Clinical improvement of Long-COVID is associated with reduction in autoantibodies, lipids, and inflammation following therapeutic apheresis.

In the aftermath of the COVID-19 pandemic, we are witnessing an unprecedented wave of post-infectious complications. Most prominently, millions of patients with Long-Covid complain about chronic fatigue and severe post-exertional malaise. Therapeutic apheresis has been suggested as an efficient treatment option for alleviating and mitigating symptoms in this desperate group of patients. However, little is known about the mechanisms and biomarkers correlating with treatment outcomes. Here, we have analyzed in different cohorts of Long-Covid patients specific biomarkers before and after therapeutic apheresis. In patients that reported a significant improvement following two cycles of therapeutic apheresis, there was a significant reduction in neurotransmitter autoantibodies, lipids, and inflammatory markers. Furthermore, we observed a 70% reduction in fibrinogen, and following apheresis, erythrocyte rouleaux formation and fibrin fibers largely disappeared as demonstrated by dark field microscopy. This is the first study demonstrating a pattern of specific biomarkers with clinical symptoms in this patient group. It may therefore form the basis for a more objective monitoring and a clinical score for the treatment of Long-Covid and other postinfectious syndromes.

Post COVID and Apheresis - Where are we Standing?

A continual increase in cases of Long/Post COVID constitutes a medical and socioeconomic challenge to health systems around the globe. While the true extent of this problem cannot yet be fully evaluated, recent data suggest that up to 20% of people with confirmed SARS-CoV-2 suffer from clinically relevant symptoms of Long/Post COVID several weeks to months after the acute phase. The clinical presentation is highly variable with the main symptoms being chronic fatigue, dyspnea, and cognitive symptoms. Extracorporeal apheresis has been suggested to alleviate symptoms of Post/COVID. Thus, numerous patients are currently treated with apheresis. However, at present there is no data from randomized controlled trials available to confirm the efficacy. Therefore, physicians rely on the experience of practitioners and centers performing this treatment. Here, we summarize clinical experience on extracorporeal apheresis in patients with Post/COVID from centers across Germany.

Efficacy and Safety of Topical Hypericin Photodynamic Therapy for Early-Stage Cutaneous T-Cell Lymphoma (Mycosis Fungoides): The FLASH Phase 3 Randomized Clinical Trial.

Importance: Given that mycosis fungoides-cutaneous T-cell lymphoma (MF/CTCL) is chronic, there is a need for additional therapies with minimal short- and long-term adverse effects. Topical synthetic hypericin ointment, 0.25%, activated with visible light is a novel, nonmutagenic photodynamic therapy (PDT). Objectives: To determine the efficacy and safety of topical synthetic hypericin ointment, 0.25%, activated with visible light as a nonmutagenic PDT in early-stage MF/CTCL. Design, Settings, and Participants: This was a multicenter, placebo-controlled, double-blinded, phase 3 randomized clinical trial (FLASH study) conducted from December 2015 to November 2020 at 39 academic and community-based US medical centers. Participants were adults (≥18 years) with early-stage (IA-IIA) MF/CTCL. Interventions: In cycle 1, patients were randomized 2:1 to receive hypericin or placebo to 3 index lesions twice weekly for 6 weeks. In cycle 2, all patients received the active drug for 6 weeks to index lesions. In cycle 3 (optional), both index and additional lesions received active drug for 6 weeks. Main Outcomes and Measures: The primary end point was index lesion response rate (ILRR), defined as 50% or greater improvement in modified Composite Assessment of Index Lesion Severity (mCAILS) score from baseline after 6 weeks of therapy for cycle 1. For cycles 2 and 3, open label response rates were secondary end points. Adverse events (AEs) were assessed at each treatment visit, after each cycle, and then monthly for 6 months. Data analyses were performed on December 21, 2020. Results: The study population comprised 169 patients (mean [SD] age, 58.4 [16.0] years; 96 [57.8%] men; 120 [72.3%] White individuals) with early-stage MF/CTCL. After 6 weeks of treatment, hypericin PDT was more effective than placebo (cycle 1 ILRR, 16% vs 4%; P = .04). The ILRR increased to 40% in patients who received 2 cycles of hypericin PDT (P < .001 vs cycle 1 hypericin) and to 49% after 3 cycles (P < .001 vs cycle 1 hypericin). Significant clinical responses were observed in both patch and plaque type lesions and were similar regardless of age, sex, race, stage IA vs IB, time since diagnosis, and number of prior therapies. The most common treatment-related AEs were mild local skin (13.5%-17.3% across cycles 1-3 vs 10.5% for placebo in cycle 1) and application-site reactions (3.2%-6.9% across cycles 1-3 vs 4% for placebo in cycle 1). No drug-related serious AEs occurred. Conclusion and Relevance: The findings of this randomized clinical trial indicate that synthetic hypericin PDT is effective in early-stage patch and plaque MF/CTCL and has a favorable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT02448381.

Chronic post-COVID-19 syndrome and chronic fatigue syndrome: Is there a role for extracorporeal apheresis?

As millions of patients have been infected by SARS-CoV-2 virus a vast number of individuals complain about continuing breathlessness and fatigue even months after the onset of the disease. This overwhelming phenomenon has not been well defined and has been called "post-COVID syndrome" or "long-COVID" [1]. There are striking similarities to myalgic encephalomyelitis also called chronic fatigue syndrome linked to a viral and autoimmune pathogenesis. In both disorders neurotransmitter receptor antibodies against ß-adrenergic and muscarinic receptors may play a key role. We found similar elevation of these autoantibodies in both patient groups. Extracorporeal apheresis using a special filter seems to be effective in reducing these antibodies in a significant way clearly improving the debilitating symptoms of patients with chronic fatigue syndrome. Therefore, such a form of neuropheresis may provide a promising therapeutic option for patients with post-COVID-19 syndrome. This method will also be effective when other hitherto unknown antibodies and inflammatory mediators are involved.

Extracorporeal apheresis therapy for Alzheimer disease-targeting lipids, stress, and inflammation.

Current therapeutic approaches to Alzheimer disease (AD) remain disappointing and, hence, there is an urgent need for effective treatments. Here, we provide a perspective review on the emerging role of "metabolic inflammation" and stress as a key factor in the pathogenesis of AD and propose a novel rationale for correction of metabolic inflammation, increase resilience and potentially slow-down or halt the progression of the neurodegenerative process. Based on recent evidence and observations of an early pilot trial, we posit a potential use of extracorporeal apheresis in the prevention and treatment of AD. Apolipoprotein E, lipoprotein(a), oxidized LDL (low density lipoprotein)'s and large LDL particles, as well as other proinflammatory lipids and stress hormones such as cortisol, have been recognized as key factors in amyloid plaque formation and aggravation of AD. Extracorporeal lipoprotein apheresis systems employ well-established, powerful methods to provide an acute, reliable 60-80% reduction in the circulating concentration of these lipid classes and reduce acute cortisol levels. Following a double-membrane extracorporeal apheresis in patients with AD, there was a significant reduction of proinflammatory lipids, circulating cytokines, immune complexes, proinflammatory metals and toxic chaperones in patients with AD. On the basis of the above, we suggest designing clinical trials to assess the promising potential of such "cerebropheresis" treatment in patients with AD and, possibly, other neurodegenerative diseases.

Metabolic and Non-Metabolic Peripheral Neuropathy: Is there a Place for Therapeutic Apheresis?

As the rate of obesity and the incidence of diabetes mellitus have been increasing, diabetic neuropathy has become the most common cause of peripheral neuropathy in developed countries. In addition, a variety of pathogenetically heterogeneous disorders can lead to impairment of the peripheral nervous system including amyloidosis, vitamin deficiencies, uremia and lipid disorders, alcohol abuse, autoimmune and infectious diseases as well as exposure to environmental toxins. We have noted that a combination of these disorders may aggravate the manifestations of peripheral diabetic neuropathy, an effect, which is most pronounced when metabolic and non-metabolic pathologies lead to cumulative damage. Current treatment options are limited and generally have unsatisfactory results in most patients. Therapeutic apheresis (INUSpherese®) allows the removal of metabolic, inflammatory, immunologic and environmental contributors to the disease process and may be an effective treatment option. We reviewed the developments in therapeutic apheresis for metabolic and non-metabolic peripheral neuropathy, including the current literature as well as data from our university diabetes center.

Lipid Profiles in Lyme Borreliosis: A Potential Role for Apheresis?

Dyslipidemia and dyslipoproteinemia are common causes of metabolic and cardiovascular diseases. On the other hand, intracellular bacteria, such as Borrelia burgdorferi, utilize host lipids to survive and disseminate within the host. Recent data suggest that elevated lipids are a contributing factor to the maintenance and severity of Lyme disease and its complications. Here we review and discuss the role of lipids in Borreliosis and report on a pilot trial to examine the potential roles of circulating lipids and lipoproteins in patients with Borrelia infection. In this analysis we assessed the clinical and lipid profiles of 519 patients (319 women, 200 men) with a proven history of Lyme disease, before and after an extracorporeal double membrane filtration. Lipid profiles pre- and post-apheresis were analyzed in conjunction with clinical symptoms and parameters of inflammation. Circulating cholesterol, triglycerides, LDL, LP(a), and other inflammatory lipids were significantly reduced after the apheresis, while symptoms of the disorder and bioindexes of inflammation such as CRP improved. Further studies should be initiated to investigate the possibly causal relation between Lyme disease and circulating lipids and to design appropriate therapeutic strategies.

Thermal stability and epitope integrity of a lyophilized ricin toxin subunit vaccine.

Biodefense vaccine are destined to be stockpiled for periods of time and deployed in the event of a public health emergency. In this report, we compared the potency of liquid and lyophilized (thermostabilized) formulations of a candidate ricin toxin subunit vaccine, RiVax, adsorbed to aluminum salts adjuvant, over a 12-month period. The liquid and lyophilized formulations were stored at stressed (40 °C) and unstressed (4 °C) conditions and evaluated at 3, 6 and 12-month time points for potency in a mouse model of lethal dose ricin challenge. At the same time points, the vaccine formulations were interrogated in vitro by competition ELISA for conformational integrity using a panel of three monoclonal antibodies (mAbs), PB10, WECB2, and SyH7, directed against known immunodominant toxin-neutralizing epitopes on RiVax. We found that the liquid vaccine under stress conditions declined precipitously within the first three months, as evidenced by a reduction in in vivo potency and concomitant loss of mAb recognition in vitro. In contrast, the lyophilized RiVax vaccine retained in vivo potency and conformational integrity for up to one year at 4 °C and 40 °C. We discuss the utility of monitoring the integrity of one or more toxin-neutralizing epitopes on RiVax as a possible supplement to animal studies to assess vaccine potency.

Dusquetide: Reduction in oral mucositis associated with enduring ancillary benefits in tumor resolution and decreased mortality in head and neck cancer patients.

Innate immunity is a key component in the pathogenesis of oral mucositis, a universal toxicity of chemoradiation therapy (CRT). Dusquetide, a novel Innate Defense Regulator, has demonstrated both nonclinical and clinical efficacy in ameliorating severe oral mucositis (SOM). Long term follow-up studies from the Phase 2 clinical study evaluating dusquetide as a treatment for SOM in head and neck cancer (HNC) patients receiving CRT have now been completed. Extended analysis indicates that dusquetide therapy was well-tolerated and did not contribute to increased infection, tumor growth or mortality. Potential ancillary benefits of duquetide therapy were also identified.

Dusquetide: A novel innate defense regulator demonstrating a significant and consistent reduction in the duration of oral mucositis in preclinical data and a randomized, placebo-controlled phase 2a clinical study.

Dusquetide, a novel Innate Defense Regulator, modulates the innate immune system at a key convergence point in intracellular signaling pathways and has demonstrated activity in both reducing inflammation and increasing clearance of bacterial infection. Innate immunity has also been implicated in the pathogenesis of oral mucositis (OM), a universal toxicity of chemoradiation therapy (CRT). Testing the hypothesis that dusquetide can mitigate the development and duration of OM, preclinical studies have been completed and correlated with interim results from a Phase 2 clinical study in patients undergoing CRT for head and neck cancer. Dusquetide reduced the duration of OM in mouse and hamster models by approximately 50%, which was recapitulated by the 50% reduction of severe OM (SOM) in the Phase 2 trial. A reduction in the clinical rate of infection was also observed, consistent with previously reported preclinical studies. In aggregate, these results not only demonstrate the safety and efficacy of dusquetide in addressing this unmet medical need, but also provide proof of concept for the translation of dusquetide action between animal models and the human clinical setting, and further support the contention that innate immunity is an important driver for the initiation and continued impact of OM.

A novel approach for emerging and antibiotic resistant infections: Innate defense regulators as an agnostic therapy.

Innate Defense Regulators (IDRs) are short synthetic peptides that target the host innate immune system via an intracellular adaptor protein which functions at key signaling nodes. In this work, further details of the mechanism of action of IDRs have been discovered. The studies reported here show that the lead clinical IDR, SGX94, has broad-spectrum activity against Gram-negative and Gram-positive bacterial infections caused by intracellular or extracellular bacteria and also complements the actions of standard of care antibiotics. Based on in vivo and primary cell culture studies, this activity is shown to result from the primary action of SGX94 on tissue-resident cells and subsequent secondary signaling to activate myeloid-derived cells, resulting in enhanced bacterial clearance and increased survival. Data from non-clinical and clinical studies also show that SGX94 treatment modulates pro-inflammatory and anti-inflammatory cytokine levels, thereby mitigating the deleterious inflammatory consequences of innate immune activation. Since they act through host pathways to provide both broad-spectrum anti-infective capability as well as control of inflammation, IDRs are unlikely to be impacted by resistance mechanisms and offer potential clinical advantages in the fight against emerging and antibiotic resistant bacterial infections.

Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial.

CONTEXT: Inhaled nitric oxide has been shown to improve oxygenation in acute lung injury. OBJECTIVE: To evaluate the clinical efficacy of low-dose (5-ppm) inhaled nitric oxide in patients with acute lung injury. DESIGN AND SETTING: Multicenter, randomized, placebo-controlled study, with blinding of patients, caregivers, data collectors, assessors of outcomes, and data analysts (triple blind), conducted in the intensive care units of 46 hospitals in the United States. Patients were enrolled between March 1996 and September 1999. PATIENTS: Patients (n = 385) with moderately severe acute lung injury, a modification of the American-European Consensus Conference definition of acute respiratory distress syndrome (ARDS) using a ratio of PaO2 to FiO2 of < or =250, were enrolled if the onset was within 72 hours of randomization, sepsis was not the cause of the lung injury, and the patient had no significant nonpulmonary organ system dysfunction at randomization. INTERVENTIONS: Patients were randomly assigned to placebo (nitrogen gas) or inhaled nitric oxide at 5 ppm until 28 days, discontinuation of assisted breathing, or death. MAIN OUTCOME MEASURES: The primary end point was days alive and off assisted breathing. Secondary outcomes included mortality, days alive and meeting oxygenation criteria for extubation, and days patients were alive following a successful unassisted ventilation test. RESULTS: An intent-to-treat analysis revealed that inhaled nitric oxide at 5 ppm did not increase the number of days patients were alive and off assisted breathing (mean [SD], 10.6 [9.8] days in the placebo group and 10.7 [9.7] days in the inhaled nitric oxide group; P =.97; difference, -0.1 day [95% confidence interval, -2.0 to 1.9 days]). This lack of effect on clinical outcomes was seen despite a statistically significant increase in PaO2 that resolved by 48 hours. Mortality was similar between groups (20% placebo vs 23% nitric oxide; P =.54). Days patients were alive following a successful 2-hour unassisted ventilation trial were a mean (SD) of 11.9 (9.9) for placebo and 11.4 (9.8) for nitric oxide patients (P =.54). Days alive and meeting criteria for extubation were also similar: 17.0 placebo vs 16.7 nitric oxide (P =.89). CONCLUSION: Inhaled nitric oxide at a dose of 5 ppm in patients with acute lung injury not due to sepsis and without evidence of nonpulmonary organ system dysfunction results in short-term oxygenation improvements but has no substantial impact on the duration of ventilatory support or mortality.

Differential indication of lipoprotein apheresis during pregnancy.

Lipoprotein apheresis is an effective treatment for severe disorders of lipid metabolism. It is the only life prolonging therapy for patients with homozygous familial hypercholesterolemia. Changes of lipid metabolism during pregnancy related to changes of hormone concentrations do not cause clinical complications in the majority of cases. However, in particular clinical situations there is the need to offer a therapeutic option. Increasing morbidity and mortality of mother and child due to severe disorders of lipid metabolism have to be prevented. In general, lipid lowering drugs are contraindicated during pregnancy. Therefore, lipoprotein apheresis offers an alternative, which could be used in select cases to treat acute or chronic hyperlipoproteinemia associated with pregnancy. This article summarizes experiences with patients, who became pregnant during chronic lipoprotein apheresis, or who were treated by lipoprotein apheresis because of acute disorders of lipid metabolism during pregnancy. In conclusion, after individual risk benefit analysis for mother and child lipoprotein apheresis can be safely performed during pregnancy.

Neurodevelopmental and medical outcomes of persistent pulmonary hypertension in term newborns treated with nitric oxide.

OBJECTIVE: To determine the medical and neurodevelopmental outcome of children with moderately severe persistent pulmonary hypertension of the newborn (PPHN) treated with or without inhaled nitric oxide (I-NO). STUDY DESIGN: Term infants with PPHN and a baseline oxygenation index of 24 +/- 9 at study entry were randomly assigned to early treatment with placebo or initial doses of I-NO (5, 20, and 80 ppm). Outcome was measured at approximately 1 year by frequency of hospitalization, growth, and neurodevelopmental and audiologic evaluation. RESULTS: Of 155 children enrolled, 144 survived, and there was follow-up for 133. No significant differences between the placebo and the I-NO groups were seen in any long-term outcome. Rehospitalization occurred in 22%, and growth did not differ. The composite neurodevelopment and audiologic outcome showed impairment in 46% of the infants. There were major neurologic abnormalities in 13%, cognitive delays in 30%, and hearing loss in 19% of the infants. CONCLUSIONS: Moderately severe PPHN at 24 hours after birth is associated with high rates of rehospitalization and disability at 1 year. Adverse outcomes were the same in I-NO and control groups.