID and consequently restore vascular homeostasis in persisting COVID-19 infection. We randomly assigned 17 Long COVID patients to receive repeated H.E.L.P. apheresis treatments in short intervals (1-7 sessions) until they recovered from major clinical symptoms. Of these 17 treated patients, 16 patients felt immediate improvement and 12 patients nearly reached full recovery after completion of the treatment. A 6–10-month follow-up revealed that 15 patients maintained their improvements. Thus, of the 17 patients with severe Long COVID symptoms, 16 patients had experienced a great benefit. One patient did not improve, although his oxygen saturation ameliorated. Therefore, H.E.L.P. apheresis serves as a promising and safe treatment option for Long COVID patients. These improvements in symptoms highlight the benefits of H.E.L.P. apheresis as an effective treatment for Long COVID and stresses the urgent need for larger controlled-studies-into-this-treatment.

Keywords: Case report; H.E.L.P apheresis; PASC; COVID-19; Long COVID; Rheology; Heparin; Fibrinogen

List of Abbreviations

ACE-2: angiotensin converting enzyme-2; ATP: adenosine triphosphate; CRP: C-reactive protein; CT: computerized tomography; H.E.L.P.: Heparin-mediated Extracorporeal Lowdensity lipoprotein (LDL) Precipitation; IL: interleukin; LDL: low-density lipoprotein; Lp(a): lipoprotein(a); ME/CFS: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; NO: nitric oxide; PASC: post-acute sequelae SARS-COV-2 infection; PEM: postexertional malaise; PFIB: plasma fibrinogen; SARS CoV-2: severe acute respiratory syndrome coronavirus 2; VEGF: vascular endothelial growth factor; VLDL: very-low-density lipoprotein; VWF: von Willebrand Factor; WHO: World Health Organization; MRI: magnetic resonance imaging

Introduction

The severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) can cause a severe acute multi-organ illness which subsequently leads to the chronic debilitating illness postacute sequelae SARS-COV-2 infection (PASC); more commonly referred to as “Long COVID” (hereafter termed Long COVID). The acute illness does not have the clinical, radiological, or pathological features of a classic infectious pneumonia.

Endothelial cells and platelets are both activated by SARS CoV-2 through angiotensin converting enzyme-2 (ACE-2) [1,2].

This disrupts clotting physiology, characterised by increased levels of von Willebrand Factor (VWF), platelet hyperactivation, activation of the intrinsic clotting pathway, and impaired fibrinolysis [3]. Subsequently, this leads to a state of persistent hypercoagulation characterised by widespread microthrombi and fibrinoid deposits, which are resistant to fibrinolysis [4]. The early characterization of acute COVID-19 by assessing platelet dysfunction and the presence of circulating fibrin amyloid-like microclots using fluorescence microscopy has been proposed as a rational framework for diagnosis [3].

Long COVID is a clinical syndrome most characterised by disabling fatigue, cognitive dysfunction, and post-exertional malaise (PEM) [5]. Nearly half of patients (hospitalised or otherwise) report persistent symptoms after one year post their initial acute COVID-19 infection [6]. The precise cause of Long COVID is unknown; however, endotheliitis has been demonstrated and there are multiple reports of late thrombotic events [7-9]. Furthermore, there is evidence of persistent circulating fibrin amyloid-like microclots in plasma which could adversely affect organ function [10-13]. These fibrin amyloid-like microclots trap alpha-2-antiplasmin, fibrinogen, and amyloids, and are particularly resistant to fibrinolysis [10,12].

Long COVID is a debilitating condition with currently no proven effective treatment. In this case series, H.E.L.P. apheresis was used to treat patients with Long COVID. Developed in 1984 by Seidel and Wieland, H.E.L.P. apheresis was used primarily for patients with severe hyperlipidaemia or familial homozygous hypercholesterolemia, and has been in clinical use for 38 years [14]. Furthermore, it is used for improved blood flow in coronary heart disease, heart transplantation, aortocoronary bypass surgery, preeclampsia, cerebrovascular disease, and unstable angina pectoris [15]. In pilot studies by Bengsch et al., [16] H.E.L.P. apheresis has been tested in septic multi-organ failure and in haemolytic uremic syndrome [16].

It has been proposed that H.E.L.P. apheresis could benefit acute and Long COVID patients [17] owing to its anti-inflammatory effects, including the removal of cytokines such as interleukin (IL)-6, IL-8, and TNF-α. It also reduces C-reactive protein (CRP) concentrations by more than 50% [16]. Furthermore, H.E.L.P. apheresis, exhibits anticoagulant properties reducing the procoagulation and fibrinolytic cascades by 35% to 50% [18], while antithrombin III is only reduced by 25% [18]. Fibrinogen is a main determinant in microcirculation, plasma viscosity, and erythrocyte aggregability [19]. Hence, decreased fibrinogen concentrations will relieve the rheology of the pulmonary circulation without a reduction in erythrocyte concentration [17]. It will also facilitate oxygen exchange and significantly reduce the plasma viscosity and erythrocyte aggregability by 19% and 60%, respectively [20]. Additionally, H.E.L.P. apheresis has been found to remove circulating fibrinolysis-resistant microclots [18,19]. Vascular endothelial growth factor (VEGF) and nitric oxide (NO) are also favourably influenced by H.E.L.P. apheresis [20], and an improvement in cerebral blood flow in cardiac patients has been observed, with a 63% increase in the CO2 reserve capacity [21]. Additionally, H.E.L.P. apheresis lowers low-density lipoprotein (LDL) cholesterol and lipoprotein(a) [Lp(a)] concentrations [22,23], improving endothelial function [24,21,20]. Hence, H.E.L.P. apheresis has the potential to de-escalate the coagulation cascade while minimizing risks of bleeding [17].

Furthermore, heparin used in the H.E.L.P. apheresis system can bind and remove COVID-19 particles as well as bind the SARS-CoV-2 S1 spike protein [25]. Lastly, the heparin adsorber eliminates endo- and exotoxins, regardless of their bacterial or viral origin [26,16]. Since the SARS-CoV-2 virus is able produce neurotoxic “conotoxins” by acting as a bacteriophage on the gut and lung microbiome of infected patients [27], this property of H.E.L.P. apheresis would prove beneficial in this patient group. In essence, these vascular, anti-inflammatory, and anticoagulant effects could be helpful in COVID-19 disease and Long COVID [17]. In this article, where “apheresis” is mentioned, it can be assumed that it is H.E.L.P apheresis, except if explicitly stated otherwise.

Methods

In this pilot study, we have observed 17 patients (Age 2363, median 40 years; 10 males, 7 females). The group was a combination of self-referred individuals and those referred by their physicians. The history of acute COVID-19 infection was either confirmed by the presence of a positive PCR or antibody test in the patient’s medical history or diagnosed as a case of probable COVID-19 infection based on symptom presentation at the time of acute illness using World Health Organization (WHO) recommendations. All patients had either received a formal diagnosis of Long COVID from their primary care practitioner or from a clinician experienced in the condition (Dr. BR Jaeger) at the H.E.L.P. apheresis centre. Participants were pre-screened with a detailed intake form prior to the study, which was also used to acquire baseline characteristics. Additionally, the participants signed an informed consent form before the H.E.L.P apheresis treatments. All participants had been in full-time employment and had normal exercise function prior to COVID-19. Any patient comorbidities are illustrated in Figure 1 below. After acute COVID-19, they developed severe symptoms of Long COVID (symptom duration 2-12 months, median 3 months).


Figure 1: Comorbidities within the participant group. Seven different comorbidities were reported within the study group. These comorbidities were experienced prior to the COVID-19 infection. Among the 17 patients; 21 comorbidity instances were reported. Each instance is represented by one of the seven comorbidities. These comorbidities likely could have affected the intensity and severity of symptoms experienced.

The patients were treated with an average of four H.E.L.P. apheresis treatments, (minimum 1; maximum 7) an average of seven days between each treatment. During H.E.L.P. apheresis, blood cells are separated from plasma in an extracorporeal circuit, 400 000 units of unfractionated heparin are added to the plasma, and the pH is lowered to 5.12 using an acetate buffer. This is the isoelectric point for the optimal precipitation of the apolipoproteins from LDL cholesterol, Lp(a), and very-low-density lipoprotein (VLDL), which are removed in the precipitation filter, together with 60% of fibrinogen. Excess heparin is adsorbed, and bicarbonate dialysis restores the pH balance, eliminating the risk of haemorrhage. The patient’s blood cells are reinfused in parallel with a saline solution. During each treatment, between 2 and 4 litres of blood are treated and depending on the flow rate achieved, lasts between 2 and 4 hours. This process is illustrated in Figure 2.


Figure 2: H.E.L.P. apheresis flow scheme. Blood cells are first separated from plasma in an extracorporeal circuit, 400,000 units of unfractionated heparin are added to the plasma, and the pH is lowered to 5.12 using an acetate buffer. This is the isoelectric point for optimal precipitation of apolipoproteins from LDL cholesterol, Lp(a), and VLDL. Excess heparin is then adsorbed, and bicarbonate dialysis balances the pH to counter any risk of haemorrhage. The blood cells are then reinfused in parallel with a saline solution. This marks the completion of one H.E.L.P. apheresis cycle. The duration of the procedure is usually 1.5 to 3 hours, depending on the flow rate achieved, and between 2.5 and 4 litres of blood are treated per session.

The aim of this retrospective study was to treat patients and to establish whether H.E.L.P. apheresis treatment assists in the symptom relief and treatment of Long COVID patients. This was assessed in the form of a questionnaire before and after the patients underwent treatment, and a follow-up with the patients 6-10 months after the last apheresis treatment.

Furthermore, blood tests were conducted before and after each H.E.L.P apheresis treatment to measure, amongst others, fibrinogen, D-Dimer, and CRP concentrations. Although valuable, our aim was not to compare before and after concentrations related to an individual H.E.L.P apheresis treatment. It has been thoroughly reported that a H.E.L.P apheresis treatment successfully decreases the concentrations of these biomarkers. Instead, we are interested in the maintenance of improvements i.e., can the lowered concentration seen directly after a H.E.L.P apheresis treatment be preserved in Long COVID patients, at least until the next treatment. Furthermore, we aim to evaluate the change in the concentrations of these biomarkers over the course of consecutive H.E.L.P apheresis treatments.  Therefore, we will group blood results in ‘before’ (B) and ‘after’ (A) groups for each patient and each biomarker. The change in biomarker concentration due to the number of H.E.L.P apheresis treatments will be evaluated within each group (before group and after group) in the form of linear regression. We aim to express the results in terms of the slope (m) of the linear regression. In the case of fibrinogen, D-Dimer, and CRP, a negative linear regression (mA/B<0) will indicate an improvement in coagulability due to the number of H.E.L.P apheresis treatments (nH), whereas a positive linear regression (mA/B>0) will indicate an increase in coagulation risk. Additionally, no change is represented by mA/B=0. The number of ‘before’ values available are expressed as nB and the number of ‘after’ values are expressed as nA.

Results

The procedure resulted in the removal of substantial amounts of solid material which could be observed in the filter (Figure 3). 16 of the 17 patients had substantial improvement in all symptoms after the completion of all their H.E.L.P. treatments, including breathlessness, fatigue, and cognition. Although many of the patients had a reduction in their former exercise habits/regimens and working abilities after their acute COVID-19 infection, 12 patients reported complete or near-complete resolution of all symptoms after treatment, with many restored to their pre-infection baseline levels and being able to work full-time again. An extensive description of every patient’s case can be found below. A telephonic review in December 2021 revealed that the benefits were either preserved or continued to increase in 15 patients (follow-up 6-10 months; median 7 months). Only two patients had significant new or continued symptoms.


Figure 3: Solid fibrinogen material in the H.E.L.P apheresis machine filter. After a H.E.L.P apheresis treatment, the filters contain a white/yellow gel-like substance. This is the precipitated and filtered solid fibrinogen, LDL, VLDL, and Lp(a). This filter also removes other molecules not visible to the naked-eye, such as inflammatory mediators, clotting factors, SARS-CoV-2 S1 spike protein, and neurotoxic “conotoxins”.

A summary of patient responses to the H.E.L.P. apheresis treatments can be seen in Figure 4, as well as a detailed description of the symptom alleviation in Figure 5.